血管痉挛型心绞痛(VSA)是冠状动脉的血管痉挛,在东亚人群中尤为普遍。然而,尚不完全了解全基因组水平VSA的特定遗传结构.
■确定与VSA相关的遗传因素。
■这是VSA的病例对照全基因组关联研究。使用来自日本生物银行的数据(BBJ;2002-2008年和2013-2018年的入选患者),纳入无冠状动脉疾病(CAD)的对照组。使用阵列或一组阵列对来自BBJ的患者进行基因分型。在2002年至2005年之间招募的患者被分类在第一个数据集中,2006年至2008年期间招募的人员被分类在第二个数据集中.为了在第一个和第二个数据集中复制全基因组关联研究,在第三个数据集中分析了2013年至2018年期间招募的BBJ最新患者的VSA病例和对照样本。
■与VSA相关的单核苷酸变体。
■带VSA和不带CAD的对照的病例。
■共5720例(平均[SD]年龄,67[10]岁;3672名男性[64.2%])和153864名对照(平均[SD]年龄,62[15]岁;77362名男性[50.3%])在3个数据集中被纳入本研究。RNF213基因座的变体在3个数据集上显示出与VSA的最强关联(比值比[OR],2.34;95%CI,1.99-2.74;P=4.4×10-25)。此外,rs112735431,一种亚洲特有的罕见有害变体(第Arg4810Lys)实验证明与血管生成减少有关,并且众所周知的烟雾病的因果风险是解释该关联的因果变异的最有希望的候选者。rs112735431对VSA的作用大小与其他CADs不同。此外,rs112735431的纯合携带者显示出与VSA的关联,其特征是具有较大的效应估计(OR,18.34;95%CI,5.15-65.22;P=7.0×10-6),偏离加法模型(OR,4.35;95%CI,1.18-16.05;P=0.03)。分层分析显示,rs112735431在男性(χ21=7.24;P=0.007)和较年轻的年龄组(OR,3.06;95%CI,2.24-4.19),与VSA的流行病学特征相对应。在注册表中,在随访期间,没有风险等位基因rs112735431的CAD的携带者由于急性心肌梗死而具有极高的死亡率(风险比,2.71;95%CI,1.57-4.65;P=3.3×10-4)。正如以前报道的那样,未发现VSA和烟雾病之间可能的重叠.
■这项研究的结果表明,由RNF213位点变异体介导的血管细胞功能障碍可能会促进冠状血管痉挛,风险等位基因的存在可以作为预后的预测因素。
UNASSIGNED: Vasospastic angina (VSA) is vasospasm of the coronary artery and is particularly prevalent in East Asian populations. However, the specific genetic architecture for VSA at genome-wide levels is not fully understood.
UNASSIGNED: To identify genetic factors associated with VSA.
UNASSIGNED: This was a case-control genome-wide association study of VSA. Data from Biobank Japan (BBJ; enrolled patients from 2002-2008 and 2013-2018) were used, and controls without coronary artery disease (CAD) were enrolled. Patients from the BBJ were genotyped using arrays or a set of arrays. Patients recruited between 2002 and 2005 were classified within the first dataset, and those recruited between 2006 and 2008 were classified within the second dataset. To replicate the genome-wide association study in the first and second datasets, VSA cases and control samples from the latest patients in the BBJ recruited between 2013 and 2018 were analyzed in a third dataset.
UNASSIGNED: Single-nucleotide variants associated with VSA.
UNASSIGNED: Cases with VSA and controls without CAD.
UNASSIGNED: A total of 5720 cases (mean [SD] age, 67 [10] years; 3672 male [64.2%]) and 153 864 controls (mean [SD] age, 62 [15] years; 77 362 male [50.3%]) in 3 datasets were included in this study. The variants at the RNF213 locus showed the strongest association with VSA across the 3 datasets (odds ratio [OR], 2.34; 95% CI, 1.99-2.74; P = 4.4 × 10-25). Additionally, rs112735431, an Asian-specific rare deleterious variant (p.Arg4810Lys) experimentally shown to be associated with reduced angiogenesis and a well-known causal risk for Moyamoya disease was the most promising candidate for a causal variant explaining the association. The effect size of rs112735431 on VSA was distinct from that of other CADs. Furthermore, homozygous carriers of rs112735431 showed an association with VSA characterized by a large effect estimate (OR, 18.34; 95% CI, 5.15-65.22; P = 7.0 × 10-6), deviating from the additive model (OR, 4.35; 95% CI, 1.18-16.05; P = .03). Stratified analyses revealed that rs112735431 exhibited a stronger association in males (χ21 = 7.24; P = .007) and a younger age group (OR, 3.06; 95% CI, 2.24-4.19), corresponding to the epidemiologic features of VSA. In the registry, carriers without CAD of the risk allele rs112735431 had a strikingly high mortality rate due to acute myocardial infarction during the follow-up period (hazard ratio, 2.71; 95% CI, 1.57-4.65; P = 3.3 × 10-4). As previously reported, a possible overlap between VSA and Moyamoya disease was not found.
UNASSIGNED: Results of this study suggest that vascular cell dysfunction mediated by variants in the RNF213 locus may promote coronary vasospasm, and the presence of the risk allele could serve as a predictive factor for the prognosis.