Chauvet Cristina, Charron Sophie, Ménard Annie, Xiao Chunjie, Roy Julie, Deng Alan Y
Research Centre-CHUM, University of Montreal, Montreal, Quebec, Canada.
J Hypertens. 2008 May;26(5):893-901. doi: 10.1097/HJH.0b013e3282f85ded.
Although genetic mapping of quantitative trait loci for blood pressure to large chromosome segments is readily achievable, their final identification confronts formidable hurdles. Restriction of the genes lodging in one quantitative trait locus interval to experimental limitation can facilitate their positional cloning. We previously delineated several quantitative trait loci for blood pressure on chromosome 10 of Dahl salt-sensitive rats, but their chromosome delimitations were either large or not definitive.
In this study, we systematically and comprehensively constructed congenic strains with submegabase (Mb) genome resolution and analyzed their blood pressure by telemetry.
Three quantitative trait loci have been conclusively delimited by three congenic strains, each independently lowering the blood pressure. Their intervals are demarcated by genomic regions between 350 and 910 kilobases (kb) in size. Two of the three quantitative trait loci share an epistatic relationship and are separated from one another by less than 170 kb. Two additional quantitative trait loci for blood pressure were also tentatively delineated and their intervals range from 520 kb to 1.75 Mb. Possible genes dwelling in each quantitative trait locus-interval number between 11 and 17. None of these genes is known to exert a functional impact on blood pressure. Work is underway to find candidate genes with mutations that could be responsible for the blood pressure effect.
Novel diagnostic, prognostic, preventive and/or therapeutic targets for essential hypertension and hypertension-associated diseases are likely to emerge from the identification of these quantitative trait loci. Potential applications of these quantitative trait loci to humans are suggested from the positive results from several association studies, demonstrating the existence of quantitative trait loci in the broad homologous regions.
虽然将血压数量性状基因座定位到较大的染色体片段上很容易实现，但最终鉴定这些基因座却面临巨大障碍。将位于一个数量性状基因座区间内的基因限制在实验范围内，有助于它们的定位克隆。我们之前在 Dahl 盐敏感大鼠的 10 号染色体上划定了几个血压数量性状基因座，但它们的染色体定位要么范围较大，要么不明确。
在本研究中，我们系统且全面地构建了具有亚兆碱基（Mb）基因组分辨率的近交系，并通过遥测技术分析它们的血压。
三个近交系已明确划定了三个数量性状基因座，每个基因座都能独立降低血压。它们的区间由大小在 350 至 910 千碱基（kb）之间的基因组区域界定。这三个数量性状基因座中的两个存在上位关系，彼此间隔不到 170 kb。另外还初步划定了两个血压数量性状基因座，其区间范围为 520 kb 至 1.75 Mb。每个数量性状基因座区间内可能存在的基因数量在 11 至 17 个之间。目前尚不清楚这些基因中是否有对血压产生功能影响的。正在开展工作寻找可能导致血压效应的具有突变的候选基因。
通过鉴定这些数量性状基因座，可能会出现原发性高血压及高血压相关疾病的新型诊断、预后、预防和/或治疗靶点。几项关联研究的阳性结果表明在广泛的同源区域存在数量性状基因座，提示了这些数量性状基因座在人类中的潜在应用。
