TY - JOUR
T1 - Allelic heterogeneity in NCF2 associated with systemic lupus erythematosus (SLE) susceptibility across four ethnic populations
AU - Kim-Howard, Xana
AU - Sun, Celi
AU - Molineros, Julio E.
AU - Maiti, Amit K.
AU - Chandru, Hema
AU - Adler, Adam
AU - Wiley, Graham B.
AU - Kaufman, Kenneth M.
AU - Kottyan, Leah
AU - Guthridge, Joel M.
AU - Rasmussen, Astrid
AU - Kelly, Jennifer
AU - Sánchez, Elena
AU - Raj, Prithvi
AU - Li, Quan Zhen
AU - Bang, So Young
AU - Lee, Hye Soon
AU - Kim, Tae Hwan
AU - Kang, Young Mo
AU - Suh, Chang Hee
AU - Chung, Won Tae
AU - Park, Yong Beom
AU - Choe, Jung Yoon
AU - Shim, Seung Cheol
AU - Lee Shin-Seok, S. S.
AU - Han, Bok Ghee
AU - Olsen, Nancy J.
AU - Karp, David R.
AU - Moser, Kathy
AU - Pons-Estel, Bernardo A.
AU - Wakeland, Edward K.
AU - James, Judith A.
AU - Harley, John B.
AU - Bae, Sang Cheol
AU - Gaffney, Patrick M.
AU - Alarcón-Riquelme, Marta
AU - Acevedo, Eduardo
AU - La Torre, Ignacio García De
AU - Maradiaga-Ceceña, Marco A.
AU - Cardiel, Mario H.
AU - Esquivel-Valerio, Jorge A.
AU - Rodriguez-Amado, Jacqueline
AU - Moctezuma, José Francisco
AU - Miranda, Pedro
AU - Perandones, Carlos
AU - Castel, Cecilia
AU - Laborde, Hugo A.
AU - Alba, Paula
AU - Musuruana, Jorge
AU - Goecke, Annelise
AU - Foster, Carola
AU - Orozco, Lorena
AU - Baca, Vicente
AU - Looger, Loren L.
AU - Nath, Swapan K.
N1 - Funding Information:
This work was supported by grants from the US National Institutes of Health (AI103399, AR060366, AI094377, AI083194, CA141700, AR058621, AI101934, AI082714, AR053483, GM103510, GM103456) and A121983, the Korea Healthcare Technology R&D Project, Ministry for Health & Welfare, Republic of Korea.
PY - 2014/3
Y1 - 2014/3
N2 - 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 (PEA = 1.01 × 10-54, PHS = 3.68 × 10-10, PAA = 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 (PHS = 7.04 × 10-7, PKR = 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.
AB - 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 (PEA = 1.01 × 10-54, PHS = 3.68 × 10-10, PAA = 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 (PHS = 7.04 × 10-7, PKR = 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.
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U2 - 10.1093/hmg/ddt532
DO - 10.1093/hmg/ddt532
M3 - Article
C2 - 24163247
AN - SCOPUS:84894384556
SN - 0964-6906
VL - 23
SP - 1656
EP - 1668
JO - Human molecular genetics
JF - Human molecular genetics
IS - 6
M1 - ddt532
ER -