By Bethann Hromatka
Autoimmune diseases are caused by an overactive immune system. In these diseases, white blood cells, which normally help your body fight infections, ramp up and attack your own cells and organs. These disorders can be very debilitating and are relatively common, affecting roughly 1 in 20 individuals. Some well-known examples include psoriasis, Crohn’s disease, celiac disease, multiple sclerosis, systemic lupus erythematosus (or lupus), type 1 diabetes, and rheumatoid arthritis. Although most of these disorders manifest in different parts of the body, all are characterized by excess inflammation.
Our understanding of the causes of immune disorders has been limited due to their complexity. These diseases are not caused by changes in a single gene, but are influenced by many genes as well as environmental and lifestyle factors. For example, mutations in at least 22 different genes have been linked to type 1 diabetes to date. At the same time, it is well known that non-genetic factors can increase or decrease a person’s risk of developing this disease.
An interesting observation about autoimmune diseases is that they tend to run in families. For instance, a mother with type 1 diabetes might have a daughter with celiac disease. Or, someone with Crohn’s disease might also develop celiac disease or psoriasis. There also appears to be a pharmacological link—for example the VGX™-1027 drug is used to treat both rheumatoid arthritis and type 1 diabetes. These observations have led researchers to wonder if there could be a common genetic basis to autoimmune diseases.
A recent study published in PLoS Genetics on behalf of the FOCiS Network of Consortia tested this very hypothesis: do some mutations put an individual at risk for more than one autoimmune disease? To address this question, the researchers looked at previously published genome wide association studies (GWAS) and compiled a list of 107 SNPs1 that associated with at least one of seven immune diseases. Then, they applied a new statistical method to identify SNP versions that were linked to multiple autoimmune diseases.
The authors reported that nearly half of the SNPs influenced risk for at least two autoimmune diseases. In most cases, the same version of the SNP was associated with higher risk for each disease. For example, the T version at rs6441961, the G version at rs1893217, and the A version at rs3821236 are associated with higher odds for multiple diseases (see table at the end of this post for details). Interestingly, 9 SNPs (including rs6822844, rs2476601, rs3087243, rs2082412) were simultaneously associated with higher odds for one disease and lower odds for a different disease. One SNP—rs3184504 in the SH2B3 gene—was associated to varying degrees with all seven diseases; the C version was risky for celiac disease and multiple sclerosis, but protective for psoriasis, rheumatoid arthritis, lupus, Crohn’s disease and type 1 diabetes.
(23andMe customers can view their data for these SNPs and results for available Health reports in their accounts using the table at the end of this post.)
The authors also found that certain SNPs grouped together based on their disease associations. For example, SNPs associated with both Crohn’s disease and psoriasis formed a distinct cluster and those linked to both rheumatoid arthritis and type 1 diabetes also comprised a distinct cluster. In many cases, SNPs in a particular group were located in genes involved in the same biological processes. These results suggest that shared genetic factors can point to the underlying cellular pathways that are disrupted in different classes of immune disorders.
These findings are exciting because they point to a common genetic basis to autoimmune diseases. Understanding the genetic relatedness of diseases could help researchers develop new therapies to target common cellular pathways or redirect currently available treatments to a genetically related disease. Similarly, the approach used in this paper could be applied to other classes of complex diseases, such as psychiatric disorders, to determine if they also share common genetic components.
Table: SNPs associated with multiple autoimmune diseases
|SNP||Gene Region||Version||Increased Risk||Decreased Risk||Relevant 23andMe Health Reports|
|rs6441961||CCR1||T||Celiac Disease, Type 1 Diabetes||Celiac Disease|
|rs1893217||PTPN2||G||Rheumatoid Arthritis, Crohn’s Disease, Celiac Disease, Type 1 Diabetes||Crohn’s Disease, Type 1 Diabetes|
|rs3821236*||STAT4||A||Rheumatoid Arthritis, Lupus, Type 1 Diabetes||Lupus, Rheumatoid Arthritis|
|rs1990760||IFIH1||C||Lupus, Type 1 Diabetes||Type 1 Diabetes, Selective IgA Deficiency|
|rs6822844||IL2-IL21||T||Rheumatoid Arthritis||Celiac Disease||Celiac Disease|
|rs2476601||PTPN22||A||Rheumatoid Arthritis, Lupus,Type 1 Diabetes||Crohn’s Disease||Rheumatoid Arthritis, Type 1 Diabetes, Hashimoto’s Thyroiditis, Generalized Vitiligo|
|rs3087243||CTLA4||A||Celiac Disease||Rheumatoid Arthritis, Type 1 Diabetes||Type 1 Diabetes|
|rs3212227**||IL12B||T||Psoriasis, Lupus||Crohn’s Disease||Psoriasis|
|rs3184504||SH2B3||C||Multiple Sclerosis, Celiac Disease||Rheumatoid Arthritis, Lupus, Crohn’s Disease, Type 1 Diabetes||Type 1 Diabetes|
* rs3821236 is highly correlated with rs7574865, which is mentioned in the Lupus and Rheumatoid Arthritis Established Research reports
**rs3212227 is equivalent to rs2082412 reported in the study.
1 The authors did not include SNPs in the Major Histocompatibility Complex (MHC), which contains genes for proteins used by the immune system to recognize foreign molecules. Variations in this region of the genome are already established as being linked to multiple immune diseases.
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SNPwatch: Three New Genetic Variants Associated With Rheumatoid Arthritis Risk
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