Dataset Information

Low-density-lipoprotein cholesterol concentrations and risk of incident diabetes: epidemiological and genetic insights from the Framingham Heart Study.

ABSTRACT: AIMS/HYPOTHESIS:Statins and niacin (nicotinic acid) reduce circulating LDL-cholesterol (LDL-C) levels by different mechanisms. Yet, both increase the risk of diabetes mellitus. Our objective was to relate blood LDL-C concentrations and a genetic risk score (GRS) for LDL-C to the risk of incident diabetes in individuals not treated with lipid-modifying therapy. METHODS:We evaluated participants of the Framingham Heart Study who attended any of Offspring cohort examination cycles 3-8 and Third Generation cohort examination cycle 1 (N =14,120 person-observations, 6,011 unique individuals; mean age 50 ± 11 years, 56% women), who were not treated with lipid-modifying or antihypertensive medications and who were free from cardiovascular disease at baseline. Incident diabetes was assessed at the next examination. RESULTS:The GRS was significantly associated with LDL-C concentrations (sex- and age-adjusted estimated influence 0.24, p < 0.0001). On follow-up (mean 4.5 ± 1.5 years), 312 individuals (2.2%) developed new-onset diabetes. In multivariable models, a higher LDL-C concentration was associated with lower risk of diabetes (OR per SD increment 0.81, 95% CI 0.70, 0.93, p = 0.004). The GRS was associated with incident diabetes in a similar direction and of comparable magnitude (OR per SD increment 0.85, 95% CI 0.76, 0.96, p = 0.009). CONCLUSIONS/INTERPRETATION:Among individuals not treated with lipid-modifying therapy low LDL-C concentrations were associated with increased diabetes risk. These observations may contribute to our understanding of why lipid-lowering treatment may cause diabetes in some individuals. Additional studies are warranted to elucidate the molecular mechanisms underlying our observations.

SUBMITTER: Andersson C

PROVIDER: S-EPMC4631796 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Low-density-lipoprotein cholesterol concentrations and risk of incident diabetes: epidemiological and genetic insights from the Framingham Heart Study.

Andersson Charlotte C Lyass Asya A Larson Martin G MG Robins Sander J SJ Vasan Ramachandran S RS

Diabetologia 20150926 12

<h4>Aims/hypothesis</h4>Statins and niacin (nicotinic acid) reduce circulating LDL-cholesterol (LDL-C) levels by different mechanisms. Yet, both increase the risk of diabetes mellitus. Our objective was to relate blood LDL-C concentrations and a genetic risk score (GRS) for LDL-C to the risk of incident diabetes in individuals not treated with lipid-modifying therapy.<h4>Methods</h4>We evaluated participants of the Framingham Heart Study who attended any of Offspring cohort examination cycles 3- ...[more]

PMID: 26409460

Similar Datasets

Project description:Background Elevated lipoprotein(a) is a well-established risk factor for atherosclerotic vascular disease but is not measured in routine clinical care. Screening of high lipoprotein(a) in individuals with moderate elevations of low-density lipoprotein cholesterol (LDL-C) may identify individuals at high risk of cardiovascular disease. Methods and Results We examined 2606 Framingham Offspring participants (median age, 54 years; 45% men) prospectively with a median follow-up of 15 years (n=392 incident cardiovascular events). Individuals with higher (≥100 nmol/L) versus lower lipoprotein(a) were divided into groups based on LDL-C <135 mg/dL versus ≥135 mg/dL. In Cox models, after adjustment for known risk factors, high lipoprotein(a) (≥100 nmol/L) and LDL-C ≥135 mg/dL were each significant predictors of cardiovascular disease (LDL-C ≥135 mg/dL: hazard ratio [HR], 1.34; 95% CI, 1.09-1.64; P=0.006; high lipoprotein (a): HR, 1.31; 95% CI, 1.03-1.66; P=0.026). Across the groups of high/low lipoprotein (a) and LDL-C ≥135 mg/dL or <135 mg/dL, the absolute cardiovascular disease risks at 15 years were 22.6% (high lipoprotein(a)/LDL-C ≥135 mg/dL, n=248), 17.3% (low lipoprotein(a)/LDL-C ≥135 mg/dL, n=758), 12.7% (high lipoprotein(a)/LDL-C <135 mg/dL, n=275) and 11.5% (low lipoprotein(a)/LDL-C <135 mg/dL, n=1328, reference group). Among individuals with LDL-C ≥135 mg/dL, those with high lipoprotein(a) had a 43% higher risk (HR, 1.43; 95% CI, 1.05-1.97; P=0.02). Presence of high lipoprotein(a) with moderate LDL-C levels (135-159 mg/dL) yielded absolute risks equivalent to those with LDL-C ≥160 mg/dL (23.5%, 95% CI, 17.4%-31.3%; and 20.7%, 95% CI, 16.8%-25.3%, respectively). Conclusions Concomitant elevation of LDL-C ≥135 mg/dL and lipoprotein(a) ≥100 nmol/L is associated with a high absolute risk of incident cardiovascular disease. lipoprotein(a) measurement in individuals with moderate elevations in LDL-C, who do not otherwise meet criteria for statins, may identify individuals at high cardiovascular risk.

