Lupus

Tuesday, April 24, 2012

Genetics in lupus and other diseases


This is a very interesting topic, and unfortunately the research on genetics and lupus is in it’s infancy.  There were just 3 new genes found by scientists that increase the risk of developing SLE.  There are obviously some environmental factors that are contributing to the development of lupus, or trigger lupus, in those with the genetic components needed to get the disease.  Another topic that people with lupus have questioned is, is there a link between autoimmune diseases and brain disorders like autism or schizophrenia?  I hope this can help answer some questions.
Genetics in Lupus
 The most common symptoms of lupus are fever, rash, and arthritis. Women tend to develop lupus more commonly than men, and people of African descent develop lupus more commonly than people of European descent.
Lupus is only one of many "auto-immune" diseases. "Auto" means that the body has an immune reaction against itself. Rheumatoid arthritis and scleroderma are also auto-immune diseases.
Given that lupus, rheumatoid arthritis, and scleroderma are all auto-immune disorders, how do physicians tell them apart? The answer is surprisingly old-fashioned. In the case of lupus, physicians compare the patient's symptoms and blood tests to a list of 11 criteria that experts agreed on in 1982. If the patient's data match 4 or more of the criteria, a diagnosis of lupus can be made.
Auto-immunity causes some, but not all, symptoms of lupus. Other symptoms are caused by problems cleaning up the remnants of auto-immune attacks. These remnants are called "immune complexes" and they circulate in the blood, where they can irritate the inside wall of blood vessels.
Thus, lupus is more correctly viewed as arising from problems with control of the immune system. It happens that these control problems show up as auto-immunity.
Can lupus run in families?
Yes. This was first observed in the 1950s. More recent studies show that the brother or sister of a lupus patient is 25 times more likely to develop lupus than someone in the general population.
When lupus runs in families, is the reason genes or environment?
As in most human disease, the answer appears to be "both." Lupus has strong genetic components. It has environmental components as well.
Lupus in twins
Studies of twins provide the clearest insight into the relative importance of genes and environment. For example, in 1992 researchers looked at 107 pairs of twins in which at least one twin had lupus.
Type of twin pair
Number of twin pairs
Twin pairs in which both twins had lupus
("concordance rate")
Identical twins
45
24%
(11 of 45 pairs)
Non-identical twins
62
2%
(1 of 62 pairs)

If lupus were governed only by genes, then every time one identical twin has lupus, the other should have it, too. (Because identical twins have the same genes.) In other words, the "concordance rate" should be 100%. The table shows, however, that there is a 24% concordance between identical twins. This shows that lupus has an environmental component.
If lupus were purely an environmental condition, then genes should make no difference at all. The concordance rate would be the same for identical twins and non-identical twins. The table shows, however, that the concordance rate is more than ten times higher in identical twins (24%) as compared with non-identical twins (2%). This shows that lupus has a genetic component.
What genes are involved in lupus?
In 95% of cases, genetic susceptibility to lupus is not caused by a single gene. Multiple genes are involved. Identifying them has been slow because different genes seem to be at work in different ethnic groups.
HLA Genes
Because lupus is an auto-immune disease, scientists first studied genes that control the immune system. The HLA family of genes, all located on the short arm of chromosome 6 , are important controllers of the immune system. They are divided into 3 classes:
  • HLA class I genes -- These genes have little to do with lupus.
  • HLA class II genes -- Many genes in this group are linked to lupus:
    • The combination of the DR3 and DQ2 variants, or the DR2 and DQ6 variants raise the risk of lupus by a factor of 2 or 3. These genes account for only a small part of the genetic risk for lupus.
    • Many studies of class II genes show no links with lupus. Scientists, therefore, tried dividing lupus into subtypes, according to the results of various blood tests. When they did this, many links between class II genes and lupus subtypes were seen. This suggests that systemic lupus erythematosus is not one disease, but several similar diseases.
  • HLA class III genes -- Many genes in this group are linked to lupus:
    • The C4A and C2 genes are discussed below, in the section on "complement genes."
    • Certain variants of the TNF genes raise the risk of lupus in some ethnic groups.
Complement Genes
Less than 5% of patients with lupus owe their genetic susceptibility to a single gene. Many of these genes relate to the body's "complement system." The complement system is part of the immune system.
  • The C1q genes on chromosome 1 sometimes code for a variant of the C1q complement protein that is less efficient than usual. When this happens, lupus can result, especially in children. The C1q protein has both an "attack" function and a "clean-up" function in the immune system. Scientists believe that lupus can be triggered if the remnants of an immune system attack are not cleaned up efficiently.
  • Deficiencies of other complement proteins also lead to lupus, including deficiencies of the proteins coded by the C4A and C2 genes on chromosome 6 , and the C1r and C1s genes on chromosome 12.
  • The MBL2 gene on chromosome 10 is the blueprint for a protein called mannose binding protein that is similar in shape to C1q. In Spanish and African-American populations, certain variants of this gene are more common in persons with lupus. Combinations of this gene and the C4 gene are more strongly associated with lupus than either gene alone.
Other Genes
  • Three studies have scanned the entire human genome for linkages with lupus. One part of the short arm of chromosome 1 was positive in all 3 studies. Other parts were positive in two of three studies. These results were reassuring, because other studies had identified suspicious genes in precisely these areas of chromosome 1:
    • The FCGR2A gene influences how the body cleans up the results of immune attacks. Certain variants of this gene raise the risk of kidney disease in African-Americans with lupus.
    • The APT1LG1 and ADPRT genes are part of the body's system that controls the lifespan of cells ("apoptosis"). Similar genes in laboratory mice are linked to lupus, but more studies of humans are needed.
  • Regions on chromosomes 2, 6, 14, 16, and 20 also came up positive in at least two of the whole-genome studies mentioned above.
  • Another powerful genetic effect is gender. Ninety percent of all lupus cases are in women.
Actually, the C1q protein is not a single protein coded by a single gene. Nature is often more complicated than it first appears.
Strictly speaking, C1q is the name for a complex of 3 different types of proteins, called A, B, and C. Each of these 3 proteins is made from its own gene on chromosome 1 . Six copies of A, B, and C group together, meaning that C1q is actually a complex of 18 individual proteins! Scientists are not sure whether the A, B, or C gene causes the problem that leads to lupus.

Two heart medications, procainamide and hydralazine, can trigger an illness that is similar to systemic lupus erythematosus, but not identical. This illness is called drug-induced lupus. At least two genes can contribute to susceptibility to drug-induced lupus:
  • The N-acetyl-transferase 2 gene on chromosome 8 influences how the body processes toxins. It plays a role in several human diseases. There are 2 major variants of the gene: "fast" and "slow." People with the "slow" variant are more likely to develop drug-induced lupus.
  • The HLA class II genes on chromosome 6 , are also involved: People with the DR4 variant are more likely to develop drug-induced lupus.
Drug-induced lupus usually goes away when the offending medication is stopped, although it sometimes takes years to resolve completely.
What environmental factors are involved in lupus?
It has been difficult to pin down the environmental components of lupus. The following factors are the best known:
  • Medications -- As described above, the cardiac medications procainamide and hydralazine can trigger an illness similar to lupus. Of course, most people who take these medications do not develop an illness. We do not know why.
  • Ultraviolet radiation -- Sunlight can worsen the skin problems of people with lupus.
  • Sex hormones -- Women get lupus more commonly than men. And certain men who have higher-than-normal levels of female sex hormones (due to a medical condition called Klinefelter syndrome) develop lupus at a rate between that of women and other men.
The evidence for other environmental factors -- including infections, diet, and chemical agents and toxins -- is weak and inconsistent. Once the genetics of lupus is better clarified, it will be easier to determine the environmental factors influencing the disease.
When lupus runs in families, why don't all family members have it?
It helps to frame this question a little differently.... All members of a family do not have the same height, weight, and face. So, it makes sense that they don't all have the same conditions and diseases -- or the same susceptibility to various diseases.
Here again, it's genetic and environmental differences that explain differences in our appearance and health. Some family members will inherit genes that predispose to lupus, and others will not. Some family members will be exposed to environmental agents that trigger disease, and others will not.
There is no lupus in my family. Does this mean it will never occur in my family?
No. Anyone can develop lupus. About 90% of people with lupus do not have an immediate family member with lupus. But if someone in your family does have lupus, you are at greater risk.
How will discoveries about DNA help people and families with lupus?
Further discoveries about lupus genes will lead to more individualized medicine. Prevention, diagnosis, treatment, and prognosis will be personalized, based largely on the strengths and weaknesses found in a person's genes.
  • Treatment -- better use of existing treatments
Several medicines have been approved to treat lupus. How does your physician know which is best for you? Part of the answer may be in your genes.
In this article, we've seen how specific genes influence the development and progression of a complex condition -- lupus. Similarly, specific genes may influence the responses to different treatments. Better genetic information could explain why some drugs work better in some people than others. This will make choosing treatments less hit-and-miss than in the past.
  • Treatment -- discovery of new treatments
Whenever scientists discover a gene involved in lupus, it's a doorway to designing new treatments. If the gene is over-active, then scientists can look for ways to turn it off or interfere with its activity. If the gene is under-active or broken, then scientists can look for ways to turn it on or increase its activity.
  • Prevention, Diagnosis, Prognosis
Prevention, diagnosis, and prognosis all improve when our ability to calculate risk improves. Scientists believe genes will tell us a lot about the risk of developing lupus and the progression of lupus.
Article by DNA Sciences

