Experimental Medicine & Immunotherapeutics Division, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.
Genes (Basel). 2023 Sep 25;14(10):1862. doi: 10.3390/genes14101862.
Genome-wide scans performed in affected sib pairs have revealed small and often inconsistent clues to the loci responsible for the inherited components of hypertension. Since blood pressure is a quantitative trait regulated by many loci, two siblings at opposite extremes of the blood pressure distribution are more likely to have inherited different alleles at any given locus. Hence, we investigated an extreme discordant sib pair strategy to analyse markers from two previous loci of interest: (1) the Gordons syndrome locus that includes the WNK4 gene and (2) the ROMK locus identified in our first genome-wide scan. For this study, 24 sib pairs with strong family histories of essential hypertension were selected from the top and bottom 10% of the blood pressure distribution and genotyped for highly polymorphic microsatellite markers on chromosomes 11 and 17. The mean age of the population was 39.8 ± 7.8 years. A significant inverse correlation was found between the squared difference in pulse pressure and the number of alleles shared by IBD between the siblings for the DS11925 marker (r = -0.44, = 0.031), systolic pressure and chromosome 17 markers (D17S250: r = -0.42, = 0.040; D17S799 (r = -0.51, = 0.011), and this relationship persisted after correcting for age and gender. Markers on chromosome 17 (D17S250, D17S928 and D17S1301) and 11 (D11S1999) also correlated with diastolic pressure. These results illustrate the successful use of discordant sib pair analysis to detect linkage within relatively small numbers of pedigrees with hypertension. Further analysis of this cohort may be valuable in complementing findings from the large genome wide scans in affected sib pairs.
全基因组扫描在受影响的同胞对中进行，揭示了导致高血压遗传成分的基因座的小而常常不一致的线索。由于血压是由许多基因座调节的数量性状，因此血压分布处于极端的两个兄弟姐妹更有可能在任何特定基因座遗传不同的等位基因。因此，我们采用极端不一致的同胞对分析策略来分析两个先前感兴趣的基因座的标记：（1）包括 WNK4 基因的 Gordon 综合征基因座；（2）我们首次全基因组扫描中确定的 ROMK 基因座。 为了进行这项研究，从血压分布的前 10%和后 10%中选择了 24 对具有强烈原发性高血压家族史的同胞对，并对 11 号和 17 号染色体上的高度多态性微卫星标记进行了基因分型。人群的平均年龄为 39.8 ± 7.8 岁。在 DS11925 标记物（r = -0.44， = 0.031）、收缩压和 17 号染色体标记物（D17S250：r = -0.42， = 0.040；D17S799：r = -0.51， = 0.011）之间发现平方脉冲压差异与同胞间 IBD 共享的等位基因数之间存在显著的负相关关系，这种关系在校正年龄和性别后仍然存在。染色体 17 号（D17S250、D17S928 和 D17S1301）和 11 号（D11S1999）上的标记物也与舒张压相关。这些结果说明了使用不一致的同胞对分析来检测具有高血压的相对较小数量家系内的连锁的成功应用。对该队列的进一步分析可能有助于补充受影响的同胞对全基因组扫描中的发现。
