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Recent reports have associated  NCF2 , encoding a core component of the multi-protein NADPH oxidase (NADPHO), with systemic lupus erythematosus (SLE) susceptibility in individuals of European ancestry. To identify ethnicity-specific and -robust variants within  NCF2 , we assessed 145 SNPs in and around the  NCF2  gene in 5325 cases and 21 866 controls of European-American (EA), African-American (AA), Hispanic (HS) and Korean (KR) ancestry. Subsequent imputation, conditional, haplotype and bioinformatic analyses identified seven potentially functional SLE-predisposing variants. Association with non-synonymous rs17849502, previously reported in EA, was detected in EA, HS and AA ( P  EA  = 1.01 × 10 −54 ,  P  HS  = 3.68 × 10 −10 ,  P  AA  = 0.03); synonymous rs17849501 was similarly significant. These SNPs were monomorphic in KR. Novel associations were detected with coding variants at rs35937854 in AA ( P  AA  = 1.49 × 10 −9 ), and rs13306575 in HS and KR ( P  HS  = 7.04 × 10 −7 ,  P  KR  = 3.30 × 10 −3 ). In KR, a 3-SNP haplotype was significantly associated ( P  = 4.20 × 10 −7 ), implying that SLE predisposing variants were tagged. Significant SNP–SNP interaction ( P  = 0.02) was detected between rs13306575 and rs17849502 in HS, and a dramatically increased risk (OR = 6.55) with a risk allele at each locus. Molecular modeling predicts that these non-synonymous mutations could disrupt NADPHO complex assembly. The risk allele of rs17849501, located in a conserved transcriptional regulatory region, increased reporter gene activity, suggesting  in vivo  enhancer function. Our results not only establish allelic heterogeneity within  NCF2  associated with SLE, but also emphasize the utility of multi-ethnic cohorts to identify predisposing variants explaining additional phenotypic variance (‘missing heritability’) of complex diseases like SLE.

Allelic heterogeneity in NCF2 associated with systemic lupus erythematosus (SLE) susceptibility across four ethnic populations