Zhu D L, Wang H Y, Xiong M M, He X, Chu S L, Jin L, Wang G L, Yuan W T, Zhao G S, Boerwinkle E, Huang W
Department of Cellular and Molecular Biology, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Second Medical University, PR China.
J Hypertens. 2001 Jan;19(1):55-61. doi: 10.1097/00004872-200101000-00008.
To identify chromosome regions containing hypertension susceptibility genes in Chinese.
A three-stage study was carried out in Chinese siblings ascertained through outpatient clinics. In the first stage, 283 affected sib-pairs from 79 nuclear families were subjected to a genome-wide scan with 240 microsatellite marker loci. The second stage focused on chromosome 2 with additional markers resulting in an average distance of 5 cM and used an independent sample of 637 affected sib-pairs from 161 families. In the third stage, a fine-scale mapping study on the suggestive region was performed in an independent set of 777 affected sib-pairs from 106 families. Fourteen markers were used with an average distance less than 2 cM. Non-parametric linkage analyses (NPL), parametric linkage analyses and transmission-disequilibrium tests were used to assess evidence for linkage and association.
Three markers (D2S168 at 27.06 cM, D2S151 at 152.04 cM and D2S142 at 161.26 cM) on chromosome 2 with suggestive linkage to hypertension susceptibility genes were identified in the genome-wide scan. In stage II, the suggestive region around D2S151 and D2S142 was replicated, while the linkage around D2S168 was not. In the stage III fine-scale mapping study, multipoint linkage analyses showed LOD scores greater than 2.0 throughout a region between 157.16 cM and 162.46 cM (all P < 0.001) with a maximum peak of 2.24 (P= 0.00067) at 160.52 cM. We also observed a NPL Z-score peak of 3.27 at 157.55 cM (P= 0.00086).
The results of a suggestive region on chromosome 2q14-q23 (D2S112-D2S2370) were consistent between each of the three studies. Interestingly, this region overlaps a syntenic region that contains blood pressure quantitative trait loci identified in rat models of hypertension. These data suggest that the region near D2S142 and D2S151 deserves to be further screened for hypertension susceptibility genes.
在中国人群中鉴定含有高血压易感基因的染色体区域。
对通过门诊确定的中国同胞进行三阶段研究。第一阶段，对来自79个核心家庭的283对患病同胞对进行全基因组扫描，使用240个微卫星标记位点。第二阶段聚焦于2号染色体，增加标记后平均间距为5厘摩，并使用来自161个家庭的637对患病同胞对的独立样本。第三阶段，在来自106个家庭的777对患病同胞对的独立样本中，对提示区域进行精细定位研究。使用了14个标记，平均间距小于2厘摩。采用非参数连锁分析（NPL）、参数连锁分析和传递不平衡检验来评估连锁和关联的证据。
在全基因组扫描中，在2号染色体上鉴定出三个与高血压易感基因有提示性连锁的标记（27.06厘摩处的D2S168、152.04厘摩处的D2S151和161.26厘摩处的D2S142）。在第二阶段，D2S151和D2S142周围的提示区域得到重复，而D2S168周围的连锁未得到重复。在第三阶段的精细定位研究中，多点连锁分析显示在157.16厘摩至162.46厘摩的区域内LOD分数均大于2.0（所有P<0.001），在160.52厘摩处达到最大值2.24（P = 0.00067）。我们还在157.55厘摩处观察到NPL Z分数峰值为3.27（P = 0.00086）。
三项研究中每项研究在2q14 - q23（D2S112 - D2S2370）上提示区域的结果均一致。有趣的是，该区域与在高血压大鼠模型中鉴定出的血压数量性状位点的同区域重叠。这些数据表明，D2S142和D2S151附近区域值得进一步筛查高血压易感基因。
