Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis
Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis
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DOI：
10.1016/s2213-2600(18)30409-0
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发表时间：
2019-03-01
影响因子：
76.2
通讯作者：
Winslow, Clayborne
中科院分区：
文献类型：
--
作者：
Rhodes, Christopher J.;Batai, Ken;Winslow, Clayborne
背景 罕见的遗传变异会导致肺动脉高压，但常见的遗传变异对疾病风险和自然病程的贡献尚不清楚。我们在大型国际队列中测试了肺动脉高压的全基因组关联，并评估了相关区域对结果的贡献。方法我们进行了两项独立的全基因组关联研究（GWAS）和肺动脉高压的荟萃分析。这些 GWAS 使用了四项国际病例对照研究的数据，涉及 11,744 名欧洲血统个体（包括 2085 名患者）。一个 GWAS 使用来自 5895 个全基因组序列的基因型，另一个 GWAS 使用来自另外 5849 个个体的基因分型阵列数据。通过荟萃分析寻求达到全基因组显着性的基因座的交叉验证。使用针对每个位点最显着变异进行校正的条件分析来解析多个关联的信号。我们对相关变异进行了功能注释，并测试了与生存持续时间的关联。全因死亡率是生存分析的主要终点。 结果 SOX17 附近的一个基因座（rs10103692，比值比 1.80 [95% CI 1.55-2.08]，p=5.13 x 10(-15)）和 HLA-DPA1 和 HLA-DPB1 中的第二个基因座（此处统称为 HLA-DPA1/DPB1； II类MHC区域内的rs2856830, 1.56 [1.42-1.71], p=7.65 x 10(-20))与肺动脉高压相关。 SOX17 基因座有两个与肺动脉高压相关的独立信号（rs13266183，1.36 [1.25-1.48]，p=1.69 x 10(-12)；和 rs10103692）。功能和表观基因组数据表明，SOX17 附近的风险变异通过内皮细胞中活跃的增强子改变基因调控。肺动脉高压风险变异决定了单倍型特异性增强子活性，并且 CRISPR 介导的增强子抑制降低了 SOX17 表达。 HLA-DPA1/DPB1 rs2856830 基因型与生存密切相关。尽管基线疾病严重程度相似，但 C/C 纯合基因型肺动脉高压患者的中位生存期为 T/T 基因型患者（6.97 年 [6.02-8.05]）的两倍（13.50 年 [95% CI 12.07 至 >13.50]）。 解释 这是第一项报告 SOX17 和HLA-DPA1/DPB1 中的 HLA-DPA1/DPB1 与肺动脉高压相关。 SOX17 功能受损在肺动脉高压中可能比 SOX17 罕见突变所暗示的更为常见。需要进一步的研究来确认 HLA 分型或 rs2856830 基因分型与生存之间的关联，并确定 HLA 分型或 rs2856830 基因分型是否可以改善临床实践或试验中的风险分层。
Background Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes.Methods We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses.Findings A locus near SOX17 (rs10103692, odds ratio 1.80 [95% CI 1.55-2.08], p=5.13 x 10(-15)) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1.56 [1.42-1.71], p=7.65 x 10(-20)) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1.36 [1.25-1.48], p=1.69 x 10(-12); and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13.50 years [95% CI 12.07 to >13.50]) that of those with the T/T genotype (6.97 years [6.02-8.05]), despite similar baseline disease severity.Interpretation This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials.