Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome

Abstract

Recent research has emphasized the importance of the metabolic cluster, which includes glucose intolerance, dyslipidemia, and high blood pressure, as a strong predictor of the obesity-related morbidities and premature mortality. Fundamental to this association, commonly referred to as the metabolic syndrome, is the close interaction between abdominal fat patterning, total body adiposity, and insulin resistance. As the initial step in identifying major genetic loci influencing these phenotypes, we performed a genomewide scan by using a 10-centiMorgan map in 2,209 individuals distributed over 507 nuclear Caucasian families. Pedigreebased analysis using a variance components linkage model demonstrated a quantitative trait locus (QTL) on chromosome 3 (3q27) strongly linked to six traits representing these fundamental phenotypes [logarithm of odds (lod) scores ranged from 2.4 to 3.5]. This QTL exhibited possible epistatic interaction with a second QTL on chromosome 17 (17p12) strongly linked to plasma leptin levels (lod ‫؍‬ 5.0). Situated at these epistatic QTLs are candidate genes likely to influence two biologic precursor pathways of the metabolic syndrome. O besity is a common and chronic disorder associated with decreased longevity and increased morbidity from a variety of diseases, including type 2 diabetes mellitus, hypertension, stroke, and coronary heart disease (1). Fat distribution, specifically the pattern known as upper-body, abdominal, or visceral obesity, is a major predictor of the adverse metabolic profile predisposing to these health risks (2). Thus, abdominal-visceral fat size has emerged as a significant precursor of glucose intolerance, hyperinsulinemia, elevated plasma triglycerides, decreased high density lipoprotein-cholesterol, and increased blood pressure (3). Fundamental to this metabolic milieu are close interactions between total body adiposity, abdominalvisceral fat size, and insulin resistance. Reaven (4) provided evidence to suggest that resistance to insulin-stimulated glucose uptake is associated with a series of related metabolic variables, termed ''syndrome X,'' which cluster in the same individual and include glucose intolerance, disturbed plasma lipids, and high blood pressure (4). Because of close similarities of these features with those associated with abdominal obesity, the more collective term metabolic syndrome was introduced (5).The etiology of the abdominal obesity-metabolic syndrome is complex and is thought to involve metabolic, neuroendocrine, and genetic interactions. A metabolic-neuroendocrine cascade has been proposed in which increased free fatty acid flux from the highly lipolytic visceral adipocytes, together with imbalances in sex hormones, could cause the insulin resistance and hyperinsulinemia, with their metabolic consequences (6). Weight gain with preferential deposition of adipocytes in the abdominal-visceral region is considered secondary to adoption of Westernized diet, activity lifestyle, and reactivity to emotional, intellectual, and physical stresses (5...

Association of hypertension with single nucleotide polymorphisms in the quantitative trait locus for abdominal obesity-metabolic syndrome on chromosome 17

“…These new findings confirm and extend previous reports of the association of 17p12 with hypertension. [3][4][5] Our findings should be interpreted with a degree of caution. Single nucleotide polymorphisms that are close to each other would be expected to show linkage disequilibrium and similar associations with a particular trait.…”

“…3 This marker lies close to a quantitative trait locus for abdominal obesity-metabolic syndrome (AOMS2) at 17p12 on chromosome 17. 4 Recently, we have reported that D17S1303 was associated with hypertension. 5 The number of GATA repeats correlated inversely with diastolic blood pressure and BMI.…”

Principal-component-based multivariate regression for genetic association studies of metabolic syndrome components

“…The traits were clustered into two groups based on two previously identified linkage peaks [18] and these two groups exhibited strong correlation. After multiple-test adjustment, PCBMR successfully identified several SNPs associated with the traits, especially in the trait group of INSULIN and I/G.…”

“…Based on previous studies [18], we focused our studies on six traits (body mass index (BMI), waist circumference (WAIST), hip circumference (HIP), weight (WEIGHT), insulin (INSULIN) and insulin/glucose (I/G)) and on chromosome 3 from 182-227 cM (173.4-198.8 Mb), which contains potential pleiotropic QTL [18,19]. The most recent measures were used for all subjects.…”

A novel method, the Variant Impact On Linkage Effect Test (VIOLET), leads to improved identification of causal variants in linkage regions

“…MRC-OB was established in 1994, when families were recruited from the Take Off Pounds Sensibly Inc. membership. 16,20 Fasting plasma triglycerides were determined spectrophotometrically in triplicate. A total of 2209 individuals from 507 families of Northern European descent formed the cohort.…”