Human Molecular Genetics, 2001, Vol. 10, No. 24 2751-2765
© 2001 Oxford University Press
A genome-wide scan for coronary heart disease suggests in Indo-Mauritians a susceptibility locus on chromosome 16p13 and replicates linkage with the metabolic syndrome on 3q27
1Institute of Biology of Lille, CNRS UPRES A 8090, Lille, France, 2SSR Centre for Medical Studies and Research, Moka, Mauritius, 3Endocrinology Service, Saint Louis Hospital, Paris, France, 4Cardiac Trust Fund, Pamplemousses, Mauritius, 5Cardiac Unit, Victoria Hospital, Mauritius, 6SSR National Hospital, Pamplemousses, Mauritius, 7Barts and The London Genome Centre, Queen Mary and Westfield College, London, UK and 8Janssen Research Foundation, Beerse, Belgium
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.
+ To whom correspondence should be addressed at: Institute of Biology of Lille, UPRES A 8090, Pasteur Institute of Lille, 1, rue du Pr. Calmette, B.P. 447, 59021 Lille Cedex, France. Tel: +33 3 20 87 79 54; Fax: +33 3 20 87 72 29; Email: froguel@mail-good.pasteur-lille.frThe authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors
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