Do Anh N, Zhao Wei, Srinivasasainagendra Vinodh, Aslibekyan Stella, Tiwari Hemant K, Limdi Nita, Shah Sanjiv J, Zhi Degui, Broeckel Uli, Gu C Charles, Rao D C, Schwander Karen, Smith Jennifer A, Kardia Sharon L R, Arnett Donna K, Irvin Marguerite R
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL.
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI.
J Hypertens Manag. 2017;3(1). doi: 10.23937/2474-3690/1510025. Epub 2017 Jul 20.
Left ventricular (LV) hypertrophy, highest in prevalence among African Americans, is an established risk factor heart failure. Several genome wide association studies have identified common variants associated with LV-related quantitative-traits in African Americans. To date, however, the effect of rare variants on these traits has not been extensively studied, especially in minority groups. We therefore investigated the association between rare variants and LV traits among 1,934 African Americans using exome chip data from the Hypertension Genetic Epidemiology Network (HyperGEN) study, with replication in 1,090 African American from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. We used single-variant analyses and gene-based tests to investigate the association between 86,927 variants and six structural and functional LV traits including LV mass, LV internal dimension-diastole, relative wall thickness, left atrial dimension (LAD), fractional shortening (FS), and the ratio of LV early-to-late transmitral velocity (E/A ratio). Only rare variants (MAF <1% and <5%) were considered in gene-based analyses. In gene-based analyses, we found a statistically significant association between potassium voltage-gated channel subfamily H member 4 () and E/A ratio (P=8.710 using a burden test). Endonuclease G () was associated with LAD using the Madsen Browning weighted burden (MB) test (P=1.410). Neither gene result was replicated in GENOA, but the direction of effect of single variants in common was comparable. G protein-coupled receptor 55 ( was marginally associated with LAD in HyperGEN (P=3.2*10 using the MB test) and E/A ratio in GENOA, but with opposing directions of association for variants in common (P=0.03 for the MB test). No single variant was statistically significantly associated with any trait after correcting for multiple testing. The findings in this study highlight the potential cumulative contributions of rare variants to LV traits which, if validated, could improve our understanding of heart failure in African Americans.
左心室（LV）肥厚在非裔美国人中患病率最高，是心力衰竭的既定危险因素。多项全基因组关联研究已确定与非裔美国人左心室相关数量性状相关的常见变异。然而，迄今为止，罕见变异对这些性状的影响尚未得到广泛研究，尤其是在少数群体中。因此，我们利用高血压遗传流行病学网络（HyperGEN）研究的外显子芯片数据，调查了1934名非裔美国人中罕见变异与左心室性状之间的关联，并在动脉病遗传流行病学网络（GENOA）研究的1090名非裔美国人中进行了重复验证。我们使用单变异分析和基于基因的检验来研究86927个变异与六个左心室结构和功能性状之间的关联，这些性状包括左心室质量、左心室内径舒张期、相对壁厚、左心房内径（LAD）、缩短分数（FS）以及左心室早期与晚期二尖瓣血流速度比值（E/A比值）。基于基因的分析中仅考虑罕见变异（次要等位基因频率<1%和<5%）。在基于基因的分析中，我们发现钾电压门控通道亚家族H成员4（）与E/A比值之间存在统计学显著关联（使用负担检验，P = 8.7×10）。使用马德森·布朗宁加权负担（MB）检验，核酸内切酶G（）与LAD相关（P = 1.4×10）。两个基因的结果在GENOA研究中均未得到重复验证，但常见单变异的效应方向具有可比性。G蛋白偶联受体55（在HyperGEN研究中与LAD存在边缘关联（使用MB检验，P = 3.2×10），在GENOA研究中与E/A比值相关，但常见变异的关联方向相反（MB检验，P = 0.03）。校正多重检验后，没有单变异与任何性状存在统计学显著关联。本研究结果突出了罕见变异对左心室性状的潜在累积贡献，若得到验证，可能会增进我们对非裔美国人心力衰竭的理解。
