Showing papers by "Scott M. Grundy published in 2010"

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Abstract: Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

Meta-analysis and imputation refines the association of 15q25 with smoking quantity

Abstract: Smoking is a leading global cause of disease and mortality. We established the Oxford-GlaxoSmithKline study (Ox-GSK) to perform a genome-wide meta-analysis of SNP association with smoking-related behavioral traits. Our final data set included 41,150 individuals drawn from 20 disease, population and control cohorts. Our analysis confirmed an effect on smoking quantity at a locus on 15q25 (P = 9.45 x 10(-19)) that includes CHRNA5, CHRNA3 and CHRNB4, three genes encoding neuronal nicotinic acetylcholine receptor subunits. We used data from the 1000 Genomes project to investigate the region using imputation, which allowed for analysis of virtually all common SNPs in the region and offered a fivefold increase in marker density over HapMap2 (ref. 2) as an imputation reference panel. Our fine-mapping approach identified a SNP showing the highest significance, rs55853698, located within the promoter region of CHRNA5. Conditional analysis also identified a secondary locus (rs6495308) in CHRNA3.

Indices of Cholesterol Metabolism and Relative Responsiveness to Ezetimibe and Simvastatin

Abstract: Context: The level and duration of exposure to circulating low-density lipoprotein-cholesterol (LDL-C) are major contributors to coronary atherosclerosis. Therefore, optimal prevention will require long-term LDL-C reduction, making it important to select the most effective agent for each individual. Objective: We tested the hypothesis that individuals with high fractional absorption of cholesterol respond better to the cholesterol absorption inhibitor ezetimibe than to simvastatin, whereas low absorbers, who have elevated rates of cholesterol synthesis, respond better to simvastatin. Design, Setting, and Participants: A randomized, double-blind, placebo-controlled, crossover trial was performed in 215 African- and European-American men. Intervention: Participants were randomized to placebo, ezetimibe (10 mg/d), simvastatin (10 mg/d), and both drugs for 6 wk each. Main Outcome: Plasma levels of LDL-C, surrogate markers for cholesterol absorption (campesterol) and synthesis (lathosterol), and proprotein con...

Body Size Misperception: A Novel Determinant in the Obesity Epidemic

Abstract: The prevalence of obesity in the United States continues to rise and contributes to the incidence of cardiovascular disease.1 One obstacle to effecting weight loss and a potential target for intervention is misperception of body size. Among obese individuals (body mass index [BMI] ≥30 [calculated as weight in kilograms divided by height in meters squared]), body size misperception is defined as failure to recognize the need to lose weight.

Prevalence of the Metabolic Syndrome as Influenced by the Measure of Obesity Employed

Abstract: The metabolic syndrome (MS) is characterized by 4 independent risk factors for cardiovascular disease: elevated triglyceride-rich lipoproteins, reduced high-density lipoproteins, elevated blood pressure, and dysglycemia. Several underlying risk factors, notably obesity, accentuate these independent risk factors. This study addressed 2 questions: Is the prevalence of MS identified equally by all measures of obesity? and Should any measure of obesity be included among diagnostic components of the MS? A cohort of 8,879 women and 23,145 men in the Cooper Center Longitudinal Study (CCLS) underwent anthropometric assessment and risk-factor measurement. Most subjects were Caucasian, and 13.1% of women and 30.5% of men had MS defined by the National Cholesterol Education Program Adult Treatment Panel (ATP) III guidelines. In ATP III, MS is diagnosed by any 3 of 5 factors (i.e., the 4 independent risk factors listed previously plus abdominal obesity, defined as increased waist girth). In the CCLS, several measures of obesity (e.g., percentage body fat, body mass index, and truncal subcutaneous fat) were found to substitute for elevated waist girth without appreciably changing MS prevalence. The impact of removing obesity from the diagnostic criteria (abridged ATP III MS, defined as 3 of 4 independent risk factors) was further examined. Abridged ATP III MS was less common than ATP III MS but recognized a subgroup of patients at higher risk for cardiovascular disease. In conclusion, abridged ATP III MS appears to be preferable to ATP III MS for the detection of candidates for intensive cardiovascular risk reduction.