Francke S, Manraj M, Lacquemant C, Lecoeur C, Leprêtre F, Passa P, Hebe A, Corset L, Yan S L, Lahmidi S, Jankee S, Gunness T K, Ramjuttun U S, Balgobin V, Dina C, Froguel P
Institute of Biology, CNRS UPRES A 8090, Pasteur Institute of Lille, 1, rue du Pr. Calmette, B.P. 447, 59021 Lille Cedex, France.
Hum Mol Genet. 2001 Nov 15;10(24):2751-65. doi: 10.1093/hmg/10.24.2751.
Prevalence of coronary heart disease (CHD), of type 2 diabetes (T2DM) and of the metabolic syndrome are in Mauritius amongst the highest in the world. As T2DM and CHD are closely associated and have both a polygenic basis, we conducted a 10 cM genome scan with 403 microsatellite markers in 99 independent families of North-Eastern Indian origin including 535 individuals. Families were ascertained through a proband with CHD before 52 years of age and additional sibs with myocardial infarction (MI) or T2DM. Model-free two-point and multipoint linkage analysis were performed using the Mapmarker-Sibs (MLS) and maximum-likelihood-binomial (MLB) programs for autosomal markers and the Aspex program for chromosome X markers. In a second step, additional markers were studied to increase the genetic map density in three regions on chromosomes 3, 8 and 16 where initial indication for linkage was found. Our data show suggestive linkage with CHD on chromosome 16p13-pter with the MLS statistics at 8.69 cM (LOD = 3.06, P = 0.00017) which partially overlaps with a high pressure (HBP) peak. At the same locus, a nominal indication for linkage with T2DM was found in 35 large T2DM Pondicherian families also having Indian origin. With respect to region 8q23, we found suggestive linkage with T2DM (LOD = 2.55, P = 0.00058) as well as with HBP. On 3q27, we replicated previous indication for linkage found in Caucasians (for the metabolic syndrome and for diabetes) according to the categorized trait for CHD and MI with the MLB statistics (LOD = 2.13, P = 0.0009). The genome scan also revealed nominal evidence of linkage with CHD on 10q23 (LOD = 2.06, P = 0.00188). Interestingly, we detected in the same region overlapping linkages with three QTLs: age of onset of CHD (LOD = 2.03), HDL cholesterol (LOD = 1.48) and LDL/HDL ratio (LOD = 1.34). Ordered-subset analysis based on family body mass index ranking replicated finding on 2q37 for T2DM (at Calpain 10 locus). These results show the first evidence for susceptibility loci that predispose to CHD, T2DM and HBP in the context of the metabolic syndrome.
冠心病（CHD）、2型糖尿病（T2DM）和代谢综合征在毛里求斯的患病率位居世界前列。由于T2DM和CHD密切相关且均有多基因基础，我们对99个独立的东北印度裔家庭（共535人）进行了一项10厘摩（cM）的基因组扫描，使用了403个微卫星标记。这些家庭通过一名52岁之前患CHD的先证者以及其他患有心肌梗死（MI）或T2DM的同胞来确定。使用Mapmarker-Sibs（MLS）和最大似然二项式（MLB）程序对常染色体标记进行无模型两点和多点连锁分析，使用Aspex程序对X染色体标记进行分析。第二步，研究了额外的标记，以增加在3号、8号和16号染色体上三个初步发现有连锁迹象区域的遗传图谱密度。我们的数据显示，在16p13-pter染色体上与CHD存在提示性连锁，MLS统计值为8.69 cM（LOD = 3.06，P = 0.00017），该区域部分与一个高血压（HBP）峰值重叠。在同一基因座，在35个同样来自印度的大型T2DM本地治里家庭中也发现了与T2DM连锁的名义证据。关于8q23区域，我们发现与T2DM（LOD = 2.55，P = 0.00058）以及HBP存在提示性连锁。在3q27上，根据CHD和MI的分类性状，我们使用MLB统计值（LOD = 2.13，P = 0.0009）重复了之前在高加索人中发现的连锁迹象（针对代谢综合征和糖尿病）。基因组扫描还揭示了在10q23上与CHD连锁的名义证据（LOD = 2.06，P = 0.00188）。有趣的是，我们在同一区域检测到与三个数量性状基因座（QTL）的重叠连锁：CHD发病年龄（LOD = 2.03）、高密度脂蛋白胆固醇（HDL胆固醇，LOD = 1.48）和低密度脂蛋白/高密度脂蛋白比值（LOD = 1.34）。基于家庭体重指数排名的有序子集分析重复了在2q37上针对T2DM（在钙蛋白酶10基因座）的发现。这些结果首次证明了在代谢综合征背景下，存在易患CHD、T2DM和HBP的易感基因座。
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