New Lupus Genes Identified




WEDNESDAY, April 4 (HealthDay News) -- Three new genes linked to the chronic autoimmune disease lupus have been identified by an international team of researchers.
The analysis of more than 17,000 genetic samples from people of several ethnic groups also pinpointed another 11 genetic regions that may be related to lupus and require further study.
The researchers found that the genes IRF8 and TMEM39a are associated with lupus in European-American, African-American, Gullah (a distinctive group of African-Americans in Georgia and South Carolina) and Asian patients. The gene IKZF3 is only significantly associated with lupus in African-Americans and European-Americans.
The researchers said their findings, which appear in the April 6 issue of the American Journal of Human Genetics, show that the genes that cause lupus aren't always universal.
The next step is to study the three genes to find out exactly what role they play in lupus, said lead author Christopher Lessard, a scientist at the Oklahoma Medical Research Foundation in Oklahoma City.
Lupus affects about 1.5 million Americans, and about 90 percent of patients are women. The disease causes the immune system to become overactive and attack the body's own cells. Symptoms include fatigue, fever, rashes and joint pain.
A combination of environmental and genetic factors cause lupus. Learning more about genetic risk factors may lead to improved diagnosis and treatment of the disease.
-- Robert Preidt

New Clues on Genetic Causes of Autism

http://www.webmd.com/brain/autism/news/20110608/new-clues-on-genetic-causes-of-autism

June 8, 2011 -- Genetic mutations not inherited from parents appear to explain some cases of autism, new research suggests. And the mutations may number in the hundreds.
While the new research is a step forward, it is a small puzzle piece. "It could explain up to 2% of all autism cases," says researcher Stephan J. Sanders, MD, a postdoctoral research associate at Yale University's Child Study Center.
Even so, he says the new research -- reported as a trio of studies in the journal Neuron -- provides a solid foundation to a better understanding of the biology of the disorder, eventually leading to better treatments.
In the new research, scientists also found new clues about why boys seem to be more vulnerable to the disorder than girls.
''In combination with some other research studies, this new research shows pretty clearly there is indeed a strong genetic component to autism, and that the individual genes can be identified," say Alan Packer, PhD, associate director for research at the Simons Foundation. It funds autism research and provided the sample populations studied in the new research. 
About one in 110 U.S. children has autism or autism spectrum disorder, the neurodevelopmental disorders marked by impaired communication, social interaction problems, repetitive behaviors, and other problems.

Genetic Causes of Autism: Trio of Studies

In two of the new studies, researchers analyzed more than 1,000 families who have one autistic child and unaffected siblings. They evaluated their DNA from blood samples. The researchers used a highly sophisticated technique that can detect duplications or deletions of one or more sections of DNA.
These duplications or deletions are called copy number variants or CNVs. If they occur at random, or sporadically, and aren't inherited, they are known as de novo CNVs.
Some CNVs ''are normal parts of being human," Sanders tells WebMD. "It's very difficult to find the ones that matter. We looked for ones that were new in the child.''
They found more new CNVs in autistic children than in unaffected children, which they expected.
They zeroed in on many regions linked with these rare sporadic mutations, Sanders says, confirming previous research on which areas matter. "Basically five regions really stand out now," he says.
These include areas of chromosome 7, 15, 16, 17 and Neurexin 1.
The team estimates ''there are 130-234 CNV regions that could be linked with autism," he says.
The researchers also found that the long arm of chromosome 7, a region associated with Williams syndrome, a genetic disorder in which people are highly social and overly friendly with strangers, may also be associated with autism.
"For a long time it has been known if you have a deletion there, it causes Williams syndrome," Sanders says.
They found the children with autism were more likely to have duplications in this region.
So it appears having a duplication may make you less social -- one of the characteristics of autism.
analyzed the same families. They used a similar approach. n a second study, researchers from Cold Spring Harbor Laboratory and other institutions
They, too, confirmed a contribution from the sporadic mutations. They estimated the number of regions involved even higher, at up to 300.
They also found that girls appear to have a greater resistance to autism from genetic causes than do boys.
''When we looked at affected females, we don't see small mutations, but very large mutations," says Michael Ronemus, PhD, a researcher at Cold Spring Harbor Laboratory. "Girls are more resistant," he says. It appears to take a larger mutation to affect girls with autism compared with boys.
It's long been known that boys are much more likely to get autism than are girls.
In a third report, Ronemus and his colleagues developed a method for analysis of the genetic associations. They used a new method to help identify a network of genes affected by the rare mutations in autism.
"The genes we are finding are typically involved in early brain development, forming connections in the brain," Ronemus says. These genes are related to the development of synapses, the point of connection between two nerve cells, among other tasks, the researchers say.

Genetic Causes of Autism: Implications

While the new research provides more clues to the genetic underpinnings of autism, "the message is not 'go out and get tested,'" says Sanders."We really are not at that stage yet."
The new research provides new information ''but also confirms a lot of things we have already known,"  says Andy Shih, PhD, vice president of scientific affairs for Autism Speaks, an advocacy and research organization.
"It confirms that rare copy number variants are the main risk factors for many families," he says. However, he says, it also confirms that it's still impossible to explain the majority of cases of autism.
The sporadic mutations appear to play more of a role in families with just one child affected, Shih says. Eventually, the genetic findings could be useful information during genetic counseling in families who have one affected child, he says.
The findings are called a critical first step in the eventual goal of developing targeted treatments.

