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

Research output: Contribution to journalArticle

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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 (US)
Article numberddt532
Pages (from-to)1656-1668
Number of pages13
JournalHuman Molecular Genetics
Volume23
Issue number6
DOIs
StatePublished - Mar 2014

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Systemic Lupus Erythematosus
Single Nucleotide Polymorphism
Hispanic Americans
African Americans
Population
NADPH Oxidase
Haplotypes
Alleles
Nucleic Acid Regulatory Sequences
Computational Biology
Reporter Genes
Mutation
Genes
Proteins

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Kim-Howard, X., Sun, C., Molineros, J. E., Maiti, A. K., Chandru, H., Adler, A., ... 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

Allelic heterogeneity in NCF2 associated with systemic lupus erythematosus (SLE) susceptibility across four ethnic populations. / 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; Sánchez, 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, S. S.; 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.; Alarcón-Riquelme, Marta; Acevedo, Eduardo; La Torre, Ignacio García De; Maradiaga-Ceceña, Marco A.; Cardiel, Mario H.; Esquivel-Valerio, Jorge A.; Rodriguez-Amado, Jacqueline; Moctezuma, José Francisco; Miranda, Pedro; Perandones, Carlos; Castel, Cecilia; Laborde, Hugo A.; Alba, Paula; Musuruana, Jorge; Goecke, Annelise; Foster, Carola; Orozco, Lorena; Baca, Vicente; Looger, Loren L.; Nath, Swapan K.

In: Human Molecular Genetics, Vol. 23, No. 6, ddt532, 03.2014, p. 1656-1668.

Research output: Contribution to journalArticle

Kim-Howard, X, Sun, C, Molineros, JE, Maiti, AK, Chandru, H, Adler, A, Wiley, GB, Kaufman, KM, Kottyan, L, Guthridge, JM, Rasmussen, A, Kelly, J, Sánchez, E, Raj, P, Li, QZ, Bang, SY, Lee, HS, Kim, TH, Kang, YM, Suh, CH, Chung, WT, Park, YB, Choe, JY, Shim, SC, Lee Shin-Seok, SS, Han, BG, Olsen, NJ, Karp, DR, Moser, K, Pons-Estel, BA, Wakeland, EK, James, JA, Harley, JB, Bae, SC, Gaffney, PM, Alarcón-Riquelme, M, Acevedo, E, La Torre, IGD, Maradiaga-Ceceña, MA, Cardiel, MH, Esquivel-Valerio, JA, Rodriguez-Amado, J, Moctezuma, JF, Miranda, P, Perandones, C, Castel, C, Laborde, HA, Alba, P, Musuruana, J, Goecke, A, Foster, C, Orozco, L, Baca, V, Looger, LL & Nath, SK 2014, 'Allelic heterogeneity in NCF2 associated with systemic lupus erythematosus (SLE) susceptibility across four ethnic populations', Human Molecular Genetics, vol. 23, no. 6, ddt532, pp. 1656-1668. https://doi.org/10.1093/hmg/ddt532
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 ; Sánchez, 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, S. S. ; 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. ; Alarcón-Riquelme, Marta ; Acevedo, Eduardo ; La Torre, Ignacio García De ; Maradiaga-Ceceña, Marco A. ; Cardiel, Mario H. ; Esquivel-Valerio, Jorge A. ; Rodriguez-Amado, Jacqueline ; Moctezuma, José Francisco ; Miranda, Pedro ; Perandones, Carlos ; Castel, Cecilia ; Laborde, Hugo A. ; Alba, Paula ; Musuruana, Jorge ; Goecke, Annelise ; Foster, Carola ; Orozco, Lorena ; Baca, Vicente ; Looger, Loren L. ; Nath, Swapan K. / Allelic heterogeneity in NCF2 associated with systemic lupus erythematosus (SLE) susceptibility across four ethnic populations. In: Human Molecular Genetics. 2014 ; Vol. 23, No. 6. pp. 1656-1668.
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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.",
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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.

PY - 2014/3

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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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