Allelic heterogeneity in NCF2 associated with systemic lupus erythematosus (SLE) susceptibility across four ethnic populations.
Authors
Xana Kim Howard ; Celi Sun ; Julio E. Molineros ; Amit K. Maiti ; Hema Chandru ; Adam Adler ; Graham B. Wiley ; Kenneth M. Kaufman ; Leah Kottyan ; Joel M. Guthridge ; Astrid Rasmussen ; Jennifer Kelly ; Elena Sa´nchez ; Prithvi Raj ; Quan Zhen Li ; So Young Bang ; Hye Soon Lee ; Tae Hwan Kim ; Young Mo Kang ; Chang Hee Suh ; Won Tae Chung ; Yong Beom Park ; Jung Yoon Choe ; Seung Cheol Shim ; Shin Seok Lee ; Bok Ghee Han ; Nancy J. Olsen ; David R. Karp ; Kathy Moser ; Bernardo A. Pons Estel ; Edward K. Wakeland ; Judith A. James ; John B. Harley ; Sang Cheol Bae ; Patrick M. Gaffney ; Marta Alarco´n Riquelme ; Loren L. Looger ; Swapan K. Nath
Citation
HUMAN MOLECULAR GENETICS, Vol.23(6) : 1656-1668, 2014
African Americans/genetics ; Asian Americans/genetics ; Computational Biology ; European Continental Ancestry Group/ethnology ; European Continental Ancestry Group/genetics ; Genetic Association Studies/methods* ; Genetic Heterogeneity ; Genetic Predisposition to Disease* ; Genetic Variation ; Haplotypes ; Hispanic Americans/genetics ; Humans ; Lupus Erythematosus, Systemic/ethnology* ; Lupus Erythematosus, Systemic/genetics* ; Models, Molecular ; NADPH Oxidases/genetics* ; Polymorphism, Single Nucleotide
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 × 10(-54), PHS = 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 (PAA = 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.