More Autism Diagnoses in High-Tech Areas, Study Finds

Last Updated: 2011-Jun-24  ::  (HealthDay)
Description: http://media.healthday.com/images/editorial/guywithpc.jpgFRIDAY, June 24 (HealthDay News) -- Autism experts have long noted that they meet a lot of engineers and computer programmers who have autistic children compared to, say, salespeople. A new study suggests there may be merit to those observations.
Researchers from Cambridge University in England found that nearly three times as many children were diagnosed with an autism spectrum disorder in a region of the Netherlands known as a center of high-tech industry than in two other regions with fewer high-tech jobs.
The possible explanation: Autism is highly heritable -- meaning, it runs in families -- and has a strong genetic component related to a trait called "systemizing," which is a skill for analyzing how systems work and creating them. Workers in high-tech industries -- engineering and computing, for example -- tend to excel at systemizing.
"The theory is that people with autism may have a relative strength in systemizing, or the drive to analyze how systems work, how systems behave, how you can control them and build new ones," said study co-author Rosa Hoekstra, a visiting scientist with the Autism Research Center at Cambridge and an assistant professor of psychology at the Open University in Milton Keynes, England. "In the engineer or physicist or mathematician, these traits are advantageous, but it might cause difficulties in the children and show up as a clinical diagnosis of autism."
Some parents of autistic children have personality traits that are similar to those of autistic people, though not to the degree that they would be considered autistic, she added.
"They can function in society, but they have some personality or cognitive characteristics that are consistent with autism, such as a real preference for routines, or some social difficulties," Hoekstra said.
The study, published June 17 online in the Journal of Autism and Developmental Disorders, has implications for the distribution of services to autistic children, the authors said.
For the study, researchers asked schools in three regions of the Netherlands -- Eindhoven, Haarlem and Utrecht -- for statistics on children with an autism spectrum disorder. Children with autism often struggle with communication and social interactions, exhibit repetitive behaviors and have strong but narrow interests.
All three regions are similar in population size and socioeconomics, but Eindhoven is the Netherland's information technology hub. It's home to Eindhoven University of Technology, the High Tech Campus Eindhoven, and several technology companies, including Philips, ASML, IBM and ATOS Origin.
About 30 percent of jobs in Eindhoven are in technology or ICT compared to 16 percent in Haarlem and 17 percent in Utrecht.
The schools provided diagnostic information on more than 62,500 children. About 2.3 percent (or 229 for every 10,000) children in Eindhoven had autism, almost three times as many as in Haarlem (84 per 10,000) and four times as many as in Utrecht (57 per 10,000).
The rate in the United States is estimated to be about 1 percent.
Dr. Gary Goldstein, president and CEO of the Kennedy Krieger Institute in Baltimore, said the findings mirror his experiences with parents of autistic children. "I haven't met that many high-end people in sales with children with autism, but I met all these very successful people in the backroom processing the data," he said.
And while a doubling or a tripling of the risk is "enormous" in statistical terms, parents should also rest assured that it still means the vast majority of children -- 98 percent -- born to engineers or high-tech types will not have autism.
Researchers acknowledged their study had limitations, including the possibility that parents in the high-tech region were more attuned to the signs of autism and that the kids were more likely to be diagnosed, and that they relied on numbers from the schools but were unable to examine the kids themselves.
They are planning a follow-up study to test for other factors that might explain their finding.
Prior research has found that the mothers of children with autism are more likely to work in highly technical occupations, that autism is more common among the siblings of mathematics students, and that autism is more common among children who have fathers or grandfathers who worked as engineers, according to background information in the study.
"This suggests some link between a talent for systemizing and autism," Hoekstra said.
More information
The U.S. National Institute of Neurological Disorders and Stroke has more on autism.
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Autoimmune disease in mothers with the FMR1 premutation is associated with seizures in their children with fragile X syndrome
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2955238/
Weerasak Chonchaiya,1,2 Flora Tassone,1,3 Paul Ashwood,1,4 David Hessl,1,5 Andrea Schneider,1,5 Luis Campos,6 Danh V. Nguyen,6 and Randi J. HagermanDescription: corresponding author1,7
1Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis Health System, 2825 50th Street, Sacramento, CA 95817 USA
2Division of Growth and Development, Department of Pediatrics, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, Thailand
3Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Davis, CA USA
4Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA USA
5Department of Psychiatry and Behavioral Sciences, University of California Davis Health System, Sacramento, CA USA
6Division of Biostatistics, Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, CA USA
7Department of Pediatrics, University of California Davis Health System, Sacramento, CA USA
Randi J. Hagerman, Phone: +1-916-7030247, Fax: +1-916-7030240, Email: randi.hagerman@ucdmc.ucdavis.edu.
Description: corresponding authorCorresponding author.
Received June 16, 2010; Accepted August 23, 2010.
Description: Small right arrow pointing to:This article has been cited by other articles in PMC.
Abstract
An increased prevalence of autoimmune diseases in family members of children with autism spectrum disorders (ASD) has been previously reported. ASD is also a common problem co-occurring in children with fragile X syndrome (FXS). Why ASD occurs in some individuals with FXS, but not all, is largely unknown. Furthermore, in premutation carrier mothers, there is an increased risk for autoimmune diseases. This study compared the rate of ASD and other neurodevelopmental/behavioral problems in 61 children with FXS born to 41 carrier mothers who had autoimmune disease and in 97 children with FXS of 78 carrier mothers who did not have autoimmune disease. There were no significant differences in the mean age (9.61 ± 5.59 vs. 9.41 ± 6.31, P = 0.836), cognitive and adaptive functioning in children of mothers with and without autoimmune disease. Among children whose mothers had autoimmune disease, the odds ratio (OR) for ASD was 1.27 (95% CI 0.62–2.61, P = 0.5115). Interestingly, the OR for seizures and tics was 3.81 (95% CI 1.13–12.86, P = 0.031) and 2.94 (95% CI 1.19–7.24, P = 0.019), respectively, in children of mothers with autoimmune disease compared to children of mothers without autoimmune disease. In conclusion, autoimmune disease in carrier mothers was not associated with the presence of ASD in their children. However, seizures and tics were significantly increased in children of mothers with autoimmune disease. This suggests a potential new mechanism of seizure and tic exacerbation in FXS related to an intergenerational influence from autoimmunity in the carrier mother.
Introduction
There is a close connection between immune function and development of the central nervous system (CNS). Both systems interact across the life span of an individual so that successful neurodevelopment requires a normal balance of immune responses (Ashwood et al. 2006; Delneste et al. 1999). Autism spectrum disorders (ASD) are a complex group of heterogeneous neurodevelopmental disorders with significant social and communication deficits in which etiologies are mostly unknown. Recently, altered immunogenetics and a dysfunctional immune system have been proposed to play a role in at least a subgroup of children with ASD (Ashwood et al. 2006; Enstrom et al. 2009). In addition, an increased prevalence of autoimmune disease in family members of children with idiopathic ASD has been demonstrated in several studies (Atladottir et al. 2009; Comi et al. 1999; Money et al. 1971; Sweeten et al. 2003). Maternal autoantibodies may also affect fetal brain development during critical periods of neurodevelopment in a subset of children with ASD (Ashwood and Van de Water 2004; Dalton et al. 2003; Singer et al. 2006). Studies have shown that when IgG from mothers of children diagnosed with ASD is injected into pregnant rhesus monkeys, there are behavioral changes in the rhesus offspring including abnormal stereotypical and hyperactive behaviors, compared with offspring injected with IgG isolated from mothers of typically developing children and controls (Martin et al. 2008). These findings suggest a potential deleterious relationship between exposure to autoantibodies against the fetal brain during gestation and the risk to develop ASD.
Fragile X syndrome (FXS) is the most common known single gene cause of autism (Hagerman et al. 2008). The prevalence of autism in individuals with FXS is approximately 30% (Kaufmann et al. 2004; Rogers et al. 2001) and pervasive developmental disorder-not otherwise specified (PDD-NOS) is seen in an additional 30% (Harris et al. 2008). Therefore, the prevalence of ASD is approximately 60% in individuals with FXS (Hagerman et al. 2008; Harris et al. 2008). The mechanism of ASD in FXS is hypothesized to be related to the deficit of FMRP (the FMR1 protein) which regulates the translation of many genes that are associated with autism (Chonchaiya et al. 2009; Hagerman et al. 2008; Wang et al. 2010). Why ASD occurs in some individuals with FXS, but not all, is largely unknown (Loesch et al. 2007). Problems affecting the CNS including seizures, malformations, or other genetic disorders are more likely to occur in those with FXS and ASD compared with those with FXS without ASD (Garcia-Nonell et al. 2008). Therefore, the diagnosis of ASD in those with FXS may also be related to additional risks including genetic and environmental factors leading to additional brain dysfunction additive to the FMR1 mutation (Loesch et al. 2007).
The prevalence of autoimmune diseases including autoimmune thyroid disease, lupus, multiple sclerosis (MS), and fibromyalgia (with a postulated autoimmune component) are increased in females with the FMR1 premutation (Buskila and Sarzi-Puttini 2008; Coffey et al. 2008; Di Franco et al. 2010; Greco et al. 2008; Rodriguez-Revenga et al. 2009; Staines 2004; Zhang et al. 2009). These autoimmune disorders in some premutation carriers are thought to be related to RNA toxicity from elevated levels of FMR1 mRNA (Coffey et al. 2008; Greco et al. 2008; Zhang et al. 2009). Maternal autoimmunity may play an additional role that further contributes to ASD or may be associated with more severe ASD symptoms along the continuum of social deficits in their children with FXS. However, the association between autoimmune disease in mothers and the presence of ASD or other medical and behavioral problems particularly tics [since tics and Tourette syndrome have a potential autoimmune etiology through the mechanism of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) (Martino et al. 2009a)] that perhaps could be influenced by autoimmunity in their children with FXS has not been studied previously. We therefore investigated whether autoimmune diseases/conditions in mothers with the FMR1 premutation are associated with ASD or other problems by comparing the offspring of mothers with and without autoimmune disease (M + AI and M − AI).
Materials and methods
Subjects
Included in this study were children with FXS (n = 158) with either the full mutation or mosaicism, and their mothers (n = 119) whom were seen between 2003 and 2009 at the MIND Institute. This study was approved by the Institutional Review Board of the University of California, Davis. The children with FXS in this cohort were divided into children (n = 61) who were born to mothers who had a history of autoimmune disease and children (n = 97) whose mothers did not have autoimmune disease.
