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

Abstract

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 x 10(-54), PHS = 3.68 x 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 (PAA = 1.49 x 10(-9)), and

rs13306575 in HS and KR (P(HS) = 7.04 x 10(-7), P(KR) = 3.30 x 10(-3)). In KR, a

3-SNP haplotype was significantly associated (P = 4.20 x 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.