Genome-wide scan for metabolic syndrome and related quantitative traits in Hong Kong Chinese and confirmation of a susceptibility locus on chromosome 1q21-q25.

We conducted autosomal genome scans to map loci for metabolic syndrome (MES) and related traits in the Hong Kong Family Diabetes Study. We selected 55 families with 137 affected members (121 affected relative pairs) for nonparametric linkage analysis on MES. We also selected 179 families with 897 members (2,127 relative pairs) for variance component-based linkage analyses on seven MES-related traits: waist circumference, systolic and diastolic blood pressure (BP), triglyceride, HDL cholesterol, fasting plasma glucose, and insulin resistance index (insulin resistance index by homeostasis model assessment [HOMA%IR]). Analyses revealed three regions that showed suggestive linkage for MES and also showed overlapping signals for metabolic traits: chromosome 1 at 169.5-181.5 cM (logarithm of odds [LOD] = 4.50 for MES, 3.71 for waist circumference, and 1.24 for diastolic BP), chromosome 2 at 44.1-57.3 cM (LOD = 2.22 for MES, 2.07 for fasting plasma glucose, and 1.29 for diastolic BP), and chromosome 16 at 45.2-65.4 cM (LOD = 1.75 for MES, 1.61 for HOMA%IR, and 1.25 for HDL cholesterol). Other regions that showed suggestive linkages included chromosome 5q for diastolic BP; 2q, 3q, 6q, 9q, 10q, and 17q for triglyceride; 12p, 12q, and 22q for HDL-C; and 6q for HOMA%IR. Simulation studies demonstrated genome-wide significant linkage of the chromosome 1 region to both MES and waist circumference (P(genome-wide) = 0.002 and 0.019, respectively). In summary, we have found a susceptibility locus on chromosome 1q21-q25 involved in the pathogenesis of multiple metabolic abnormalities, in particular obesity. Our results confirm the findings of previous studies on diabetes and related phenotypes. We also suggest the locations of other loci that may contribute to the development of MES in Hong Kong Chinese.

[1]  H. Coon,et al.  Replication of Linkage of Familial Combined Hyperlipidemia to Chromosome 1q With Additional Heterogeneous Effect of Apolipoprotein A-I/C-III/A-IV Locus: The NHLBI Family Heart Study , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[2]  G. Abecasis,et al.  Merlin—rapid analysis of dense genetic maps using sparse gene flow trees , 2002, Nature Genetics.

[3]  P. O'Connell,et al.  Factors of insulin resistance syndrome--related phenotypes are linked to genetic locations on chromosomes 6 and 7 in nondiabetic mexican-americans. , 2002, Diabetes.

[4]  L. Almasy,et al.  Multipoint quantitative-trait linkage analysis in general pedigrees. , 1998, American journal of human genetics.

[5]  L. Cardon,et al.  Clustering of hypertension, diabetes, and obesity in adult male twins: same genes or same environments? , 1994, American journal of human genetics.

[6]  K. Clément,et al.  A genome-wide scan for human obesity genes reveals a major susceptibility locus on chromosome 10 , 1998, Nature Genetics.

[7]  W. Jia,et al.  Epidemiological study on obesity and its comorbidities in urban Chinese older than 20 years of age in Shanghai, China , 2002, Obesity reviews : an official journal of the International Association for the Study of Obesity.

[8]  S. Hasstedt,et al.  Quantitative trait linkage analysis of lipid-related traits in familial type 2 diabetes: evidence for linkage of triglyceride levels to chromosome 19q. , 2002, Diabetes.

[9]  Shaun Purcell,et al.  Powerful regression-based quantitative-trait linkage analysis of general pedigrees. , 2002, American journal of human genetics.

[10]  J. Hokanson,et al.  Linkage of the metabolic syndrome to 1q23-q31 in Hispanic families: the Insulin Resistance Atherosclerosis Study Family Study. , 2004, Diabetes.

[11]  C. Dina,et al.  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. , 2001, Human molecular genetics.

[12]  S. Haffner,et al.  Genetic relationship between measures of HDL phenotypes and insulin concentrations. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[13]  C. Bogardus,et al.  Subcutaneous abdominal adipocyte size, a predictor of type 2 diabetes, is linked to chromosome 1q21--q23 and is associated with a common polymorphism in LMNA in Pima Indians. , 2001, Molecular genetics and metabolism.

[14]  C. Lau,et al.  Hong Kong Cardiovascular Risk Factor Prevalence Study 1995 - 1996 , 1996 .