The diagnosis of autoimmune disease in the mother was confirmed by a physician and these diseases include autoimmune thyroid disease, systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS), Sjogren’s syndrome, psoriasis, optic neuritis, Raynaud’s phenomenon, or fibromyalgia, which has a postulated autoimmune component in its pathophysiology (Coffey et al. 2008; Di Franco et al. 2010; Greco et al. 2008; Staines 2004; Zhang et al. 2009). Sixty-one children with FXS with a mean age of 9.61 years (SD 5.59) were born to 41 mothers with a mean age of 40.54 years (SD 7.96) who had experienced autoimmune disease. They were compared to 97 children with FXS with a mean age of 9.41 years (SD 6.31), born to 78 mothers with a mean age of 38.62 years (SD 6.46) without a history of clinically defined autoimmune disease. Most mothers in each group [M + AI and M − AI, 23 (56.1%) vs. 59 (75.6%), respectively] had one child with FXS. There were 16 (39.0%) and 19 (24.4%) M + AI and M − AI, respectively, who had two children with FXS. Two (4.9%) M + AI had three children with FXS. Children with the FMR1 premutation born to these mothers were not included in the study. A description of both mothers and children with FXS are presented in Tables 1 and and22.
Description: Table 1
Characteristics of mothers with the fragile X premutation
Description: Table 2
Characteristics of children with FXS
Study protocol
All subjects underwent a full medical history and physical examination by a physician with expertise in fragile X-associated disorders (RJH) after informed consent was obtained. The medical history covered an extensive review of prenatal, perinatal and postnatal history and complications, developmental and behavioral variations and problems for each child including developmental delay or regression of development, tics (a sudden, repetitive, nonrhythmic, stereotyped motor movement or vocalization involving discrete muscle groups, such as eye blinking, shoulder shrugging, throat clearing, etc.; tics symptoms had to appear before 18 years of age and occur before taking stimulant medications if those with FXS also have co-morbid attention deficit/hyperactivity disorders), sleep problems (problems falling asleep or waking up at night), clinical seizures (seizures characteristics, onset, duration, frequency, any co-occurring loss of consciousness, other neurological deficit, associated symptoms, possible triggers if they could be defined, electrical activity recorded by an electroencephalography (EEG) testing, and anticonvulsant medications), other pertinent medical problems, review of systems, and medications. Autoimmune diseases/conditions in mothers were thoroughly obtained by self-report after questioning about all potential autoimmune disorders in the medical history mentioned above. Sometimes medical records (approximately 30%) of the mothers were available for review in those with autoimmune problems during the visits at our clinic; however, these data are not included in the analysis because it was not consistently obtained. To be documented as having an autoimmune disease in the mother or developmental, behavioral, and medical problems particularly seizures, tics, and sleep problems in children with FXS, the subjects had to have sought medical or pediatric professional help for their problems and to have been previously diagnosed and/or treated by a physician for each disease/condition (physician-documented clinical involvement). Each subject underwent a medical examination that included a head circumference. A large head or macrocephaly was defined as exceeding 2 standard deviations (SD) above normal when compared with typically developing children of the same age.
The diagnosis of ASD in those with FXS was made after the use of standardized measures including the Autism Diagnostic Observation Schedule (ADOS), the Autism Diagnostic Interview, Revised (ADI-R) and the Diagnostic and Statistical Manual of Mental Disorders (DSM IV) (American Psychiatric Association 2000; Le Couteur et al. 1989; Lord et al. 2000) followed by a team consensus discussion as previously described (Harris et al. 2008).
The developmental or cognitive abilities were assessed with age appropriate measures, including the Mullen Scales of Early Learning, the Wechsler Preschool and Primary Scale of Intelligence-Third Edition (WPPSI-III), the Wechsler Intelligence Scale for Children-Third Edition (WISC-III), the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV), the Wechsler Abbreviated Scale of Intelligence (WASI), the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III) or the Stanford-Binet Intelligence Scale, Fourth Edition. Children’s adaptive functioning was also assessed using the Vineland Adaptive Behavioral Scales, Second Edition (Vineland-II) by interviewing the caregivers (Mullen 1995; Sparrow et al. 2005; Thorndike et al. 1986; Wechsler 1991, 1997, 1999, 2002, 2003). Intellectual disability was defined as IQ less than 70.
Behavioral and emotional problems including externalizing behaviors (hyperactivity, aggression, and conduct problems), internalizing behaviors (anxiety, depression, and somatization), atypicality, withdrawal, attention problems, and adaptive skills (adaptability, social skills, leadership, activities of daily living, and functional communication) were completed by a limited percentage of parents for each group of children with FXS (autoimmune disease vs. no autoimmune disease, 72.1 vs. 54.6%) using Behavior Assessment System for Children (BASC) questionnaire (Reynolds and Kamphaus 1992, 2004). Behavior Symptoms Index (BSI), a measure of an overall level of problems consisting of the hyperactivity, aggression, depression, attention problems, atypicality and withdrawal scales, was also documented. The BASC parent rating scale yields T scores with a mean of 50 and a SD of 10. On the clinical scales, scores from 60 to 69 are in the “at-risk” range and scores of 70 and above indicate “clinically significant” problems. On the adaptive skill scales of the BASC, scores from 31 to 40 indicate “at-risk” problems and scores of 30 and lower are considered “clinically significant.” In this study, externalizing, internalizing behaviors, and BSI scores 60 or above were defined as having those problems accordingly, whereas deficits in adaptive skills were defined in which adaptive skills scores are 40 or lower. Table 3 lists the variables investigated statistically between both groups of children.
Description: Table 3
Neurodevelopmental and behavioral problems between both groups of children
Molecular analysis
A blood sample for measurement of methylation status, CGG repeat, and FMR1 mRNA levels were obtained from each subject (both mothers and children with FXS). FMR1 mRNA quantification, Southern Blot and PCR-based genotyping were performed as previously described (Tassone et al. 2000; Tassone et al. 2008).
Statistical analysis
Qualitative variables for which there were specified cut-offs including autoimmune disease in mothers, the diagnosis of ASD, intellectual disability, seizures, sleep problems, tics, macrocephaly, externalizing, internalizing behaviors, BSI and deficits in adaptive skills were rated dichotomously (presence or absence) as demonstrated in Table 3. Univariate analysis of continuous variables including age, CGG repeat size, FMR1 mRNA level, activation ratio (AR: the fraction of normal FMR1 allele as the active allele in female individuals with FXS), IQ, and adaptive functioning was based on t test. Fisher’s exact test for 2 × 2 contingency table analyses were used to assess the association between autoimmune status in the mothers of children with FXS and the diagnosis of ASD. Results are presented in terms of odds ratio (OR) and 95% confidence interval (95% CI). P value and 95% confidence interval (CI) relating to the primary hypotheses of whether there is an association of autoimmune disease in mothers to ASD in children with FXS was based on a logistic regression model using generalized estimating equations. This approach accounts for correlation within a family (i.e. mother–children correlation) in estimates of standard errors, although this did not make a material difference in the results. Also, models were explored with adjusting for mother’s age, child’s age, gender, number of offspring, whether a mother had a child before or after age 35, CGG repeat numbers, and mRNA levels. All covariates were not significant and adjusted OR estimates did not differ from OR estimates from models with only the main variable of interest—the presence of autoimmune disease. Thus, we reported this simple later model with main effect of interest. An exception is for the variable gender in the model of BSI outcome (as noted in Table 3; see “Results”). However, we did not adjust for multiple testing and the reason for this is that our original primary hypothesis relates to investigating the association between autoimmune disease in the mothers and ASD. Neurodevelopmental and behavioral outcomes, particularly the collection of BASC variables, were exploratory. BASC T scores were analyzed using general linear model adjusted for age and accounting for within-in family correlation and variation among subjects. All P reported are two-sided and the significance level is 0.05.
Results
Characteristics of subjects
Characteristics of the mothers and their offspring with FXS are illustrated in Tables 1 and and2,2, respectively. There was no significant difference in mean age between M + AI and M − AI [40.54 (SD 7.96) vs. 38.62 (SD 6.46) years, P = 0.238]. There were no significant differences in molecular variables including CGG repeats, FMR1 mRNA levels, and AR between both groups of mothers. The two most common autoimmune disorders in the mothers were autoimmune thyroid diseases (27/41, 65.9%), and fibromyalgia (11/41, 26.8%). MS and Raynaud’s phenomenon were present at a similar rate in the mothers at 12.2% (5/41). Four (4/41, 9.8%) mothers reported to have been diagnosed with rheumatoid arthritis and three (3/41, 7.3%) mothers reported having SLE. Other reported autoimmune diseases included Sjogren syndrome (1/41), optic neuritis (1/41), and psoriasis for each disease (1/41). Of the 41 M + AI, there were 29 who presented with a single autoimmune disease, whereas a further 12 reported having two or more autoimmune diseases. Twenty (48.8%) mothers had autoimmune thyroid disease alone and 3 (7.3%) mothers had been diagnosed with fibromyalgia alone. In 23 (56.1%) mothers, the mean age of diagnosis with autoimmune disease was 30.26 (SD 9.45) years. The remainder of the group neither recalled the onset of the autoimmune disease nor the data for the onset of autoimmune disease in medical records were collected before the association between autoimmune disease in the mothers and the presence of ASD in their offspring with FXS was hypothesized.
Of the 41 mothers, 13 stated that their autoimmune disease occurred during their gestation. However, a precise ascertainment of the age of onset or diagnosis for each autoimmune disease based on self-report was very difficult due to the fact that the natural course of many autoimmune diseases can include a subclinical phase that does not meet stringent clinical diagnosis (Papi et al. 2007; Poppe and Glinoer 2003; Ulff-Moller et al. 2009).
There was significant difference neither in the mean age of children with FXS in the two groups [9.61 (SD 5.59) vs. 9.41 (SD 6.31) years, in children born of M + AI and M − AI, respectively, P = 0.836] nor in the type of the fragile X mutation (percentage of full mutation/mosaic = 78.7/21.3% vs. 79.4/20.6%, P = 0.876]. With regard to gender, there were fewer male children with FXS born to M + AI when compared with children with FXS of M − AI (60.7 vs. 78.4%, P = 0.016). Mean cognitive ability in both groups of children with FXS was in a mild range of intellectual disability and was not significantly different between groups [FSIQ = 62.75 (SD 17.77) vs. 60.80 (SD 17.55), in children born of M + AI and M − AI, respectively, P = 0.523]. Likewise, the adaptive behavior composite score documented by the Vineland between both groups of children with FXS was not significantly different [64.33 (SD 18.51) vs. 63.62 (SD 18.71), in children born of M + AI and M − AI, respectively, P = 0.847].
Autoimmune disease, ASD, and other neurodevelopmental problems
Of the 61 children with FXS born to M + AI, 38 (62.3%) children met the criteria for ASD. Twenty-two (36.07%) subjects had autism and 16 (26.23%) had PDD-NOS. Of the 32 mothers with children that had FXS and ASD, autoimmune thyroid disease was present in 22 (67.6%), fibromyalgia in 8 (25.0%), and Raynaud’s phenomenon in 4 (12.5%). Among children from M + AI, the odds ratio (OR) for FXS and ASD was 1.27 (95% CI 0.62–2.61, P = 0.5115). These data suggest that autoimmune disease in the mothers may not be a relevant risk factor for autism in combination with FXS. Other variables including intellectual disability, sleep problems, and macrocephaly were not different between both groups of children. However, the rate of tics was significantly higher in the group of children with FXS born to M + AI (15/58, 25.86%) compared with M − AI [10/94, 10.64%; OR = 2.94 (95% CI 1.19–7.24), p = 0.019].
Autoimmune disease and seizures
