ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2279

Genetic Markers for Circulating Vitamin D and the Associations with Risk of Systemic Lupus Erythematosus

Linda T. Hiraki1, Adrienne H. Williams2, Arun-Prasad Manoharan3, Peter Kraft4, Carl D. Langefeld5, Robert R. Graham6 and Elizabeth W. Karlson7, 1Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard School of Public Health, Boston, MA, 2Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, 3Genentech, Inc., 4Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, MA, 5Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, 6ITGR Human Genetics, Genentech, Inc., South San Francisco, CA, 7Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: , ,

Session Information

Title: Systemic Lupus Erythematosus - Human Etiology and Pathogenesis

Session Type: Abstract Submissions (ACR)

Background/Purpose: Systemic lupus erythematosus (SLE) is a complex, life threatening autoimmune disease and a presumed consequence of susceptibility genes interacting with environmental exposures. Vitamin D deficiency has been implicated as an etiologic factor in several autoimmune diseases including SLE. Studies of common single nucleotide polymorphisms (SNPs) in the genes influencing circulating 25-hydroxyvitamin D (25(OH)D) levels (eg: vitamin D receptor, the 1-alpha hydroxylase enzyme and vitamin D binding protein) have demonstrated associations with type 1 diabetes, autoimmune thyroid disease and multiple sclerosis. Few studies to date have examined these genes in predicting SLE. We hypothesized that variations in vitamin D related genes are associated with SLE susceptibility.

Methods: Vitamin D associated SNPs were identified and meta-analyzed from SLE genome wide association studies (GWAS) in two large consortia, the International Consortium on the Genetics of Systemic Lupus Erythematosus (SLEGEN) (720 cases, 2302 controls) and Genentech (1225 cases and 4683 controls). Genotyping was done using the Illumina 550K among Genentech individuals and the Illumina 317K in SLEGEN. We imputed 550K SNPs among SLEGEN individuals using Impute and retained those SNPs with a confidence score > 0.9 and an information score > 0.5. We examined individual SNP associations with SLE risk as well as a genetic risk score (GRS) comprised of four 25(OH)D GWAS associated SNPs (rs2282679, rs3829251, rs2060793, rs6013897) in GC, DHCR7/NADSYN1, CYP2R1, CYP24A1genes. We meta-analyzed individual study results using an inverse variance weighted approach, as implemented in the software METAL. We performed gene based tests of 29 vitamin D associated genes identified by literature review, using the versatile gene-based association study (VEGAS).

Results: We did not observe a significant association between four 25(OH)D GWAS associated SNPs and SLE or with an additive GRS comprised of those 4 SNPs (OR 0.99 (95% CI  0.93, 1.07)). Of the 29 vitamin D genes interrogated using VEGAS, TNF was found to be significantly associated (p<10-5), as was CASR (p=0.002), SHBG (p=0.003), MED1 (p=0.02) and SMAD3 (p=0.03). However the four GWAS significant 25(OH)D gene regions were not found to be statistically significantly associated with SLE.

Conclusion: We did not observe a direct association between genetic markers of vitamin D and SLE risk. Further investigation into the mechanism by which vitamin D acts on SLE disease risk would provide insight into the pathogenesis and progression of disease.

Disclosure:

L. T. Hiraki,
None;

A. H. Williams,
None;

A. P. Manoharan,

Genentech and Biogen IDEC Inc.,

3;

P. Kraft,
None;

C. D. Langefeld,
None;

R. R. Graham,

Genentech and Biogen IDEC Inc.,

3;

E. W. Karlson,
None.

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