Allelic heterogeneity in NCF2 associated with systemic lupus erythematosus (SLE) susceptibility across four ethnic populationsopen access
- Authors
- 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.; Wakeland, Edward K.; James, Judith A.; Harley, John B.; Bae, Sang-Cheol; Gaffney, Patrick M.; Alarcon-Riquelme, Marta; Looger, Loren L.; Nath, Swapan K.; Acevedo, Eduardo; La Torre, Ignacio Garcia-De; Maradiaga-Cecena, Marco A.; Cardiel, Mario H.; Esquivel-Valerio, Jorge A.; Rodriguez-Amado, Jacqueline; Moctezuma, Jose Francisco; Miranda, Pedro; Perandones, Carlos; Castel, Cecilia; Laborde, Hugo A.; Alba, Paula; Musuruana, Jorge; Goecke, Annelise; Foster, Carola; Orozco, Lorena; Baca, Vicente
- Issue Date
- Mar-2014
- Publisher
- OXFORD UNIV PRESS
- Citation
- HUMAN MOLECULAR GENETICS, v.23, no.6, pp.1656 - 1668
- Indexed
- SCIE
SCOPUS
- Journal Title
- HUMAN MOLECULAR GENETICS
- Volume
- 23
- Number
- 6
- Start Page
- 1656
- End Page
- 1668
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/26540
- DOI
- 10.1093/hmg/ddt532
- ISSN
- 0964-6906
- 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), 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 ('missing heritability') of complex diseases like SLE.
- Files in This Item
-
Go to Link
- Appears in
Collections - 서울 의과대학 > 서울 내과학교실 > 1. Journal Articles
![qrcode](https://api.qrserver.com/v1/create-qr-code/?size=55x55&data=https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/26540)
Items in ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.