Data about seizures were not available for three children. However, a higher rate of clinical seizures was observed in a group of children with FXS born to M + AI (9/60, 15.0%) when compared with children with FXS of M − AI [4/95, 4.21%; OR = 3.81 (95% CI 1.13–12.86), P = 0.031]. Details of the nine children with FXS who have seizures and were born to M + AI are as follows: age range, 4.17–24 years (median age 9 years); gender, 7 boys and 2 girls; FMR1 mutations, six have the full mutation and three have mosaicism in the FMR1 gene. Three have more than one seizures type including complex partial seizures, generalized seizures, gelastic seizures and absence seizures, four had generalized tonic-clonic convulsions alone, and two experienced petit mal or absence seizures alone. Seizures onset ranged from 17 months to 9 years with a median age of onset at 3 years. With regard to treatment of seizures, seven subjects reported to take long-term anticonvulsant medications. Four of these seven subjects took more than one anticonvulsants to control the seizures. Of these nine children with FXS born to M + AI who developed clinical seizures, eight mothers had autoimmune thyroid disease. There was no history of birth asphyxia or neonatal encephalopathy. The cognitive abilities of children with seizures were similar to the whole group of children with FXS.
Details of four children with FXS who had seizures born to M − AI are as follows: age range 3.63–17.75 years (median age 8.25 years), gender 3 boys and 1 girl, all have the full mutation in the FMR1 gene; one reported to have more than one seizure type including absence, complex partial seizures, and generalized seizures, one experienced absence seizures alone, one had partial seizures alone, and one subject was noted to have two episodes of simple febrile seizures but this child has never taken any medications. Seizures onset in this group ranged from 2.67 to 5 years with a median age of onset at 3.84 years. Abnormal EEG results were confirmed in all subjects in this group of children. With regard to anticonvulsant medications, one child has taken more than one medication to treat the seizures and seizures were well controlled by one medication in two subjects in this group.
Autoimmune disease and behavioral problems
Behavioral and emotional problems documented by BASC were completed in 97 (61.4%) children with FXS in our study. The children’s age, gender and type of the fragile X mutations were not significantly different between both groups (children of M + AI and M − AI). The rate of externalizing behaviors [36.36 vs. 16.98%; OR = 3.04 (95% CI 1.10–8.38), P = 0.0319] was increased in children with FXS born to M + AI. T scores of these behavioral and emotional problems between both groups of children are illustrated in Table 4. Children with FXS born to M + AI were likely to have higher T scores on aggression, internalizing behaviors, depression, withdrawal symptoms, and BSI when compared with those children with FXS born to M − AI, even though only withdrawal symptoms and BSI scale reached a significant level for documenting the problems.
Description: Table 4
Parent rating scale (T score) of behavioral and emotional problems documented by BASC between both groups of children
Discussion
This is the first study investigating the intergenerational association between the presence of co-morbid ASD, medical problems, and behavioral problems in the children with FXS of M + AI. Evidence of an increased prevalence of autoimmune disorders including hypothyroidism, Hashimoto’s thyroiditis, type 1 diabetes, rheumatoid arthritis, SLE and ulcerative colitis have been reported in parents of children with idiopathic ASD in previous studies (Atladottir et al. 2009; Comi et al. 1999; Croen et al. 2005; Money et al. 1971; Mouridsen et al. 2007; Sweeten et al. 2003). However, this finding was not replicated in all studies (Micali et al. 2004). Our clinical sample of children with FXS did not support this finding. Therefore, autoimmunity in the mothers may not be significantly associated with ASD in the offspring with FXS. A mutation in the FMR1 gene alone involves significant dysregulation of numerous genes whose translation is controlled by FMRP leading to significant deficits in synaptic plasticity and ASD (Chonchaiya et al. 2009).
Interesting findings were that the rates of seizures, tics, and externalizing problems documented by the BASC which were significantly increased in the group of children with FXS of M + AI. The overall prevalence of seizures in children with FXS in both groups of M + AI and M − AI was similar to the 10–20% rate seizures previously reported in FXS (Berry-Kravis 2002; Musumeci et al. 1999).
The pathophysiology of seizures in those with FXS is hypothesized to be related to the imbalance of the excitatory and inhibitory neurotransmitter systems, especially the mGluR5 pathway and the gamma-aminobutyric acid A (GABAA) pathway in the absence of FMRP. There is a lower expression of GABA receptors in the fragile X knock out (KO) mouse (D’Hulst et al. 2006) and an increased expression of glutamic acid decarboxylase (GAD), the enzyme responsible for GABA synthesis in the KO mouse (El Idrissi et al. 2005). Interestingly, other factors including autoimmunity or immune-mediated responses may influence these pathways leading to seizures. For instance, the presence of autoantibody to GAD was demonstrated in the sera of non-fragile X patients with early onset of chronic drug-resistant epilepsy leading to loss of GAD and decreased GABA synthesis that ultimately contributed to a lower seizure threshold (McKnight et al. 2005). In addition, autoantibodies to GluR3B-peptide of glutamate/α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptor subtype 3 or to a peptide of N-methyl-d-aspartate (NMDA) receptor subunit 2A (NR2A) subunit of glutamate/NMDA receptors have been found to be elevated in non-fragile X patients with epilepsy (Ganor et al. 2005). However, there are no studies of autoimmunity in mothers of children with epilepsy or seizures available. Moreover, the impact of autoimmunity on seizures in individuals with FXS has not been studied and our work provides just the first step in this direction. This study suggests that autoimmunity in the mother may influence the risk of seizures in the offspring with FXS.
A tic disorder has been reported in approximately 20% in individuals with FXS (Hagerman 2002). The pathophysiology of tic disorders is quite complex. There are genetic and environmental influences that involve a number of brain structures including basal ganglia, cortico-striato-thalamo-cortical circuits, dopaminergic, glutamatergic, and the serotoninergic neuronal system (Harris and Singer 2006; Rampello et al. 2006). Although there is familial aggregation in those with Tourette syndrome, the most severe and chronic form of a tic disorder, but family members also share common environmental factors in addition to their similar genetic backgrounds (O’Rourke et al. 2009). The potential role of various abnormal immune-mediated responses followed by different triggers/factors causing or exacerbating tics or Tourette syndrome has been previously reported in conditions including PANDAS, possible involvement of non-streptococcal and viral infection in aggravating tics symptoms, or the presence of different antibodies/auto-antibodies in either sera or against striatal structures in human subjects, and animal models, respectively. These antibodies include anti-phospholipid auto-antibodies and antineuronal antibodies (Martino et al. 2009a; Morer et al. 2008; Rampello et al. 2006). There are no studies of other autoimmunity in mothers of children with tics or Tourette syndrome available, although there are family studies that show a higher incidence of Tourette syndrome in the parents and the etiology in a subgroup of those with Tourette syndrome includes autoantibodies against the basal ganglia as mentioned above so this can also be an autoimmune disease itself (Martino et al. 2009b; O’Rourke et al. 2009). Therefore, an increase rate of tics in our study may suggest another potential hypothesis that future studies should take into account of autoimmunity in the mothers or the inheritance of autoimmune tendencies in their offspring with FXS may be related to a higher rate of tics in these children.
Taken together, our findings suggest that future studies should consider how autoimmunity in the mothers may interact with the FMR1 mutation to disrupt critical networks in the brain, particularly GABA and glutamate systems or perhaps through other mechanisms leading to clinical seizures, tics, and behavioral problems in their offspring with FXS. Children with FXS born to M + AI may be genetically more prone to produce antibodies that exacerbate an underlying seizure and tic tendency in FXS. This hypothesis requires further prospective study with larger sample sizes.
The weaknesses of our study includes a clinical sample with an assessment of autoimmune disease that is documented only by medical history which can be influenced by poor recall, small numbers of study subjects and the lack of documentation of specific antibodies that may affect the offspring. However, a possible association between the autoimmunity in mothers and medical and neurodevelopmental problems in their children with FXS was assessed years after our routine data collection and therefore was blinded and unbiased regarding autoimmune disease in the mother. Although there were gender differences between both groups of offspring, other characteristics particularly age, molecular data, cognitive abilities, and adaptive functioning were not significantly different between both groups of offspring. The gender difference was accounted for in the analyses using logistic regression and general linear models. However, if we had had more male offspring of M + AI, it is likely that we would have found more significant differences between the two groups of children because boys with FXS have a higher rate of intellectual and behavioral impairments including autism compared to girls with FXS.
An important limitation of the current study relates to our statistically significant findings (e.g. seizures, tics, and BASC behavioral outcome) among our exploratory/secondary variables. Although these findings suggest specific outcomes to examine in future studies, these statistically significant findings are not adjusted for multiple testing; thus, the overall type I error rate is inflated. Mothers provided data regarding their own medical history and their offspring’s behavioral data, it is possible that psychological factors, such as anxiety or depression associated with autoimmune disease or the premutation could have introduced a negative bias in these behavioral ratings. This point, however, raises another potential explanation for our findings, specifically high rates of stress and anxiety associated with raising children with FXS could potentially contribute to a pro-inflammatory environment that may facilitate autoimmunity tendency in the premutation mothers (Stojanovich 2010; Stojanovich and Marisavljevich 2008). The issue regarding whether or not the autoimmune disease occurred during the gestation cannot be accurately assessed with this retrospective data. Therefore, prospectively collected data is needed to investigate risk during pregnancy and biological markers of immune function should be obtained to elucidate this possible intergenerational relationship.
In conclusion, autoimmune disease in mothers was not significantly associated with the presence of ASD in their children with FXS. However, clinical seizures, tics, and behavioral problems were significantly increased in children with FXS born to M + AI. These data suggest an additional mechanism of seizure and tic exacerbation in FXS related to an intergenerational influence from autoimmunity in the mother.
Acknowledgments
This work was supported by National Institute of Health Grants HD036071, and HD02274; Neurotherapeutic Research Institute (NTRI) Grants DE019583, and DA024854; National Institute on Aging Grants AG032119 and AG032115; National Institute of Mental Health Grant MH77554; National Center for Resources UL1 RR024146; and support from the Health and Human Services Administration of Developmental Disabilities Grant 90DD05969. We also thank Antoniya Boyd and Jacky Au from the UC Davis MIND. Institute for their help with data processing and providing some BASC questionnaires to the parents, respectively.
Conflict of interest Randi Hagerman has received funding from Seaside Therapeutics, Roche, Novartis, Neuropharm, Forest, Johnson and Johnson, and Curemark to carry out treatment trials. There are no other conflicts of interest from the authors.
Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
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Is autism an autoimmune disease? This article is a pay article so to view in it’s entirety you must go to the website and pay for it.

