Quantitative trait linkage analysis of lipid-related traits in familial type 2 diabetes - Evidence for linkage of triglyceride levels to chromosome 19q
Quantitative trait linkage analysis of lipid-related traits in familial type 2 diabetes - Evidence for linkage of triglyceride levels to chromosome 19q
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DOI：
10.2337/diabetes.51.2.528
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发表时间：
2002-02-01
期刊：
影响因子：
7.7
通讯作者：
Hasstedt, SJ
中科院分区：
文献类型：
--
作者：
Elbein, SC;Hasstedt, SJ
大血管病变是2型糖尿病的主要并发症。流行病学数据表明，大血管并发症的风险可能早于高血糖症的发生。高胆固醇血症、低水平HDL胆固醇和致动脉粥样硬化特征性的胰岛素抵抗/代谢综合征也在家族性2型糖尿病激酶的非糖尿病成员中流行。为了确定与血脂相关的性状的基因，我们首先使用440个标记在19个多重家庭的379名成员中进行了10 cM的基因组扫描，确定了两个糖尿病兄弟姐妹（筛选研究）。然后，我们将初始比值对数（LOD）评分> 1.5的三个地区的结果扩展到另外23个家庭，总共576个基因型个体（扩展研究）。我们发现所有血脂指标的遗传率在0.31至0.52的范围内，类似于其他人报道的家族。然而，我们发现甘油三酯水平与染色体19 q13.2相关的最强证据，在筛选研究中非常接近ApoC 2/ ApoE/ApoC 1/ApoC 4基因簇（LOD 2.56）;在扩展研究中LOD增加至3.16。甘油三酯与HDL胆固醇比值显示在同一位置的LOD评分略低（2.73，大家族）。LOD评分>2.0的其他区域包括HDL与染色体1 q21-q23的连锁，其中家族性2型糖尿病和家族性混合型高脂血症的易感性基因座已被定位，以及N1 DDM 1基因座区域中的染色体2 q。然而，在扩展研究中，这两个地区都没有显示出更强的联系证据。我们的研究结果表明，在19q13.2上ApoE/ApoC 2/ApoC 1/ApoC 4簇内或附近的基因可能有助于常见的糖尿病家族成员及其后代中观察到的高甘油三酯血症和低HDL，因此可能是胰岛素抵抗综合征的候选位点。
Macrovascular disease is a major complication of type 2 diabetes. Epidemiological data suggest that the risk of macrovascular complications may predate the onset of hyperglycemia. Hypertriglyceridemia, low levels of HDL cholesterol, and an atherogenic profile characterize the insulin resistance/metabolic syndrome that is also prevalent among nondiabetic members of familial type 2 diabetic kindreds. To identify the genes for lipid-related traits, we first performed a 10-cM genome scan using 440 markers in 379 members of 19 multiplex families ascertained for two diabetic siblings (screening study). We then extended findings for three regions with initial logarithm of odds (LOD) scores > 1.5 to an additional 23 families, for a total of 576 genotyped individuals (extended study). We found heritabilities for all lipid measures in the range of 0.31 to 0.52, similar to those reported by others in unselected families. However, we found the strongest evidence for linkage of triglyceride levels to chromosome 19q13.2, very close to the ApoC2/ ApoE/ApoC1/ApoC4 gene cluster (LOD 2.56) in the screening study; the LOD increased to 3.16 in the extended study. Triglyceride-to-HDL cholesterol ratios showed slightly lower LOD scores (2.73, extended family) in this same location. Other regions with LOD scores >2.0 included HDL linkage to chromosome 1q21-q23, where susceptibility loci for both familial-type 2 diabetes and familial combined hyperlipidemia have been mapped, and to chromosome 2q in the region of the N1DDM1 locus. Neither region showed stronger evidence for linkage in the extended studies, however. Our results suggest that genes in or near the ApoE/ApoC2/ ApoC1/ApoC4 cluster on 19q13.2 may contribute to the commonly observed hypertriglyceridemia and low HDL seen in diabetic family members and their offspring, and thus may be a candidate locus for the insulin resistance syndrome.