Rodríguez Santiago, Gaunt Tom R, O'Dell Sandra D, Chen Xiao-He, Gu Dongfeng, Hawe Emma, Miller George J, Humphries Stephen E, Day Ian N M
Human Genetics Division, University of Southampton, School of Medicine, Southampton General Hospital, Southampton, UK.
Hum Mol Genet. 2004 Apr 1;13(7):715-25. doi: 10.1093/hmg/ddh070. Epub 2004 Jan 28.
The IGF2-INS-TH genomic region has been implicated in various common disorders including the metabolic syndrome, type 2 diabetes and coronary heart disease (CHD). Here we present detailed haplotype analysis of 2743 males 51-62 years old in relation to body weight and composition, blood pressure (BP) and plasma triglycerides (TG). Use of the total data set was complicated by the number of loci typed, missing data, multi-allelic markers and continuous trait phenotypes. Different algorithms and subsets of the data were analysed using the programmes haplotype trend regression, haplo.score, evolutionary-based haplotype analysis package and Phase, in conjunction with SPSS. Ten haplotypes designated in frequency order *1(20.0%) to *10(3.4%) represented 89% of all haplotypes. Haplotype *5 protected against obesity. Haplotype *4 carriers exhibited elevated BP and fat mass, haplotype *6 was associated with raised plasma TG levels. Haplotype *8 also showed similar magnitude effects as *4. These cohort trait analyses and detailed haplotypic analyses enable integration with published case data. Haplotypes *4, *6 and *8 are the only INS VNTR class III-bearing haplotypes, although differing in flanking haplotype, whereas *5 displays unique features in all three genes (with significant commonality with type 1 diabetes-predisposition haplotypes). We propose that long repeat insertion in the insulin gene promoter ('class III'), reported to result in low insulin production, predisposes to the metabolic syndrome features of elevated BP, fat mass or TG level, therefore appearing more frequently in type 2 diabetic, polycystic ovary syndrome and CHD cases. The functional element(s) of *5 for weight-lowering could reside in any of the three genes.
IGF2-INS-TH基因组区域与包括代谢综合征、2型糖尿病和冠心病（CHD）在内的多种常见疾病有关。在此，我们对2743名51至62岁男性的体重和身体组成、血压（BP）及血浆甘油三酯（TG）进行了详细的单倍型分析。由于所分型的基因座数量、缺失数据、多等位基因标记以及连续性状表型等因素，对整个数据集的分析变得复杂。使用单倍型趋势回归、haplo.score、基于进化的单倍型分析软件包和Phase等程序，并结合SPSS，对不同的算法和数据子集进行了分析。按频率顺序指定的10种单倍型1（20.0%）至10（3.4%）占所有单倍型的89%。单倍型5可预防肥胖。单倍型4携带者的血压和脂肪量升高，单倍型6与血浆TG水平升高有关。单倍型8也显示出与4相似程度的影响。这些队列性状分析和详细的单倍型分析能够与已发表的病例数据相结合。单倍型4、6和8是仅有的携带胰岛素可变数目串联重复序列（INS VNTR）III类的单倍型，尽管其侧翼单倍型不同，而*5在所有三个基因中都表现出独特特征（与1型糖尿病易患单倍型有显著共性）。我们提出，胰岛素基因启动子中的长重复插入（“III类”）据报道会导致胰岛素产生减少，易引发血压升高、脂肪量增加或TG水平升高等代谢综合征特征，因此在2型糖尿病、多囊卵巢综合征和冠心病病例中更频繁出现。*5降低体重的功能元件可能存在于这三个基因中的任何一个。
