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

作者：Kim Howard Xana; Sun Celi; Molineros Julio E; Maiti Amit K; Chandru Hema; Adler Adam; Wiley Graham B; Kaufman Kenneth M; Kottyan Leah; Guthridge Joel M; Rasmussen Astrid; Kelly Jennifer; Sanchez Elena; Raj Prithvi; Li Quan Zhen; Bang So Young; Lee Hye Soon; Kim Tae Hwan; Kang Young Mo; Suh Chang Hee; Chung Won Tae; Park Yong Beom; Choe Jung Yoon; Shim Seung Cheol; Lee Shin Seok; Han Bok Ghee; Olsen Nancy J; Karp David R; Moser Kathy; Pons Estel Bernardo A

来源：Human Molecular Genetics, 2014, 23(6): 1656-1668.

DOI：10.1093/hmg/ddt532

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), P-HS = 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 (P-AA = 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, a3-SNP haplotype was significantly associated (P 5 4.20 3 10 27), implying that SLE predisposing variants were tagged. Significant SNP-SNP interaction (P 5 0.02) was detected between rs13306575 and rs17849502 in HS, and adramatically increased risk(OR 5 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 (%26apos;missing heritability%26apos;) of complex diseases like SLE.

• 出版日期2014-3-15