[15]  R. DeFronzo,et al.  Insulin Resistance: A Multifaceted Syndrome Responsible for NIDDM, Obesity, Hypertension, Dyslipidemia, and Atherosclerotic Cardiovascular Disease , 1991, Diabetes Care.

[16]  L Sun,et al.  Statistical tests for detection of misspecified relationships by use of genome-screen data. , 2000, American journal of human genetics.

[17]  G. Heiss,et al.  Familial components of the multiple metabolic syndrome: the ARIC Study , 1997, Diabetologia.

[18]  R. Hanson,et al.  A Locus Influencing Total Serum Cholesterol on Chromosome 19p: Results From an Autosomal Genomic Scan of Serum Lipid Concentrations in Pima Indians , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[19]  R. D'Agostino,et al.  Prevalence and characteristics of the metabolic syndrome in the San Antonio Heart and Framingham Offspring Studies. , 2003, Diabetes.

[20]  Andreas Busjahn,et al.  Support for linkage of familial combined hyperlipidemia to chromosome 1q21–q23 in Chinese and German families , 2000, Clinical genetics.

[21]  M. Leppert,et al.  A genome-wide affected sibpair linkage analysis of hypertension: the HyperGEN network. , 2003, American journal of hypertension.

[22]  A. Y. Chan,et al.  The Metabolic Syndrome in Hong Kong Chinese. The interrelationships among its components analyzed by structural equation modeling , 1996, Diabetes Care.

[23]  M. McCarthy,et al.  Evaluating the results of genomewide linkage scans of complex traits by locus counting. , 2002, American journal of human genetics.

[24]  C. Bouchard,et al.  Genome-wide linkage scan for the metabolic syndrome in the HERITAGE Family Study. , 2003, The Journal of clinical endocrinology and metabolism.

[25]  L. Peltonen,et al.  Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1) , 2004, Nature Genetics.

[26]  J. Weber,et al.  Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[27]  U. de Faire,et al.  Genetic and environmental architecture of the features of the insulin-resistance syndrome. , 1997, American journal of human genetics.

[28]  E. Lander,et al.  Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results , 1995, Nature Genetics.

[29]  M. McCarthy,et al.  Growing evidence for diabetes susceptibility genes from genome scan data , 2003, Current diabetes reports.

[30]  J. Blangero,et al.  The genetic basis of plasma variation in adiponectin, a global endophenotype for obesity and the metabolic syndrome. , 2001, The Journal of clinical endocrinology and metabolism.

[31]  Donna K Arnett,et al.  Quantitative-trait loci influencing body-mass index reside on chromosomes 7 and 13: the National Heart, Lung, and Blood Institute Family Heart Study. , 2002, American journal of human genetics.

[32]  J. Pankow,et al.  Linkage analysis of a composite factor for the multiple metabolic syndrome: the National Heart, Lung, and Blood Institute Family Heart Study. , 2003, Diabetes.

[33]  G. Reaven.  Role of Insulin Resistance in Human Disease , 1988, Diabetes.

[34]  P. Zimmet,et al.  Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO Consultation , 1998, Diabetic medicine : a journal of the British Diabetic Association.

[35]  T. Lehtimäki,et al.  Linkage of familial combined hyperlipidaemia to chromosome 1q21–q23 , 1998, Nature Genetics.

[36]  Lisa J. Martin,et al.  A comprehensive linkage analysis for myocardial infarction and its related risk factors , 2002, Nature Genetics.

[37]  W. Dietz,et al.  Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. , 2002, JAMA.

[38]  M. Ng,et al.  Genome-wide scan for type 2 diabetes loci in Hong Kong Chinese and confirmation of a susceptibility locus on chromosome 1q21-q25. , 2004, Diabetes.

[39]  J. Blangero,et al.  Genetic analysis of the IRS. Pleiotropic effects of genes influencing insulin levels on lipoprotein and obesity measures. , 1996, Arteriosclerosis, thrombosis, and vascular biology.

[40]  M. Boehnke,et al.  Accurate inference of relationships in sib-pair linkage studies. , 1997, American journal of human genetics.

[41]  T. Rice,et al.  Cross-trait familial resemblance for body fat and blood lipids: familial correlations in the Quebec Family Study. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[42]  R. Elston,et al.  A whole-genome scan for obstructive sleep apnea and obesity. , 2003, American journal of human genetics.

[43]  N J Cox,et al.  Allele-sharing models: LOD scores and accurate linkage tests. , 1997, American journal of human genetics.

[44]  J R O'Connell,et al.  PedCheck: a program for identification of genotype incompatibilities in linkage analysis. , 1998, American journal of human genetics.