Population Health Research Institute, Hamilton Health Sciences, Hamilton, ON, Canada.
BMC Med Genet. 2012 Jul 18;13:56. doi: 10.1186/1471-2350-13-56.
Germline mutations of BRCA1/2 are associated with hereditary breast and ovarian cancer. Recent data suggests excess mortality in mutation carriers beyond that conferred by neoplasia, and recent in vivo and in vitro studies suggest a modulatory role for BRCA proteins in endothelial and cardiomyocyte function. We therefore tested the association of BRCA2 variants with clinical cardiovascular disease (CVD).
Using data from 1,170 individuals included in two multi-ethnic population-based studies (SHARE and SHARE-AP), the association between BRCA2 variants and CVD was evaluated. 15 SNPs in BRCA2 with minor allele frequencies (MAF) > 0.01 had been previously genotyped using the cardiovascular gene-centric 50 k SNP array. 115 individuals (9.8%) reported a CVD event, defined as myocardial infarction (MI), angina, silent MI, stroke, and angioplasty or coronary artery bypass surgery. Analyses were adjusted for age and sex. The SNPs rs11571836 and rs1799943 were subsequently genotyped using the MassARRAY platform in 1,045 cases of incident MI and 1,135 controls from the South Asian subset of an international case-control study of acute MI (INTERHEART), and rs11571836 was imputed in 4,686 cases and 4500 controls from the Pakistan Risk of Myocardial Infarction Study (PROMIS).
Two BRCA2 SNPs, rs11571836 and rs1799943, both located in untranslated regions, were associated with lower risk of CVD (OR 0.47 p = 0.01 and OR 0.56 p = 0.03 respectively) in the SHARE studies. Analysis by specific ethnicities demonstrated an association with CVD for both SNPs in Aboriginal People, and for rs11571836 only in South Asians. No association was observed in the European and Chinese subgroups. A non-significant trend towards an association between rs11571836 and lower risk of MI was observed in South Asians from INTERHEART [OR = 0.87 (95% CI: 0.75-1.01) p = 0.068], but was not evident in PROMIS [OR = 0.96 (95% CI: 0.90-1.03) p = 0.230]. Meta-analysis of both case-control studies resulted in a combined OR of 0.94 (95% CI: 0.89-1.004, p = 0.06).
Although there was an association between two SNPs in BRCA2 and CVD in a multi-ethnic population, these results were not replicated in two South Asian case-control studies of incident MI. Future studies exploring the association between BRCA variants and cardiovascular disorders are needed to clarify the role, if any, for BRCA variants in CVD pathogenesis.
BRCA1/2 的种系突变与遗传性乳腺癌和卵巢癌有关。最近的数据表明，突变携带者的死亡率超出了肿瘤导致的死亡率，最近的体内和体外研究表明 BRCA 蛋白在血管内皮和心肌细胞功能中具有调节作用。因此，我们检测了 BRCA2 变体与临床心血管疾病 (CVD) 的关联。
利用来自两项多民族人群为基础研究 (SHARE 和 SHARE-AP) 的 1170 名个体的数据，评估了 BRCA2 变体与 CVD 的关系。之前使用心血管基因中心 50 k SNP 阵列对 BRCA2 中 15 个 MAF>0.01 的 SNP 进行了基因分型。115 名个体（9.8%）报告了 CVD 事件，定义为心肌梗死 (MI)、心绞痛、无症状 MI、中风、血管成形术或冠状动脉旁路移植术。分析调整了年龄和性别。随后在南亚亚组的一项急性 MI 国际病例对照研究（INTERHEART）中对 1045 例新发 MI 病例和 1135 例对照使用 MassARRAY 平台对 rs11571836 和 rs1799943 进行了基因分型，并在巴基斯坦心肌梗死风险研究 (PROMIS) 中对 4686 例病例和 4500 例对照进行了 rs11571836 的推断。
两个 BRCA2 SNP，rs11571836 和 rs1799943，均位于非翻译区，与 SHARE 研究中的 CVD 风险降低相关（OR 0.47，p=0.01 和 OR 0.56，p=0.03）。按特定种族进行的分析表明，这两个 SNP 与原住民的 CVD 相关，而 rs11571836 仅与南亚人相关。在欧洲和中国人亚组中未观察到关联。在 INTERHEART 的南亚人群中，rs11571836 与 MI 风险降低呈非显著趋势相关 [OR=0.87（95%CI：0.75-1.01），p=0.068]，但在 PROMIS 中未观察到 [OR=0.96（95%CI：0.90-1.03），p=0.230]。两项病例对照研究的荟萃分析得出的合并 OR 为 0.94（95%CI：0.89-1.004，p=0.06）。
尽管在多民族人群中，BRCA2 的两个 SNP 与 CVD 之间存在关联，但在两项南亚新发 MI 的病例对照研究中并未复制这些结果。需要进一步的研究来探索 BRCA 变体与心血管疾病之间的关联，以阐明 BRCA 变体在 CVD 发病机制中的作用（如果有）。