http://www.sciencedirect.com/science/article/pii/S1568997204001120
  • Paul Ashwood,
  • Judy Van de WaterDescription: Corresponding author contact information, Description: E-mail the corresponding author
  • Department of Internal Medicine, Division of Rheumatology, and UC Davis M.I.N.D. Institute, University of California, Davis, 95616, United States
  • Accepted 17 July 2004. Available online 3 October 2004.

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Abstract

Autism spectrum disorder (ASD) is a spectrum of behavioral anomalies characterized by impaired social interaction and communication, often accompanied by repetitive and stereotyped behavior. The condition manifests within the first 3 years of life and persists into adulthood. There are numerous hypotheses regarding the etiology and pathology of ASD, including a suggested role for immune dysfunction. However, to date, the evidence for involvement of the immune system in autism has been inconclusive. While immune system abnormalities have been reported in children with autistic disorder, there is little consensus regarding the nature of these differences which include both enhanced autoimmunity and reduced immune function. In this review, we discuss current findings with respect to immune function and the spectrum of autoimmune phenomena described in children with ASD.


Autism tied to autoimmune diseases in immediate family    http://www.usatoday.com/news/health/2009-07-12-autism13_N.htm


By Liz Szabo, USA TODAY
Danish researchers have found another clue to the mysterious causes of autism, according to a study published online this month in Pediatrics.
In a study of children born in Denmark from 1993 to 2004, doctors found that many children with autism or related disorders also had a family history of autoimmune diseases. Autoimmune diseases, such as type 1 diabetes and rheumatoid arthritis, develop when antibodies that normally fight infectious organisms instead attack the body itself.
In the study, doctors examined patterns of disease among children, mothers, fathers and siblings.
For the first time, researchers found an increased risk of autism spectrum disorders in children whose mothers have celiac disease, a digestive condition in which people cannot tolerate gluten, a protein found in wheat, rye and barley. Autism spectrum disorders include a range of neurological problems affecting communication and socializing.
The study also confirms the results of many earlier papers, says author Hjördis Atladottir of Denmark's University of Aarhus. For example, doctors found an increased risk of autism in children with a family history of type 1 diabetes and an increased risk of autism spectrum disorders in children whose mothers have rheumatoid arthritis.
Researchers say their study leaves many questions unanswered. But they say it's possible babies are affected by their mother's antibodies while in the womb. Their mother's disease also may create an abnormal environment.
Although the study is designed to find associations among diseases, it is not able to prove that autoimmune disorders cause autism, says the University of Washington's Karen Toth, a clinical psychologist who was not involved in the study.
But Toth says it's possible that the same genes are involved in autoimmune diseases and autism. Researchers have known for many years that autism can run in families, Toth says. And scientists have found genes that may be involved in autism.
Children may also have an increased risk if they are exposed in the womb to certain drugs — such as thalidomide, valproic acid or cocaine — or to infectious diseases such as rubella, Toth says.
Recent studies also have found that babies born prematurely have higher risks of autism.
Children also are at higher risk if their fathers are older than 40 or if children have conditions such as epilepsy or Fragile X syndrome, which causes mental retardation, according to the Mayo Clinic.
People with autoimmune diseases shouldn't be alarmed, Atladottir says. The vast majority of people with these conditions do not have children with autism, he says. In the study, only 3,325 of the more than 689,196 children studied were diagnosed with autism spectrum disorders.

