Identification of candidate loci at 6p21 and 21q22 in a genome-wide association study of cardiac manifestations of neonatal lupus.
Identification of candidate loci at 6p21 and 21q22 in a genome-wide association study of cardiac manifestations of neonatal lupus.
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DOI：
10.1002/art.27658
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发表时间：
2010-11
影响因子：
--
通讯作者：
Buyon, Jill P.
中科院分区：
文献类型：
--
作者：
Clancy, Robert M.;Marion, Miranda C.;Kaufman, Kenneth M.;Ramos, Paula S.;Adler, Adam;Harley, John B.;Langefeld, Carl D.;Buyon, Jill P.
新生儿狼疮的心脏表现包括房室传导缺陷和心肌病，发生在暴露于抗Ro/SSA抗体的胎儿中，并且死亡率很高。有强有力的证据表明，遗传因素对这种风险有贡献。本研究旨在评估单核苷酸多态性（SNPs）与新生儿心脏狼疮的相关性。使用Illumina 370 K SNP平台对患有心脏新生儿狼疮的欧洲血统儿童（n = 116）进行基因分型，并与3，351名对照合并。确定与新生儿心脏狼疮相关性的比值比（OR）和95%置信区间（95%CI）。在HLA区域发现了17个与心脏新生儿狼疮最显著的相关性。MICB基因附近的区域显示出最强的变异（rs3099844; Pdom = 4.52 × 10−10，OR 3.34 [95% CI 2.29-4.89]），其次是C6 orf 10内的错义变体（rs7775397; Pdom = 1.35 × 10−9，OR 3.30），位于NOTCH 4和BTNL 2之间，以及肿瘤坏死因子α基因附近的几个SNP，包括rs 2857595（Padd = 1.96 × 10−9，OR 2.37）、rs2230365（Padd = 1.00 × 10−3，OR 0.46）和rs3128982（Padd = 6.40 × 10−6，OR 1.86）。在HLA区域之外，在21 q22，转录调节因子ets相关亚型1的上游检测到相关性（rs743446; P = 5.45 × 10−6，OR 2.40）。尽管HLA，没有个别位点先前牵连在自身免疫性疾病实现全基因组意义。这些结果表明，与炎症和凋亡反应相关的基因附近的变异可能会促进被动获得的自身抗体引发的心脏损伤。
Cardiac manifestations of neonatal lupus, comprising atrioventricular conduction defects and cardiomyopathy, occur in fetuses exposed to anti-Ro/SSA antibodies, and carry substantial mortality. There is strong evidence of a genetic contribution to the risk. This study was undertaken to evaluate single-nucleotide polymorphisms (SNPs) for associations with cardiac neonatal lupus. Children of European ancestry with cardiac neonatal lupus (n = 116) were genotyped using the Illumina 370K SNP platform and merged with 3,351 controls. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for association with cardiac neonatal lupus were determined. The 17 most significant associations with cardiac neonatal lupus were found in the HLA region. The region near the MICB gene showed the strongest variant (rs3099844; Pdom = 4.52 × 10−10, OR 3.34 [95% CI 2.29–4.89]), followed by a missense variant within C6orf10 (rs7775397; Pdom = 1.35 × 10−9, OR 3.30), which lies between NOTCH4 and BTNL2, and several SNPs near the tumor necrosis factor α gene, including rs2857595 (Padd = 1.96 × 10−9, OR 2.37), rs2230365 (Padd = 1.00 × 10−3, OR 0.46), and rs3128982 (Padd = 6.40 × 10−6, OR 1.86). Outside the HLA region, an association was detected at 21q22, upstream of the transcription regulator ets-related isoform 1 (rs743446; P = 5.45 × 10−6, OR 2.40). HLA notwithstanding, no individual locus previously implicated in autoimmune diseases achieved genome-wide significance. These results suggest that variation near genes related to inflammatory and apoptotic responses may promote cardiac injury initiated by passively acquired autoantibodies.
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