Project description:BackgroundRemnant lipoproteins (RLPs), the triglyceride-enriched precursors to low-density lipoprotein, are an emerging risk factor for coronary heart disease (CHD). We sought to determine the association of RLP cholesterol (RLP-C) levels with incident CHD in 2 diverse, prospective, longitudinal observational US cohorts.Methods and resultsWe analyzed cholesterol levels from serum lipoprotein samples separated via density gradient ultracentrifugation in 4114 US black participants (mean age 53.8 years, 64% women) from the Jackson Heart Study and a random sample of 818 predominantly white participants (mean age 57.3 years, 52% women) from the Framingham Offspring Cohort Study. Multivariable-adjusted hazard ratios (HRs) for RLP-C (the sum of very low-density lipoprotein3 cholesterol and intermediate-density lipoprotein cholesterol) were derived to estimate associations with incident CHD events consisting of myocardial infarction, CHD death, and revascularizations for each cohort separately and as a combined population. There were 146 CHD events in the combined population. After adjustments for age, sex, body mass index, smoking, blood pressure, diabetes, and lipid-lowering therapy for the combined population, RLP-C (HR 1.23 per 1-SD increase, 95% CI 1.06-1.42, P<0.01) and intermediate-density lipoprotein cholesterol (HR 1.26 per 1-SD increase, 95% CI 1.08-1.47, P<0.01) predicted CHD during an 8-year follow-up. Associations were attenuated by high-density lipoprotein cholesterol and ultimately lost significance with inclusion of real low-density lipoprotein cholesterol, which excludes Lp(a) and IDL cholesterol fractions. Similar associations were seen in multivariable analyses within each cohort.ConclusionRLP-C levels are predictive of incident CHD in this diverse group of primary prevention subjects. Interventions aimed at reducing RLP-C to prevent CHD warrant further intensive investigation.Clinical trial registrationURL: http://www.ClinicalTrials.gov. Unique identifier: NCT00415415.

Project description:BACKGROUND: Cholesterol concentrations in blood are related to cardiovascular diseases. Recent genome-wide association studies (GWAS) of cholesterol levels identified a number of single-locus effects on total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) levels. Here, we report single-locus and epistasis SNP effects on TC and HDL-C using the Framingham Heart Study (FHS) data. RESULTS: Single-locus effects and pairwise epistasis effects of 432,096 SNP markers were tested for their significance on log-transformed TC and HDL-C levels. Twenty nine additive SNP effects reached single-locus genome-wide significance (p < 7.2 x 10-8) and no dominance effect reached genome-wide significance. Two new gene regions were detected, the RAB3GAP1-R3HDM1-LCT-MCM6 region of chr02 for TC identified by six new SNPs, and the OSBPL8-ZDHHC17 region (chr12) for HDL-C identified by one new SNP. The remaining 22 single-locus SNP effects confirmed previously reported genes or gene regions. For TC, three SNPs identified two gene regions that were tightly linked with previously reported genes associated with TC, including rs599839 that was 10 bases downstream PSRC1 and 3.498 kb downstream CELSR2, rs4970834 in CELSR2, and rs4245791 in ABCG8 that slightly overlapped with ABCG5. For HDL-C, LPL was confirmed by 12 SNPs 8-45 kb downstream, CETP by two SNPs 0.5-11 kb upstream, and the LIPG-ACAA2 region by five SNPs inside this region. Two epistasis effects on TC and thirteen epistasis effects on HDL-C reached the significance of "suggestive linkage". The most significant epistasis effect (p = 5.72 x 10-13) was close to reaching "significant linkage" and was a dominance x dominance effect of HDL-C between LMBRD1 (chr06) and the LRIG3 region (chr12), and this pair of gene regions had six other D x D effects with "suggestive linkage". CONCLUSIONS: Genome-wide association analysis of the FHS data detected two new gene regions with genome-wide significance, detected epistatic SNP effects on TC and HDL-C with the significance of suggestive linkage in seven pairs of gene regions, and confirmed some previously reported gene regions associated with TC and HDL-C.

Project description:Background Limited data are available on the prospective relationship between beverage consumption and plasma lipid and lipoprotein concentrations. Two major sources of sugar in the US diet are sugar-sweetened beverages (SSBs) and 100% fruit juices. Low-calorie sweetened beverages are common replacements. Methods and Results Fasting plasma lipoprotein concentrations were measured in the FOS (Framingham Offspring Study) (1991-2014; N=3146) and Generation Three (2002-2001; N=3584) cohorts. Beverage intakes were estimated from food frequency questionnaires and grouped into 5 intake categories. Mixed-effect linear regression models were used to examine 4-year changes in lipoprotein measures, and Cox proportional hazard models were used to estimate hazard ratios for incident dyslipidemia, adjusting for potential confounding factors. We found that regular (>1 serving per day) versus low (<1 serving per month) SSB consumption was associated with a greater mean decrease in high-density lipoprotein cholesterol (β±standard error -1.6±0.4 mg/dL; Ptrend<0.0001) and increase in triglyceride (β±standard error: 4.4±2.2 mg/dL; Ptrend=0.003) concentrations. Long-term regular SSB consumers also had a higher incidence of high triglyceride (hazard ratio, 1.52; 95% CI, 1.03-2.25) compared with low consumers. Although recent regular low-calorie sweetened beverage consumers had a higher incidence of high non-high-density lipoprotein cholesterol (hazard ratio, 1.40; 95% CI, 1.17-1.69) and low-density lipoprotein cholesterol (hazard ratio, 1.27; 95% CI, 1.05-1.53) concentrations compared with low consumers, cumulative average intakes of low-calorie sweetened beverages were not associated with changes in non-high-density lipoprotein cholesterol, low-density lipoprotein cholesterol concentrations, or incident dyslipidemias. Conclusions SSB intake was associated with adverse changes in high-density lipoprotein cholesterol and triglyceride concentrations, along with a higher risk of incident dyslipidemia, suggesting that increased SSB consumption may contribute to the development of dyslipidemia.

Dataset Information

Low-density-lipoprotein cholesterol concentrations and risk of incident diabetes: epidemiological and genetic insights from the Framingham Heart Study.

Publications

Low-density-lipoprotein cholesterol concentrations and risk of incident diabetes: epidemiological and genetic insights from the Framingham Heart Study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets