Cullina Sinead, Wojcik Genevieve L, Shemirani Ruhollah, Klarin Derek, Gorman Bryan R, Sorokin Elena P, Gignoux Christopher R, Belbin Gillian M, Pyarajan Saiju, Asgari Samira, Tsao Phil S, Damrauer Scott M, Abul-Husn Noura S, Kenny Eimear E
medRxiv. 2023 Mar 29:2023.03.27.23287788. doi: 10.1101/2023.03.27.23287788.
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 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 Bio biobank in New York City (NYC). 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, 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), <6.44×10 ). To investigate whether genetic factors may explain this increased risk, we performed admixture mapping by testing the association between local ancestry (LA) and PAD in Dominican Bio participants (N=1,940) separately for European (EUR), African (AFR) and Native American (NAT) continental ancestry tracts. We identified a NAT ancestry tract at chromosome 2q35 that was significantly associated with PAD (OR=2.05 (95% CI 1.51-2.78), <4.06×10 ) with 22.5% vs 12.5% 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) , 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. In summary, we showed how leveraging health systems data helped understand nuances of PAD risk across HL sub-groups and admixture mapping approaches elucidated a novel risk locus in a Dominican population.
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，影响着约800万美国人，并且已知存在种族和民族差异。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/拉丁裔（HLs）与EAs相比，PAD发病率较低或相近，尽管他们的PAD危险因素负担反常地高，然而最近的研究表明不同亚组之间的患病率可能有所不同。在此，我们研究了纽约市（NYC）生物银行中大量不同的成年人队列。我们观察到，EAs中PAD的患病率为1.7%，而AAs和HLs中分别为8.5%和9.4%；在HL亚组中，波多黎各人和多米尼加人群的患病率分别为11.4%和11.5%。对常见危险因素进行校正后的随访分析表明，与EAs相比，多米尼加人患PAD的风险增加最高（OR = 3.15（95% CI 2.33 - 4.25），P < 6.44×10⁻⁶）。为了研究遗传因素是否可以解释这种风险增加，我们通过分别测试多米尼加生物银行参与者（N = 1940）中欧洲（EUR）、非洲（AFR）和美洲原住民（NAT）大陆祖先片段的局部祖先（LA）与PAD之间的关联，进行了混合映射。我们在2号染色体q35处发现了一个NAT祖先片段，它与PAD显著相关（OR = 2.05（95% CI 1.51 - 2.78），P < 4.06×10⁻⁵），杂合NAT片段携带者与非携带者的PAD患病率分别为22.5%和12.5%。该位点的精细定位涉及位于长链基因间非编码RNA（lincRNA）内的标签单核苷酸多态性rs78529201，lincRNA是与血栓形成和内皮细胞细胞外重塑相关关键基因的基因表达调节剂，这表明2q35位点与PAD病因之间存在推定联系。总之，我们展示了如何利用卫生系统数据帮助理解HL亚组中PAD风险的细微差别，以及混合映射方法如何在多米尼加人群中阐明一个新的风险位点。