Association of Schizophrenia and Autoimmune Diseases: Linkage of Danish National Registers
William W. Eaton, Ph.D.; Majella Byrne, Ph.D.; Henrik Ewald, Dr.Med.Sc.; Ole Mors, Ph.D.; Chuan-Yu Chen, Ph.D.; Esben Agerbo, M.S.; Preben Bo Mortensen, M.D., Dr.Med.Sc.
Am J Psychiatry 2006;163:521-528. 10.1176/appi.ajp.163.3.521
text A A A
Abstract
OBJECTIVE: Individuals with schizophrenia and their relatives tend to have either higher or lower than expected prevalences of autoimmune disorders, especially rheumatoid arthritis, celiac disease, autoimmune thyroid diseases, and type 1 diabetes. The purpose of the study was to estimate the association of schizophrenia with these disorders as well as a range of other autoimmune diseases in a single large epidemiologic study. METHOD: The Danish Psychiatric Register, the National Patient Register, and a register with socioeconomic information were linked to form a data file that included all 7,704 persons in Denmark diagnosed with schizophrenia from 1981 to 1998 and their parents along with a sample of matched comparison subjects and their parents. The data linkage required that the autoimmune disease occur before the diagnosis of schizophrenia. RESULTS: A history of any autoimmune disease was associated with a 45% increase in risk for schizophrenia. Nine autoimmune disorders had higher prevalence rates among patients with schizophrenia than among comparison subjects (crude incidence rate ratios ranging from 1.9 to 12.5), and 12 autoimmune diseases had higher prevalence rates among parents of schizophrenia patients than among parents of comparison subjects (adjusted incidence rate ratios ranging from 1.3 to 3.8). Thyrotoxicosis, celiac disease, acquired hemolytic anemia, interstitial cystitis, and Sjögren’s syndrome had higher prevalence rates among patients with schizophrenia than among comparison subjects and also among family members of schizophrenia patients than among family members of comparison subjects. CONCLUSIONS: Schizophrenia is associated with a larger range of autoimmune diseases than heretofore suspected. Future research on comorbidity has the potential to advance understanding of pathogenesis of both psychiatric and autoimmune disorders.
Theories on autoimmune aspects of schizophrenia invoke the notion of early infection by microorganisms possessing antigens that are so similar to tissue in the CNS that resulting antibodies act against the brain R1633CJHGHHBAR1633CJHGHBAC. Comparisons of schizophrenia patients and healthy subjects have revealed differences in immunologic parameters R1633CJHCIHBH, but there have been failures to replicate. There has been repeated evidence of a genetic locus for schizophrenia in the area of the human leukocyte antigens (HLA), also with failures to replicate R1633CJHEFBFGR1633CJHJDGHD. Obstetric complications have been implicated in schizophrenia, and some have speculated that infection in the mother produces antibodies that are transmitted to the fetus, producing autoantibodies that disrupt neural development and raise risk for schizophrenia R1633CJHIGHAB, R1633CJHCIEIB.
Schizophrenia patients or their relatives have been reported to have either higher or lower than expected prevalences of some autoimmune disorders, including rheumatoid arthritis R1633CJHCGGIH, type 1 diabetes R1633CJHCBDAA, thyroid disorders R1633CJHCBDAA, R1633CJHIBHIA, and celiac disease R1633CJHBEJAJ. This article presents a systematic comparison of the prevalence of 29 autoimmune disorders for all patients in the nation of Denmark diagnosed with schizophrenia between 1981 and 1998 and their parents along with a group of healthy subjects and their parents.

Method

Abstract  |  Method  |  Results  |  Discussion  |  References  
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The Registers

Data from Danish registers were linked using the unique personal identification number that has been allocated to all residents in Denmark since 1968 R1633CJHFGJDJ. Socioeconomic information was obtained from the Integrated Database for Longitudinal Labor Market Research, which was created by linking a number of employment and education databases R1633CJHECCHE.
The Danish Psychiatric Register, which records contacts with psychiatric facilities throughout Denmark, was the source of patients with schizophrenia R1633CJHCIAHE, R1633CJHJBFFG. There are no private psychiatric facilities in Denmark, and all treatment is free of charge. Information on autoimmune diseases originated from the National Patient Register, which has collected data on all admissions to Danish hospitals since 1977 R1633CJHFFIEF. Since 1995 it has included all contacts in emergency rooms and outpatient clinics. Diagnoses in the psychiatric and patient registers were according to ICD-8 until the end of 1993 and according to ICD-10 from the beginning of 1994. The disease categories used here were designed to separate, as much as possible, syndromes with an autoimmune basis from similar syndromes with other causes.
The study procedures were approved by the Danish Data Protection Board and the Johns Hopkins Bloomberg School of Public Health Committee on Human Research.

Subjects

The 7,704 schizophrenia patients comprised all persons over age 15 admitted to a Danish psychiatric facility for the first time between 1981 and 1998 with a diagnosis of schizophrenia and known maternal identity. This group of patients, 66% of whom were male, has been described elsewhere R1633CJHBAEHA. For each patient, 25 comparison subjects matched by year of birth and sex were selected randomly from a 5% sample of the Integrated Database for Longitudinal Labor Market Research. Comparison subjects were excluded if they had been admitted to a psychiatric facility before the first admission of the patient. In 92% of the patients and 96% of the comparison subjects, the father was known. Socioeconomic and disease information on the patients, comparison subjects, and their parents relates to the status just before the first contact with the patient. Wealth of the parents was organized into the highest quartile of the two parents for each individual, based on the distribution of wealth in the entire Integrated Database for Longitudinal Labor Market Research.

Statistical Analysis

Statistical methods included estimation of prevalence proportions in patients and comparison subjects, and conditional logistic regression analyses that yielded an incidence rate ratio. The strata for the logistic regression are formed by the matching variables of year of birth and sex. Multivariate models adjust for known risk factors for schizophrenia: urbanicity of birth, socioeconomic status, and family history of schizophrenia. An initial logistic regression model predicts the occurrence of schizophrenia from prior occurrence of any of 29 autoimmune diseases. Later models are developed that predict schizophrenia from the occurrence of each of the specific autoimmune diseases. Separate prediction models are developed from the autoimmune status of the patients and from the parents of the patients to suggest effects of genetics as distinct from environment.

Results

Abstract  |  Method  |  Results  |  Discussion  |  References  
Description: http://ajp.psychiatryonline.org/Images/icons/article_section_previous.pngDescription: http://ajp.psychiatryonline.org/Images/icons/article_section_next.png
There were 29 autoimmune diseases with which either the patient or a parent was diagnosed before the patient had been diagnosed with schizophrenia. t1 shows prevalence data. There were 175, 16, and two patients with one, two, and three autoimmune diseases, respectively. Schizophrenia was associated with nearly 50% higher lifetime prevalence of one or more autoimmune disorders (t2). The analysis in t2 adjusts for known risk factors for schizophrenia (as well as controlling for sex and age in the matching process), revealing relationships that mirror the scientific literature R1633CJHHBACI.
Nine autoimmune diseases had higher lifetime prevalence among schizophrenia patients than among comparison subjects at a 95% level of statistical significance: thyrotoxicosis, intestinal malabsorption, acquired hemolytic anemia, chronic active hepatitis, interstitial cystitis, alopecia areata, myositis, polymyalgia rheumatica, and Sjögren’s syndrome (t3). Two disorders had sizable incidence rate ratios but did not meet traditional levels of significance: thyroiditis (incidence rate ratio=3.3) and ankylosing spondylitis (incidence rate ratio=2.7). Even so-called significant findings were based on small numbers: a single case of Sjögren’s disorder produced the incidence rate ratio of 12.5; likewise three cases of acquired hemolytic anemia produced the large incidence rate ratio of 12.5.
Twelve autoimmune diseases had higher prevalence among parents of schizophrenia patients than among parents of comparison subjects: thyrotoxicosis, thyroiditis, type 1 diabetes, intestinal malabsorption, pernicious anemia, acquired hemolytic anemia, interstitial cystitis, psoriasis, seropositive rheumatoid arthritis, other rheumatoid arthritis, dermatomyositis, and Sjögren’s syndrome (t4). Chronic active hepatitis, alopecia areata, myositis, and polymyalgia rheumatica were autoimmune disorders with higher prevalences than expected in the schizophrenia patients but not in their parents.

