Center for Human Genetics, Duke University, Durham, North Carolina, United States of America.
PLoS One. 2013 Aug 2;8(8):e71779. doi: 10.1371/journal.pone.0071779. Print 2013.
Given the importance of cardiovascular disease (CVD) to public health and the demonstrated heritability of both disease status and its related risk factors, identifying the genetic variation underlying these susceptibilities is a critical step in understanding the pathogenesis of CVD and informing prevention and treatment strategies. Although one can look for genetic variation underlying susceptibility to CVD per se, it can be difficult to define the disease phenotype for such a qualitative analysis and CVD itself represents a convergence of diverse etiologic pathways. Alternatively, one can study the genetics of intermediate traits that are known risk factors for CVD, which can be measured quantitatively. Using the latter strategy, we have measured 21 cardiovascular-related biomarkers in an extended multigenerational pedigree, the CARRIAGE family (Carolinas Region Interaction of Aging, Genes, and Environment). These biomarkers belong to inflammatory and immune, connective tissue, lipid, and hemostasis pathways. Of these, 18 met our quality control standards. Using the pedigree and biomarker data, we have estimated the broad sense heritability (H2) of each biomarker (ranging from 0.09-0.56). A genome-wide panel of 6,015 SNPs was used subsequently to map these biomarkers as quantitative traits. Four showed noteworthy evidence for linkage in multipoint analysis (LOD score ≥ 2.6): paraoxonase (chromosome 8p11, 21), the chemokine RANTES (22q13.33), matrix metalloproteinase 3 (MMP3, 17p13.3), and granulocyte colony stimulating factor (GCSF, 8q22.1). Identifying the causal variation underlying each linkage score will help to unravel the genetic architecture of these quantitative traits and, by extension, the genetic architecture of cardiovascular risk.
鉴于心血管疾病 (CVD) 对公众健康的重要性，以及疾病状态及其相关风险因素的遗传性已得到证实，确定这些易感性背后的遗传变异是了解 CVD 发病机制并为预防和治疗策略提供信息的关键步骤。虽然人们可以寻找 CVD 易感性背后的遗传变异，但对于这种定性分析来说，很难定义疾病表型，而 CVD 本身代表了多种病因途径的融合。或者，人们可以研究已知是 CVD 风险因素的中间特征的遗传学，这些特征可以进行定量测量。我们使用后一种策略，在一个扩展的多代系谱中测量了 21 种与心血管相关的生物标志物，即 CARRIAGE 家族（卡罗莱纳州老龄化、基因和环境的相互作用）。这些生物标志物属于炎症和免疫、结缔组织、脂质和止血途径。其中，18 个符合我们的质量控制标准。使用系谱和生物标志物数据，我们估计了每个生物标志物的广义遗传力 (H2)（范围从 0.09 到 0.56）。随后使用包含 6015 个 SNP 的全基因组面板来映射这些作为定量性状的生物标志物。多点分析中发现有四个生物标志物显示出显著的连锁证据（LOD 得分≥2.6）：对氧磷酶 (8p11，21)、趋化因子 RANTES (22q13.33)、基质金属蛋白酶 3 (MMP3，17p13.3) 和粒细胞集落刺激因子 (GCSF，8q22.1)。确定每个连锁评分背后的因果变异将有助于揭示这些定量性状的遗传结构，并扩展到心血管风险的遗传结构。
