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A substantial genetic contribution to systemic lupus erythematosus (SLE) risk is conferred by major histocompatibility complex (MHC) gene(s) on chromosome 6p21. Previous studies in SLE have lacked statistical power and genetic resolution to fully define MHC influences. We characterized 1,610 Caucasian SLE cases and 1,470 parents for 1,974 MHC SNPs, the highly polymorphic  HLA-DRB1  locus, and a panel of ancestry informative markers. Single-marker analyses revealed strong signals for SNPs within several MHC regions, as well as with  HLA-DRB1  (global p = 9.99×10 −16 ). The most strongly associated  DRB1  alleles were:  *0301  (odds ratio, OR = 2.21, p = 2.53×10 −12 ),  *1401  (OR = 0.50, p = 0.0002), and  *1501  (OR = 1.39, p = 0.0032). The MHC region SNP demonstrating the strongest evidence of association with SLE was rs3117103, with OR = 2.44 and p = 2.80×10 −13 . Conditional haplotype and stepwise logistic regression analyses identified strong evidence for association between SLE and the extended class I, class I, class III, class II, and the extended class II MHC regions. Sequential removal of SLE–associated  DRB1  haplotypes revealed independent effects due to variation within  OR2H2  (extended class I, rs362521, p = 0.006),  CREBL1  (class III, rs8283, p = 0.01), and  DQB2  (class II, rs7769979, p = 0.003, and rs10947345, p = 0.0004). Further, conditional haplotype analyses demonstrated that variation within  MICB  (class I, rs3828903, p = 0.006) also contributes to SLE risk independent of  HLA-DRB1*0301 . Our results for the first time delineate with high resolution several MHC regions with independent contributions to SLE risk. We provide a list of candidate variants based on biologic and functional considerations that may be causally related to SLE risk and warrant further investigation.

plos genetics

High-Density SNP Screening of the Major Histocompatibility Complex in Systemic Lupus Erythematosus Demonstrates Strong Evidence for Independent Susceptibility Regions