Discussion

Abstract  |  Method  |  Results  |  Discussion  |  References  
Description: http://ajp.psychiatryonline.org/Images/icons/article_section_previous.pngDescription: http://ajp.psychiatryonline.org/Images/icons/article_section_next.png
Five autoimmune disorders appeared more frequently in patients with schizophrenia prior to schizophrenia onset as well as in the patients’ parents: thyrotoxicosis, intestinal malabsorption, acquired hemolytic anemia, interstitital cystitis, and Sjögren’s syndrome.
The relationship between intestinal malabsorption, or celiac disease, and schizophrenia was noticed as early as 1961 R1633CJHBHIJC. Celiac disease is an immune-mediated reaction to gluten that presents with diarrhea, weight loss, and abdominal complaints as well as a range of less common signs and symptoms, including some psychiatric and neurological symptoms R1633CJHGGBDD, R1633CJHGBDEJ. The psychological interpretation for the first case series was reinterpreted by Dohan R1633CJHECIAJ as an inherited defect in which the environmental trigger of gluten precipitated schizophrenia in some individuals. Dohan presented two series of ecological data supporting the idea: one temporal series from countries in Europe during World War II R1633CJHECIAJ and a number of comparisons in the western Pacific based on anthropological data R1633CJHGDGII. The literature includes case studies, biological explanations for the association, and clinical trials of gluten withdrawal (e.g., references R1633CJHGAJGCR1633CJHJEDIF. Data from the Oxford Record Linkage Study R1633CJHEIHJD revealed an odds ratio of about three for cross-sectional comorbidity of schizophrenia and celiac disease, and we have published a short report on celiac disease and schizophrenia that used a nearly identical dataset to this one R1633CJHBEJAJ.
Autoimmune thyroiditis is characterized by hypothyroidism with clinical manifestations of goiter and lymphocyte infiltration of the gland R1633CJHGJGGI. Thyrotoxicosis (Graves disease) causes sustained hyperthyroidism with clinical complications in thyroid-associated ophthalmology and dermopathy R1633CJHJCAAA. Kraepelin reported clinical observations of enlarged thyroid gland in dementia praecox R1633CJHJBAFD. Subsequent clinical evidence has shown an excess of thyroid hormone dysfunction in schizophrenia, and some have attributed these observations to dysfunction of the hypothalamus-pituitary-thyroid axis and neuroleptic medications R1633CJHCHDDCR1633CJHGFGHJ. Our findings on thyroid disorders confirm prior research R1633CJHCBDAA, R1633CJHIBHIA, R1633CJHCDDIE, R1633CJHHHFJG.
Acquired hemolytic anemia is the clinical manifestation of the production of antibodies against red blood cells R1633CJHCAIGB, R1633CJHDEDAJ. Our findings on acquired hemolytic anemia are consistent with a prior study R1633CJHCBDAA that showed an excess of hemolytic anemia in (just two) relatives of schizophrenia patients compared with the single instance in healthy subjects (odds ratio=2.02, 95% CI=0.11–121.6).
Interstitial cystitis is a bladder condition characterized by increased urinary frequency or pelvic pain R1633CJHJGIJF, R1633CJHEHAFA. Although interstitial cystitis has been recently genetically linked to panic disorder R1633CJHCHCAC, we are unaware of prior research linking it to schizophrenia. The causes and pathogenesis for interstitial cystitis are not known.
Sjögren’s syndrome is characterized by progressive destruction of the exocrine glands, manifesting in a decrease in the production of saliva and tears R1633CJHFEFBG. Sjögren’s syndrome generally affects women, and the estimated prevalence varies from approximately 0.1%–6% R1633CJHJFIBIR1633CJHBCIBA. It sometimes occurs with other rheumatic disorders such as systemic lupus erythematosus, but we are unaware of any prior research linking it to schizophrenia.
This analysis does not support certain results in the epidemiologic literature on schizophrenia. For example, two studies have reported an excess of type I diabetes in the relatives of individuals with schizophrenia R1633CJHCBDAA, R1633CJHHHFJG, consistent with the data reported here in t4; other studies, however, have reported a negative association between the two disorders R1633CJHFGECG.
The most consistent finding in the area of schizophrenia and autoimmune diseases is the negative relationship with rheumatoid arthritis R1633CJHCGGIH, R1633CJHBBJGJ, R1633CJHHHCFB. The incidence rate ratio for the schizophrenia patients was very close to 1.0 in this analysis, whereas in most other studies rheumatoid arthritis is much less common in individuals with schizophrenia. Our analysis required that the rheumatoid arthritis appear before the patient was diagnosed with schizophrenia, which may have influenced this result, since many cases of rheumatoid arthritis have onset much later than the age at onset for schizophrenia. The incidence rate ratio for parents of schizophrenia patients was greater than 1.0, contrary to the expected direction. There are two small studies of rheumatoid arthritis in the mothers of schizophrenia patients R1633CJHCBDAA, R1633CJHFFADF, which suggest an inverse relationship.

Parallel Genetic Studies of Schizophrenia and Autoimmune Diseases

One of the possible hypotheses for our observed results is that schizophrenia shares a genetic diathesis with the family of autoimmune diseases, yielding the nearly 50% increase in risk for other autoimmune disorders as shown in t2. For example, Becker and colleagues R1633CJHDACFH hypothesized that common complex diseases may be a result of the collective effects of disease-specific loci, common nondisease-specific loci, and specific environmental triggers, the so-called common variants/multiple diseases hypothesis. This contrasts slightly with the notion that a single or limited number of genes specific to each autoimmune disorder might be associated with schizophrenia—straightforward pleiotropy R1633CJHDCIBH. The data relevant to these hypotheses, for the most part, come from separate, parallel genetic research studies of specific disorders. For autoimmune diseases, a source of general vulnerability may be the HLA system. Association studies have highlighted the role of HLA genes for certain autoimmune diseases R1633CJHBDFIH, R1633CJHCFHED. Case/control and family studies suggest that genes in HLA class II regions (e.g., HLA-DR3, DQA1, DRB1) are related to thyrotoxicosis and thyroiditis R1633CJHBDFIH, but the evidence is limited R1633CJHDGJHE. Several studies have suggested the HLA-related susceptibility for celiac disease lies in the DQ alleles R1633CJHGCHEH, R1633CJHJDHGD, but there is some evidence for linkage with other HLA regions R1633CJHJIHHE, R1633CJHGDBFE. There is a line of research on HLA class II (e.g., DQA, DRB1, and DQB1) in relation to the primary Sjögren’s syndrome R1633CJHHJBAIR1633CJHDHADG. Little is known about associations linking HLA and interstitial cystitis. The epidemiologic association between all these disorders could be a result of 1) direct involvement of HLA antigens or 2) physical closeness between loci for the autoimmune disorders and schizophrenia loci in HLA regions.
Outside the HLA region, the search for variants for common autoimmune diseases has not, as yet, suggested many clusters related to schizophrenia R1633CJHJDJAE. An exception is that linkage studies have suggested that schizophrenia and celiac disease may have genes that are close to each other or identical R1633CJHJDHII, R1633CJHECCDI. Another exception is that the HOPA (human opposite paired) gene on chromosome Xq13, which codes for a coactivator for the T4 receptor and in which mutations have been found associated with hypothyroidism R1633CJHIJHAA, has recently been linked with the elevated risk of schizophrenia R1633CJHDHDDD, R1633CJHHFHDH. Because the HOPA gene is expressed throughout the CNS and other tissues, especially in the period of fetal development, the abnormality in the HOPA gene is hypothesized to raise risk for schizophrenia. Separate association studies have connected the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene to schizophrenia R1633CJHFAABG and to rheumatoid arthritis R1633CJHCIIIB, and a similar pattern exists for the IL1B gene R1633CJHCAHDJ, R1633CJHHJHDC. The CTL-4 gene has been associated with schizophrenia in at least one study R1633CJHGDFBF, and with type 1 diabetes, autoimmune thyroid diseases, and rheumatoid arthritis in numerous studies R1633CJHDACFH. There have also been suggestive association study findings for the IL10 gene R1633CJHGDFGJ and type 1 diabetes, rheumatoid arthritis, and Sjögren’s syndrome R1633CJHDACFH as well as for the TNF gene R1633CJHHCBEB and psoriasis, rheumatoid arthritis, and type 1 diabetes R1633CJHDACFH.

Limitations

These data suffer from important limitations. The rarity of the autoimmune disorders is problematic, even for this study that involved an entire nation. Ascertainment was based on diagnosis received in normal medical specialty settings. There is likely to be underascertainment, since individuals with many of these disorders will not always be in attendance at a specialty clinic or inpatient setting. The argument could be made that schizophrenia, and many autoimmune diseases, are so serious that they inevitably end up in specialty treatment and the register system. But some diseases, such as hypothyroid disorder and type 1 diabetes, may be treated by primary care practitioners and never enter the registers. However, for any given disease, these biases would exist equally for patients and comparison subjects, and for parents of both groups; as a consequence the net effect is to lower the degree of association, making the findings conservative.
Another explanation for the low prevalence of autoimmune diseases is that many of them have onset later than schizophrenia, so that the prevalence in patients is much lower than what might be expected. These findings—even findings on parents of patients—may be limited to a subset of autoimmune diseases that have early onset. This possibility cannot be addressed with these data. Another limitation of the present study is the fact that the analyses were carried out in subjects matched by gender, making it impossible to examine gender-related differences, even though the etiology of autoimmune diseases and of schizophrenia probably differ by sex R1633CJHFHDCJ, R1633CJHEHJJH. Finally, we cannot be certain that treatment for autoimmune disease is not a risk factor for schizophrenia.
Conclusions from these analyses, especially when the focus is on individual disorders, must necessarily be circumspect because of the opportunistic nature of the statistical analysis. Results reviewed from genetic association and linkage studies likewise are suggestive at best. On the other hand, findings concerning celiac disease and autoimmune thyroid diseases are consistent with the scientific literature, and this analysis is a confirmation based on a stronger dataset than has existed before. In future clinical studies it may be interesting to search for a family history of autoimmune diseases, and specific autoantibodies, in patients with schizophrenia. Eventually, individual or family disease comorbidity may help to elucidate shared etiologic pathways.
 
 







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