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

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 Sánchez, Prithvi Raj, Quan Zhen Li, So Young Bang, Hye Soon Lee, Tae Hwan Kim, Young Mo Kang, Chang Hee SuhWon Tae Chung, Yong Beom Park, Jung Yoon Choe, Seung Cheol Shim, S. S. Lee Shin-Seok, 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 Alarcón-Riquelme, Eduardo Acevedo, Ignacio García De La Torre, Marco A. Maradiaga-Ceceña, Mario H. Cardiel, Jorge A. Esquivel-Valerio, Jacqueline Rodriguez-Amado, José Francisco Moctezuma, Pedro Miranda, Carlos Perandones, Cecilia Castel, Hugo A. Laborde, Paula Alba, Jorge Musuruana, Annelise Goecke, Carola Foster, Lorena Orozco, Vicente Baca, Loren L. Looger, Swapan K. Nath

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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 (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.

Original languageEnglish
Article numberddt532
Pages (from-to)1656-1668
Number of pages13
JournalHuman molecular genetics
Volume23
Issue number6
DOIs
Publication statusPublished - 2014 Mar 1

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All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Kim-Howard, X., Sun, C., Molineros, J. E., Maiti, A. K., Chandru, H., Adler, A., Wiley, G. B., Kaufman, K. M., Kottyan, L., Guthridge, J. M., Rasmussen, A., Kelly, J., Sánchez, E., Raj, P., Li, Q. Z., Bang, S. Y., Lee, H. S., Kim, T. H., Kang, Y. M., ... Nath, S. K. (2014). Allelic heterogeneity in NCF2 associated with systemic lupus erythematosus (SLE) susceptibility across four ethnic populations. Human molecular genetics, 23(6), 1656-1668. [ddt532]. https://doi.org/10.1093/hmg/ddt532