Framingham Heart Study 100K Project: genome-wide associations for blood pressure and arterial stiffness.
Framingham Heart Study 100K Project: genome-wide associations for blood pressure and arterial stiffness.
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DOI：
10.1186/1471-2350-8-s1-s3
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发表时间：
2007-09-19
影响因子：
--
通讯作者：
Mitchell GF
中科院分区：
文献类型：
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作者：
Levy D;Larson MG;Benjamin EJ;Newton-Cheh C;Wang TJ;Hwang SJ;Vasan RS;Mitchell GF
大约四分之一的成年人患有高血压，高血压会增加心脏病、中风、肾病和死亡的风险。动脉僵硬度增加是收缩期高血压和心血管疾病发病机制中的关键因素。血压（BP）和动脉僵硬度的遗传性表明重要的遗传贡献。在心脏病研究的家系中，我们分析了全基因组SNP，在1971-1975年的一次检查中，使用Affytron 100 K基因芯片与收缩压（SBP）和舒张压（DBP）的相关性（n = 1260），在1998-2001年的最近一次检查中（n = 1233），以及1971-2001年的长期平均SBP和DBP（n = 1327，平均年龄52岁，54%为女性），并通过动脉张力计测量动脉硬度（颈动脉-股动脉和颈动脉-肱动脉脉搏波速度、前向和反射压力波振幅以及平均动脉压; 1998-2001，n = 644）。在主要分析中，我们使用加性遗传效应模型中的广义估计方程，使用多变量调整残差来检验SNP与感兴趣表型之间的关联。共分析了70，987个常染色体SNP，次要等位基因频率≥ 0.10，基因型调用率≥ 0.80，Hardy-Weinberg平衡p ≥ 0.001。作为候选基因搜索的一部分，我们还检测了6个肾素-血管紧张素-醛固酮通路基因中的69个SNP与BP和动脉硬化表型的相关性。在初步分析中，没有一个关联达到全基因组显著性。对于六种BP表型，七种SNP产生p值< 10-5。SBP和DBP的最低p值分别为rs 10493340（p = 1.7 × 10-6）和rs 1963982（p = 3.3 × 10-6）。对于5种张力表型，5个SNP的p值< 10-5;最低p值为MEF 2C（心脏形态发生调节因子）的反射波（rs6063312，p = 2.1 × 10-6）和颈动脉-肱动脉脉搏波速度（rs770189，p = 2.5 × 10-6）。我们发现，在肾素-血管紧张素-醛固酮通路中，SNPs与血压或动脉僵硬度仅有微弱的相关性。这些结果的全基因组关联测试血压和动脉硬化表型在一个社区为基础的样本的成年人可能有助于识别高血压和动脉疾病的遗传基础，帮助识别高风险个体，并指导新的治疗高血压。需要进行更多的研究来复制这些分析中确定的任何关联。
About one quarter of adults are hypertensive and high blood pressure carries increased risk for heart disease, stroke, kidney disease and death. Increased arterial stiffness is a key factor in the pathogenesis of systolic hypertension and cardiovascular disease. Substantial heritability of blood-pressure (BP) and arterial-stiffness suggests important genetic contributions. In Framingham Heart Study families, we analyzed genome-wide SNP (Affymetrix 100K GeneChip) associations with systolic (SBP) and diastolic (DBP) BP at a single examination in 1971–1975 (n = 1260), at a recent examination in 1998–2001 (n = 1233), and long-term averaged SBP and DBP from 1971–2001 (n = 1327, mean age 52 years, 54% women) and with arterial stiffness measured by arterial tonometry (carotid-femoral and carotid-brachial pulse wave velocity, forward and reflected pressure wave amplitude, and mean arterial pressure; 1998–2001, n = 644). In primary analyses we used generalized estimating equations in models for an additive genetic effect to test associations between SNPs and phenotypes of interest using multivariable-adjusted residuals. A total of 70,987 autosomal SNPs with minor allele frequency ≥ 0.10, genotype call rate ≥ 0.80, and Hardy-Weinberg equilibrium p ≥ 0.001 were analyzed. We also tested for association of 69 SNPs in six renin-angiotensin-aldosterone pathway genes with BP and arterial stiffness phenotypes as part of a candidate gene search. In the primary analyses, none of the associations attained genome-wide significance. For the six BP phenotypes, seven SNPs yielded p values < 10-5. The lowest p-values for SBP and DBP respectively were rs10493340 (p = 1.7 × 10-6) and rs1963982 (p = 3.3 × 10-6). For the five tonometry phenotypes, five SNPs had p values < 10-5; lowest p-values were for reflected wave (rs6063312, p = 2.1 × 10-6) and carotid-brachial pulse wave velocity (rs770189, p = 2.5 × 10-6) in MEF2C, a regulator of cardiac morphogenesis. We found only weak association of SNPs in the renin-angiotensin-aldosterone pathway with BP or arterial stiffness. These results of genome-wide association testing for blood pressure and arterial stiffness phenotypes in an unselected community-based sample of adults may aid in the identification of the genetic basis of hypertension and arterial disease, help identify high risk individuals, and guide novel therapies for hypertension. Additional studies are needed to replicate any associations identified in these analyses.