Journal Article

Risk Alleles for Systemic Lupus Erythematosus in a Large Case-Control Collection and Associations with Clinical Subphenotypes

Harley, John B., Lee, Annette T., Petri, Michelle, Gregersen, Peter K., Alarcón-Riquelme, Marta E., Taylor, Kimberly E., Chung, Sharon A., Jacob, Chaim O., Langefeld, Carl D., Gaffney, Patrick M., Graham, Robert R., Manzi, Susan, Behrens, Timothy W., Criswell, Lindsey A., Moser, Kathy L., Ortmann, Ward A., Kamboh, M. Ilyas, Tsao, Betty P.

2011

Overview

Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. Recent studies have greatly expanded the number of established SLE risk alleles, but the distribution of multiple risk alleles in cases versus controls and their relationship to subphenotypes have not been studied. We studied 22 SLE susceptibility polymorphisms with previous genome-wide evidence of association (p < 5 x 10⁻¹²⁸) in 1919 SLE cases from 9 independent Caucasian SLE case series and 4813 independent controls. The mean number of risk alleles in cases was 15.1 (SD 3.1) while the mean in controls was 13.1 (SD 2.8), with trend p = 4 x 10⁻⁸. We defined a genetic risk score (GRS) for SLE as the number of risk alleles with each weighted by the SLE risk odds ratio (OR). The OR for high-low GRS tertiles, adjusted for intra-European ancestry, sex, and parent study, was 4.4 (95% CI 3.8-5.1). We studied associations of individual SNPs and the GRS with clinical manifestations for the cases: age at diagnosis, the 11 American College of Rheumatology classification criteria, and double-stranded DNA antibody (anti-dsDNA) production. Six subphenotypes were significantly associated with the GRS, most notably anti-dsDNA (OR(high-low) = 2.36, p = 9e-9), the immunologic criterion (OR(high-low) = 2.23, p = 3e-7), and age at diagnosis (OR(high-low) = 1.45, p = 0.0060). Finally, we developed a subphenotype-specific GRS (sub-GRS) for each phenotype with more power to detect cumulative genetic associations. The sub-GRS was more strongly associated than any single SNP effect for 5 subphenotypes (the above plus hematologic disorder and oral ulcers), while single loci are more significantly associated with renal disease (HLA-DRB1, OR = 1.37, 95% CI 1.14-1.64) and arthritis (ITGAM, OR = 0.72, 95% CI 0.59-0.88). We did not observe significant associations for other subphenotypes, for individual loci or the sub-GRS. Thus our analysis categorizes SLE subphenotypes into three groups: those having cumulative, single, and no known genetic association with respect to the currently established SLE risk loci.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Alleles / Antibodies, Antinuclear - immunology / Area Under Curve / Autoimmune diseases / Case-Control Studies / Female / Genetic aspects / Genetic Predisposition to Disease / Genetic susceptibility / Genetics and Genomics/Complex Traits / Genetics and Genomics/Disease Models / Genetics and Genomics/Genetics of Disease / Genetics and Genomics/Genetics of the Immune System / Humans / Kidney diseases / Logistic Models / Lupus / Lupus Erythematosus, Systemic - genetics / Lupus Erythematosus, Systemic - immunology / Lupus Erythematosus, Systemic - pathology / Male / Models, Genetic / Odds Ratio / Phenotype / Polymorphism, Single Nucleotide - genetics / Principal Component Analysis / Reproducibility of Results / Rheumatology/Autoimmunity, Autoimmune, and Inflammatory Diseases / Rheumatology/Systemic Lupus Erythematosos / Risk factors / ROC Curve / Studies / Systemic lupus erythematosus