Genome-wide Scan for Metabolic Syndrome and Related Quantitative Traits in Hong Kong Chinese and Confirmation of a Susceptibility Locus on Chromosome 1q21-q25

Abstract

T he clustering of multiple metabolic abnormalities, including insulin resistance, glucose intolerance, hypertension, dyslipidemia, and obesity, in particular central obesity, is known as syndrome X, or metabolic syndrome (MES) (1-3). MES is a major health problem characterized by increased morbidity and mortality. The prevalence of MES in the general adult population varies from 10 -13% in mainland Chinese (4,5) to 20 -30% in U.S. whites and Mexican Americans (6,7). However, direct comparison of these rates is difficult because of the use of different diagnostic criteria (2,3).The underlying pathogenic mechanism for the manifestation of these related diseases is unclear but likely involves multiple pathways influenced by interacting genetic and environmental factors. It has been hypothesized that insulin resistance (8) and abdominal obesity (9) may be the key factors linking the components of MES. Several lines of evidence suggest that pleiotropy or shared genetic factors contribute to the clustering of these traits. Twin studies show a higher concordance rate for MES in monozygotic than in dizygotic twins. A common latent genetic factor may influence the clustering of traits (10,11). Type 2 diabetes and hypertension show familial aggregation of MES (12). Bivariate genetic analyses in families suggest a pleiotropic effect between insulin level and obesity indexes or lipids (13,14) and between obesity indexes and lipids (15).Most linkage mapping studies for metabolic diseases focus on dichotomous traits, partly because the ascertained families include only individuals with disease. Quantitative trait linkage analysis may be a powerful alternative for mapping genes for common diseases (16). Several genome scan studies have attempted to map quantitative trait loci (QTL) for MES traits, on either individual traits or composite factors derived from principle component or factor analyses (17)(18)(19)(20). A recent genome scan for coronary heart disease used both qualitative and quantitative linkage approaches to study multiple metabolic diseases, and three suggestive loci are found to be linked to more than one trait, consistent with

Bivariate genome-wide scan for metabolic phenotypes in non-diabetic Chinese individuals from the Stanford, Asia and Pacific Program of Hypertension and Insulin Resistance Family Study

“…We were unable to replicate the results from that study by again showing evidence of linkage for metabolic syndrome on chromosome 1 at 169.5-181.5 cM and on chromosome 2 at 44.1-57.3 cM. However, we did observe a significant QTL on chromosome 16 at 45 cM (LOD=4.29 and LOD [1] =3.27 for 1 h insulin and AUC insulin), similar to the reported region at 45.2-65.4 cM (with LOD=1.75, 1.61 and 1.25 for metabolic syndrome, HOMA-IR and HDL-cholesterol respectively) in Hong Kong Chinese [7].…”

“…In search for the genetic loci for metabolic syndrome (as a categorical diagnosis) and its related traits, many studies have been conducted in different populations [11,14,16,38,39], including Chinese living in Hong Kong [7]. We were unable to replicate the results from that study by again showing evidence of linkage for metabolic syndrome on chromosome 1 at 169.5-181.5 cM and on chromosome 2 at 44.1-57.3 cM.…”

“…The clustering of these metabolic traits along with their heritable features suggests that defects in one or more genes may contribute to metabolic syndrome. Linkage analysis has been widely adopted to narrow down the broad chromosomal regions harbouring susceptibility loci and to elucidate genetic features of various metabolic phenotypes, as well as to categorically define metabolic syndrome [7][8][9]. The results, however, are mostly limited to identifying: (1) regions with logarithm of the odds (LOD) scores of linkage between a chromosomal locus and a trait that are of merely marginal significance; or (2) regions with modest contributions to overall trait variation [10].…”

Are there common genetic and environmental factors behind the endophenotypes associated with the metabolic syndrome?

“…Goldin et al [37] summarised 12 studies reporting QTLs related to the metabolic syndrome components; the QTLs were located mostly on chromosomes 1, 3, 5, 6, 7, 10, 14 and 17. Some studies have tried to locate genes responsible for the metabolic syndrome as a composite variable [38][39][40][41]. Given that genetic correlations between the endophenotypes of metabolic syndrome were weak to moderate as suggested from this study, finding genes for the metabolic syndrome as a composite variable may not be a good strategy.…”

Genotype of galectin 2 (LGALS2) is associated with insulin-glucose profile in the British Women’s Heart and Health Study

“…It should also be noted that several family-based studies have identified genetic linkage of some metabolic syndrome traits to 22q. The HyperGEN Network found linkage of diabetes status to 22q12.1 in hypertensive patients [7]; markerD22S683 near CYP2D6 on 22q was found to be linked and associated with type 2 diabetes in Northern Ontario Oji-Cree [8]; and the plasma HDL-cholesterol (HDL-c) level was linked to 22q in the Hong Kong Family Diabetes Study [9].…”