Scientists funded by the National Institutes of Health, the Alliance for Lupus Research and Massachusetts General Hospital have discovered that rare variants of a gene that encodes the enzyme sialic acid acetylesterase (SIAE) are associated with several autoimmune diseases, especially rheumatoid arthritis and Type 1 diabetes. Their findings, published online in Nature, suggest that SIAE plays an important role in autoimmunity. They also highlight the promise that rare variant analysis holds for unraveling complex, multigene diseases.

The scientists, led by Shiv Pillai, M.D., Ph.D., of Massachusetts General Hospital in Boston, hypothesized that SIAE might be associated with autoimmunity in humans after the team discovered in an earlier study that mice engineered to be deficient in SIAE developed autoantibodies (antibodies that attack the body's own tissues instead of germs), one of the hallmarks of autoimmune disease.

After searching the literature and consulting colleagues in the field, Dr. Pillai's team recognized that genome-wide association scans — which reveal common, but not rare, variants — had not turned up any common variants of the SIAE gene in people with autoimmune diseases. Convinced there was a good chance SIAE was still relevant in autoimmunity, the researchers speculated that rare variants might play a role. To test for them, the team resequenced each of the 10 exons (or gene-coding regions) of the SIAE gene in more than 1,500 patients and controls, an arduous undertaking.

Through these efforts, the team identified rare and defective SIAE variants in only 2 of the 648 controls, whereas 24 of the 923 people with autoimmune diseases had defective variants. In all, the researchers found 11 defective, heterozygous, rare variants in 16 of those 24 people — "defective" because the gene produced inactive SIAE that failed to be released by cells, and "heterozygous" because a person only needs to inherit the variant from one parent for the defect to occur. Interestingly, the other eight had a homozygous defect in the SIAE gene, meaning the same variant had to be passed on by both parents for the enzyme defect to occur. (Finding one copy of the variant gene was common among the control group, too, but possessing just that single copy failed to result in defective SIAE behavior.)

Although the defective SIAE variants were most strongly associated with rheumatoid arthritis and Type 1 diabetes, the findings also suggested they probably play a role in other autoimmune diseases, such as systemic lupus erythematosus, multiple sclerosis and inflammatory bowel disease. The precise role that SIAE plays in the body is not clear, but the enzyme appears to help important immune system cells, called B cells, maintain their "tolerance" of the body's own proteins, meaning that they do not launch immune attacks against them.

"Our studies have examined how defective rare variants in a single gene may contribute to autoimmunity. It is likely that studies of the entire set of human genes will be conducted in the coming years in autoimmune diseases and other common complex genetic disorders. Variants in each gene will need to be analyzed using an approach broadly similar to what we have described," says Dr. Pillai.

Dr. Pillai and the study's other contributors were supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute of Allergy and Infectious Diseases, the National Institute of Neurological Disorders and Stroke, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Human Genome Research Institute.

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Surolia I, Pirnie SP, Chellappa V, Taylor KN, Cariappa A, Moya J, Liu H, Bell DW, Driscoll DR, Diederichs S, Haider K, Netravali I, Le S, Elia R, Dow E, Lee A, Freudenberg J, De Jager PL, Chretien Y, Varki A, MacDonald ME, Gillis T, Behrens TW, Bloch D, Collier D, Korzenik J, Podolsky DK, Hafler D, Murali M, Sands B, Stone JH, Gregersen PK, Pillai S. Functionally defective germline variants of sialic acid acetylesterase in autoimmunity. Nature. 2010 Jun 16. [Epub ahead of print] PubMed PMID: 20555325.

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