Admixture Mapping of Peripheral Artery Disease in a Dominican Population Reveals a Novel Risk Locus on 2q35.
Admixture Mapping of Peripheral Artery Disease in a Dominican Population Reveals a Novel Risk Locus on 2q35.
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多米尼加人群外周动脉疾病的混合图谱揭示了 2q35 上的新风险位点。
DOI：
10.1101/2023.03.27.23287788
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Kenny,EimearE
中科院分区：
文献类型：
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作者：
Cullina,Sinead;Wojcik,GenevieveL;Shemirani,Ruhollah;Klarin,Derek;Gorman,BryanR;Sorokin,ElenaP;Gignoux,ChristopherR;Belbin,GillianM;Pyarajan,Saiju;Asgari,Samira;Tsao,PhilS;Damrauer,ScottM;Abul-Husn,NouraS;Kenny,EimearE
外周动脉疾病（PAD）是动脉粥样硬化性心血管疾病的一种形式，影响了1800万美国人，并且已知具有种族和民族差异。据报道，与非西班牙裔欧洲裔美国人（EAs）相比，非裔美国人（AAs）的PAD患病率显著更高。据报道，西班牙裔/拉丁美洲人（HL）的PAD发生率低于或接近EA，尽管PAD风险因素负担高得令人费解;然而，最近的研究表明，亚组之间的患病率可能不同。在这里，我们研究了纽约市生物医学银行的一个大型群体的不同成年人。我们观察到EA中PAD的患病率为1.7%，而AA和HL分别为8.5%和9.4%，在HL亚组中，波多黎各和多米尼加人群的患病率分别为11.4%和11.5%。调整常见风险因素的随访分析表明，多米尼加人相对于EA，PAD的风险增加最高[OR = 3.15（95%CI 2.33-4.25），p< 6.44 × 10−14]。为了研究遗传因素是否可以解释这种增加的风险，我们进行了混合物映射，通过测试当地血统和PAD之间的关联，在多米尼加BioMeparticipants（N = 1,813）分别从欧洲，非洲和美洲原住民（NAT）大陆血统大片。与PAD的最大关联是染色体2 q35处的NAT祖先区域[OR = 1.96（SE = 0.16），p< 2.75 × 10−05]，杂合子NAT区域携带者与非携带者的PAD患病率分别为22.6%和12.9%。在该位点的精细定位涉及位于长基因间非编码RNA（lincRNA）LINC 00607内的标签SNP rs78529201，LINC 00607是与血栓形成和内皮细胞的细胞外重塑相关的关键基因的基因表达调节剂，表明2 q35位点与PAD病因学的推定联系。在其他西班牙裔队列中重现该信号的努力没有成功。总之，我们展示了如何利用卫生系统数据帮助了解HL亚组之间PAD风险的细微差别，混合物作图方法阐明了多米尼加人群中的假定风险位点。
Peripheral artery disease (PAD) is a form of atherosclerotic cardiovascular disease, affecting ∼8 million Americans, and is known to have racial and ethnic disparities. PAD has been reported to have a significantly higher prevalence in African Americans (AAs) compared to non-Hispanic European Americans (EAs). Hispanic/Latinos (HLs) have been reported to have lower or similar rates of PAD compared to EAs, despite having a paradoxically high burden of PAD risk factors; however, recent work suggests prevalence may differ between sub-groups. Here, we examined a large cohort of diverse adults in the BioMebiobank in New York City. We observed the prevalence of PAD at 1.7% in EAs vs. 8.5% and 9.4% in AAs and HLs, respectively, and among HL sub-groups, the prevalence was found at 11.4% and 11.5% in Puerto Rican and Dominican populations, respectively. Follow-up analysis that adjusted for common risk factors demonstrated that Dominicans had the highest increased risk for PAD relative to EAs [OR = 3.15 (95% CI 2.33–4.25),p< 6.44 × 10−14]. To investigate whether genetic factors may explain this increased risk, we performed admixture mapping by testing the association between local ancestry and PAD in Dominican BioMeparticipants (N = 1,813) separately from European, African, and Native American (NAT) continental ancestry tracts. The top association with PAD was an NAT ancestry tract at chromosome 2q35 [OR = 1.96 (SE = 0.16),p< 2.75 × 10−05) with 22.6% vs. 12.9% PAD prevalence in heterozygous NAT tract carriers versus non-carriers, respectively. Fine-mapping at this locus implicated tag SNP rs78529201 located within a long intergenic non-coding RNA (lincRNA)LINC00607, a gene expression regulator of key genes related to thrombosis and extracellular remodeling of endothelial cells, suggesting a putative link of the 2q35 locus to PAD etiology. Efforts to reproduce the signal in other Hispanic cohorts were unsuccessful. In summary, we showed how leveraging health system data helped understand nuances of PAD risk across HL sub-groups and admixture mapping approaches elucidated a putative risk locus in a Dominican population.