Wu D A, Bu X, Warden C H, Shen D D, Jeng C Y, Sheu W H, Fuh M M, Katsuya T, Dzau V J, Reaven G M, Lusis A J, Rotter J I, Chen Y D
Department of Medicine, UCLA 90024, USA.
J Clin Invest. 1996 May 1;97(9):2111-8. doi: 10.1172/JCI118648.
Resistance to insulin-mediated glucose disposal is a common finding in patients with non-insulin-dependent diabetes mellitus (NIDDM), as well as in nondiabetic individuals with hypertension. In an effort to identify the generic loci responsible for variations in blood pressure in individuals at increased risk of insulin resistance, we studied the distribution of blood pressure in 48 Taiwanese families with NIDDM and conducted quantitative sib-pair linkage analysis with candidate loci for insulin resistance, lipid metabolism, and blood pressure control. We found no evidence for linkage of the angiotensin converting enzyme locus on chromosome 17, nor the angiotensinogen and renin loci on chromosome 1, with either systolic or diastolic blood pressures. In contrast, we obtained significant evidence for linkage or systolic blood pressure, but not diastolic blood pressure, to a genetic region at or near the lipoprotein lipase (LPL) locus on the short arm of chromosome 8 (P = 0.002, n = 125 sib-pairs, for the haplotype generated from two simple sequence repeat markers within the LPL gene). Further strengthening this linkage observation, two flanking marker loci for LPL locus, D8S261 (9 cM telomeric to LPL locus) and D8S282 (3 cM centromeric to LPL locus), also showed evidence for linkage with systolic blood pressure (P = 0.02 and 0.0002 for D8S261 and D8S282, respectively). Two additional centromeric markers (D8S133, 5 cM from LPL locus, and NEFL, 11 cM from LPL locus) yielded significant P values of 0.01 and 0.001, respectively. Allelic variation around the LPL gene locus accounted for as much as 52-73% of the total interindividual variation in systolic blood pressure levels in this data set. Thus, we have identified a genetic locus at or near the LPL gene locus which contributes to the variation of systolic blood pressure levels in nondiabetic family members at high risk for insulin resistance and NIDDM.
胰岛素介导的葡萄糖处置抵抗在非胰岛素依赖型糖尿病（NIDDM）患者以及患有高血压的非糖尿病个体中很常见。为了确定导致胰岛素抵抗风险增加个体血压变化的基因位点，我们研究了48个台湾NIDDM家族的血压分布，并对胰岛素抵抗、脂质代谢和血压控制的候选基因位点进行了定量同胞对连锁分析。我们没有发现17号染色体上的血管紧张素转换酶基因位点、1号染色体上的血管紧张素原和肾素基因位点与收缩压或舒张压有连锁关系的证据。相比之下，我们获得了与8号染色体短臂上脂蛋白脂肪酶（LPL）基因位点或其附近的一个基因区域的收缩压连锁的显著证据，但与舒张压没有连锁关系（对于由LPL基因内两个简单序列重复标记产生的单倍型，P = 0.002，n = 125个同胞对）。进一步加强这一连锁观察结果的是，LPL基因位点的两个侧翼标记位点D8S261（位于LPL基因位点端粒方向9厘摩处）和D8S282（位于LPL基因位点着丝粒方向3厘摩处）也显示出与收缩压连锁的证据（D8S261和D8S282的P值分别为0.02和0.0002）。另外两个着丝粒标记（D8S133，距离LPL基因位点5厘摩；NEFL，距离LPL基因位点11厘摩）分别产生了显著的P值0.01和0.001。在该数据集中，LPL基因位点周围的等位基因变异占收缩压水平个体间总变异的52 - 73%。因此，我们确定了一个位于LPL基因位点或其附近的基因位点，它导致了胰岛素抵抗和NIDDM高风险非糖尿病家庭成员收缩压水平的变化。
