Identification of a Systemic Lupus Erythematosus Risk Locus Spanning ATG16L2, FCHSD2, and P2RY2 in Koreans

Objective. Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder whose etiology is incompletely understood, but likely involves environmental triggers in genetically susceptible individuals. Using an unbiased genome-wide association (GWA) scan and replication analysis, we sought to identify the genetic loci associated with SLE in a Korean population. Methods. A total of 1,174 SLE cases and 4,246 population controls from Korea were genotyped and analyzed with a GWA scan to identify single-nucleotide polymorphisms (SNPs) significantly associated with SLE, after strict quality control measures were applied. For select variants, replication of SLE risk loci was tested in an independent data set of 1,416 SLE cases and 1,145 population controls from Korea and China. Results. Eleven regions outside the HLA exceeded the genome-wide significance level (P = 5 x 10(-8)). A novel SNP-SLE association was identified between FCHSD2 and P2RY2, peaking at rs11235667 (P = 1.03 x 10(-8), odds ratio [OR] 0.59) on a 33-kb haplotype upstream of ATG16L2. In the independent replication data set, the SNP rs11235667 continued to show a significant association with SLE (replication meta-analysis P = 0.001, overall meta-analysis P = 6.67 3 10(-11); OR 0.63). Within the HLA region, the SNP-SLE association peaked in the class II region at rs116727542, with multiple independent effects observed in this region. Classic HLA allele imputation analysis identified HLA-DRB1*1501 and HLA-DQB1*0602, each highly correlated with one another, as most strongly associated with SLE. Ten previously established SLE risk loci were replicated: STAT1-STAT4, TNFSF4, TNFAIP3, IKZF1, HIP1, IRF5, BLK, WDFY4, ETS1, and IRAK1-MECP2. Of these loci, previously unreported, independent second risk effects of SNPs in TNFAIP3 and TNFSF4, as well as differences in the association with a putative causal variant in the WDFY4 region, were identified. Conclusion. Further studies are needed to identify true SLE risk effects in other loci suggestive of a significant association, and to identify the causal variants in the regions of ATG16L2, FCHSD2, and P2RY2.Supported by grants from the NIH (5P01-AI-083194 to Drs. Lessard, Rasmussen, Gaffney, Alarcon-Riquelme, Criswell, Jacob, Kimberly, Vyse, Harley, Sivils, Langefeld, and Tsao; 5P01-AR-049084 to Drs. Kimberly and Langefeld; and R01-AR-043814 and R21-AR-065626 to Dr. Tsao), the Oklahoma Medical Research Foundation (to Drs. Lessard, Gaffney, and Sivils), the Alliance for Lupus Research (to Drs. Criswell and Tsao), and the Wake Forest School of Medicine Center for Public Health Genomics (to Dr. Langefeld). Dr. Criswell is recipient of a Kirkland Scholar Award. Sample collection and phenotyping of the subjects utilized in this study was funded by the Ministry for Health and Welfare, Republic of Korea (Korea Healthcare Technology R&D Project grant HI13C2124 to Dr. Bae, and HI13C1754 to Dr. Song). The out-of-study Korean control data were provided by the Korean Biobank Project, which is supported by the Korea Centers for Disease Control and Prevention at the Korea National Institute of Health