Allelic heterogeneity in NCF2 associated with systemic lupus erythematosus (SLE) susceptibility across four ethnic populations
Allelic heterogeneity in NCF2 associated with systemic lupus erythematosus (SLE) susceptibility across four ethnic populations
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DOI：
10.1093/hmg/ddt532
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发表时间：
2014-03-15
影响因子：
3.5
通讯作者：
Baca, Vicente
中科院分区：
文献类型：
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作者：
Kim-Howard, Xana;Sun, Celi;Baca, Vicente
最近的报告表明，编码多蛋白 NADPH 氧化酶 (NADPHO) 核心成分的 NCF2 与欧洲血统个体的系统性红斑狼疮 (SLE) 易感性相关。为了识别NCF2内种族特异性和稳健的变异，我们评估了5325个病例和21866个欧洲裔美国人（EA）、非洲裔美国人（AA）、西班牙裔（HS）和韩国人（KR）血统的对照中NCF2基因内部和周围的145个SNP。随后的插补、条件、单倍型和生物信息学分析确定了七种潜在的功能性 SLE 易感变异。在 EA、HS 和 AA 中检测到与先前在 EA 中报道的非同义 rs17849502 的关联（P-EA = 1.01 x 10(-54)、P-HS = 3.68 x 10(-10)、P-AA = 0.03）；同义 rs17849501 也同样重要。这些 SNP 在 KR 中是单态的。在 AA 中的 rs35937854（P-AA = 1.49 x 10(-9)）以及 HS 和 KR 中的 rs13306575（P-HS = 7.04 x 10(-7)，P-KR = 3.30 x 10(-3)）的编码变异中检测到新的关联。在 KR 中，a3-SNP 单倍型显着相关 (P 5 4.20 3 10 27)，这意味着 SLE 易感变异体已被标记。在 HS 中，rs13306575 和 rs17849502 之间检测到显着的 SNP-SNP 相互作用 (P 5 0.02)，并且每个位点上的风险等位基因均显着增加风险 (OR 5 6.55)。分子模型预测这些非同义突变可能会破坏 NADPHO 复合物的组装。 rs17849501 的风险等位基因位于保守的转录调控区域，增加了报告基因的活性，表明体内增强子功能。我们的结果不仅建立了与 SLE 相关的 NCF2 内的等位基因异质性，而且还强调了多种族队列的实用性，以识别解释 SLE 等复杂疾病的额外表型变异（“缺失遗传性”）的易感变异。
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.