Differential Genetic Associations for Systemic Lupus Erythematosus Based on Anti-dsDNA Autoantibody Production

被引：173

作者：

Chung, Sharon A. ^{[1
]}

Taylor, Kimberly E. ^{[1
]}

Graham, Robert R. ^{[2
]}

Nititham, Joanne ^{[1
]}

Lee, Annette T. ^{[3
]}

Ortmann, Ward A. ^{[2
]}

Jacob, Chaim O. ^{[4
]}

Alarcon-Riquelme, Marta E. ^{[5
,6
,7
]}

Tsao, Betty P. ^{[8
]}

Harley, John B. ^{[9
,10
]}

Gaffney, Patrick M. ^{[7
]}

Moser, Kathy L. ^{[7
]}

Petri, Michelle ^{[11
]}

Demirci, F. Yesim ^{[12
]}

Kamboh, M. Ilyas ^{[12
]}

Manzi, Susan ^{[13
]}

Gregersen, Peter K. ^{[3
]}

Langefeld, Carl D. ^{[14
]}

Behrens, Timothy W. ^{[2
]}

Criswell, Lindsey A. ^{[1
]}

机构：

[1] Univ Calif San Francisco, Dept Med, Rosalind Russell Med Res Ctr Arthrit, San Francisco, CA 94143 USA

[2] Genentech Inc, ITGR Human Genet, San Francisco, CA USA

[3] Feinstein Inst Med Res, Robert S Boas Ctr Genom & Human Genet, Manhasset, NY USA

[4] Univ So Calif, Keck Sch Med, Dept Med, Los Angeles, CA 90033 USA

[5] Uppsala Univ, Dept Genet & Pathol, Uppsala, Sweden

[6] Pfizer Univ Granada Junta de Andalucia, Andalusian Ctr Genom & Oncol Res, Granada, Spain

[7] Oklahoma Med Res Fdn, Arthrit & Immunol Res Program, Oklahoma City, OK 73104 USA

[8] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA

[9] US Dept Vet Affairs Med Ctr, Cincinnati, OH USA

[10] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA

[11] Johns Hopkins Univ Sch Med, Div Rheumatol, Baltimore, MD USA

[12] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA

[13] Allegheny Singer Res Inst, Pittsburgh, PA 15212 USA

[14] Wake Forest Univ Hlth Sci, Dept Biostat Sci, Wake Forest, NC USA

来源：

PLOS GENETICS | 2011年 / 7卷 / 03期

关键词：

GENOME-WIDE ASSOCIATION; RHEUMATOID-ARTHRITIS; REVISED CRITERIA; RISK; CLASSIFICATION; HAPLOTYPE; ALLELES; ITGAM; STAT4;

D O I：

10.1371/journal.pgen.1001323

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Systemic lupus erythematosus (SLE) is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS) have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti-dsDNA autoantibody production, a SLE-related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs) were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti-dsDNA autoantibody positive (anti-dsDNA +, n = 811) and anti-dsDNA autoantibody negative (anti-dsDNA -, n = 906) SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti-dsDNA + SLE. Far fewer and weaker associations were observed for anti-dsDNA - SLE. For example, rs7574865 in STAT4 had an OR for anti-dsDNA + SLE of 1.77 (95% CI 1.57-1.99, p = 2.0E-20) compared to an OR for anti-dsDNA - SLE of 1.26 (95% CI 1.12-1.41, p = 2.4E-04), with (Pheterogeneity)<0.0005. SNPs in the SLE susceptibility loci BANK1, KIAA1542, and UBE2L3 showed evidence of association with anti-dsDNA + SLE and were not associated with anti-dsDNA - SLE. In conclusion, we identified differential genetic associations with SLE based on anti-dsDNA autoantibody production. Many previously identified SLE susceptibility loci may confer disease risk through their role in autoantibody production and be more accurately described as autoantibody propensity loci. Lack of strong SNP associations may suggest that other types of genetic variation or non-genetic factors such as environmental exposures have a greater impact on susceptibility to anti-dsDNA - SLE.

引用

页数：11

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