Kidney Disease Genetics and the Importance of Diversity in Precision Medicine
Kidney Disease Genetics and the Importance of Diversity in Precision Medicine
复制标题
肾脏疾病遗传学和精准医学中多样性的重要性
DOI：
10.1142/9789814749411_0027
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发表时间：
2016
影响因子：
--
通讯作者：
D. Crawford
中科院分区：
文献类型：
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作者：
J. C. Bailey;S. Wilson;K. Brown;Robert J. Goodloe;D. Crawford
肾脏疾病是美国众所周知的健康差异，与欧洲裔美国人和墨西哥裔美国人等其他群体相比，非裔美国人的患病率更高。肌球蛋白重链 9 非肌肉 (MYH9) 基因中的常见遗传变异最初被鉴定为与非裔美国人的非糖尿病终末期肾病相关，现在人们了解到这些变异与邻近的 APOL1 中可能的致病变异存在强连锁不平衡。随后的全基因组和候选基因研究表明，MYH9 常见变异等也与不同人群的慢性肾病和肾功能定量测量相关。在精准医疗环境中，在提供与疾病风险或个体患者评估相关的数据时，重要的是要考虑不同种族/族裔群体之间不同的遗传效应或遗传关联。肾脏疾病和数量性状相关的遗传变异尚未在多个种族/族裔群体中进行系统的表征。因此，为了进一步表征这些遗传变异的患病率及其与肾脏相关性状的关联，我们对 10 种肾脏疾病或数量性状相关的单核苷酸多态性 (SNP) 进行了基因分型（rs2900976、rs10505955、rs10502868、rs1243400、rs9305354、rs12917707、 rs17319721、rs2467853、rs2032487 和 rs4821480）在 14,998 名参与者中进行，这些参与者来自基于人群的横断面国家健康和营养检查调查 (NHANES) III 和 1999-2002 年，作为环境相关基因流行病学结构 (EAGLE) 研究的一部分。在这个确定的一般成年人口中，无论其健康状况如何（6,293 名非西班牙裔白人、3,013 名非西班牙裔黑人和 3,542 名墨西哥裔美国人），我们观察到非西班牙裔黑人的慢性肾病发病率高于其他群体，正如预期的那样。我们使用线性回归进行了单一 SNP 关联检验，假设针对年龄、性别、舒张压、收缩压和 2 型糖尿病状态调整了加性遗传模型，以得出多种结果，包括肌酐（尿液）、肌酐（血清）、白蛋白（尿液）、eGFR 和白蛋白与尿肌酐比值 (ACR)。我们还使用逻辑回归测试了每个 SNP 与慢性肾脏疾病和白蛋白尿之间的关联。令人惊讶的是，所测试的 MYH9 变体均与非西班牙裔黑人的肾脏疾病或特征无关 (p>0.05)，这可能归因于该人群肾脏疾病的临床异质性。在每个种族/族裔组中观察到多种相关性，p<0.05，但在所有三组中没有一个在同一方向上一致相关。缺乏显着且一致的关联很可能是因为权力强调了对复杂疾病和特征进行遗传关联研究的大量、多样化人群的重要性，以便为不同患者人群的精准医疗工作提供信息。
Kidney disease is a well-known health disparity in the United States where African Americans are affected at higher rates compared with other groups such as European Americans and Mexican Americans. Common genetic variants in the myosin, heavy chain 9, non-muscle (MYH9) gene were initially identified as associated with non-diabetic end-stage renal disease in African Americans, and it is now understood that these variants are in strong linkage disequilibrium with likely causal variants in neighboring APOL1. Subsequent genome-wide and candidate gene studies have suggested that MYH9 common variants among others are also associated with chronic kidney disease and quantitative measures of kidney function in various populations. In a precision medicine setting, it is important to consider genetic effects or genetic associations that differ across racial/ethnic groups in delivering data relevant to disease risk or individual-level patient assessment. Kidney disease and quantitative trait-associated genetic variants have yet to be systematically characterized in multiple racial/ethnic groups. Therefore, to further characterize the prevalence of these genetic variants and their association with kidney related traits, we have genotyped 10 kidney disease or quantitative trait-associated single nucleotide polymorphisms (SNPs) (rs2900976, rs10505955, rs10502868, rs1243400, rs9305354, rs12917707, rs17319721, rs2467853, rs2032487, and rs4821480) in 14,998 participants from the population-based cross-sectional National Health and Nutrition Examination Surveys (NHANES) III and 1999-2002 as part of the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) study. In this general adult population ascertained regardless of health status (6,293 non-Hispanic whites, 3,013 non-Hispanic blacks, and 3,542 Mexican Americans), we observed higher rates of chronic kidney disease among non-Hispanic blacks compared with the other groups as expected. We performed single SNP tests of association using linear regressions assuming an additive genetic model adjusted for age, sex, diastolic blood pressure, systolic blood pressure, and type 2 diabetes status for several outcomes including creatinine (urinary), creatinine (serum), albumin (urinary), eGFR, and albumin-to-urinary creatinine ratio (ACR). We also tested for associations between each SNP and chronic kidney disease and albuminuria using logistic regression. Surprisingly, none of the MYH9 variants tested was associated with kidney diseases or traits in non-Hispanic blacks (p>0.05), perhaps attributable to the clinical heterogeneity of kidney disease in this population. Several associations were observed in each racial/ethnic group at p<0.05, but none were consistently associated in the same direction in all three groups. The lack of significant and consistent associations is most likely due to power highlighting the importance of the availability of large, diverse populations for genetic association studies of complex diseases and traits to inform precision medicine efforts in diverse patient populations.
影响因子：
6.1
作者：
Cooke, Jessica N.;Bostrom, Meredith A.;Bowden, Donald W.
通讯作者：
Bowden, Donald W.
作为使用基因组学和流行病学的人口结构 (PAGE) 研究的一部分，在与环境相关的基因流行病学结构 (EAGLE) 项目中实现高通量基因型-表型关联。
影响因子：
--
作者：
Bush,WilliamS;Boston,Jonathan;Pendergrass,SarahA;Dumitrescu,Logan;Goodloe,Robert;Brown-Gentry,Kristin;Wilson,Sarah;McClellan,Bob;Torstenson,Eric;Basford,MelissaA;Spencer,KyleeL;Ritchie,MarylynD;Crawford,DanaC
通讯作者：
Crawford,DanaC