HDL levels modulate the impact of type 2 diabetes susceptibility alleles in older adults (original) (raw)
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European Heart Journal, 2009
There are a large number of common genetic variants that have been robustly associated with low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglyceride concentrations. The majority of these have been identified or confirmed in recent genome-wide association studies, but few studies have assessed the combined effect of known lipid variants. We hypothesized that these variants would influence both the need for interventions and myocardial infarction (MI) outcomes. We aimed to estimate combined effects of proven SNPs on LDL, HDL, and triglyceride concentrations and MI history in a representative older population.
Crescent Journal of Medical and Biological Sciences, 2015
Objective: Due to existing association between high-density lipoprotein (HDL) and cardiovascular disease, detection of factors affecting this lipid is important. Environmental factors and genetic variations have an important role in HDL level. The effects of these risk factors can be time-dependent; so, study of their effects on HDL level over time is important. In this study, we used transition model to analyze binary longitudinal data to investigate single nucleotide polymorphism (SNP) and other risk factors affecting low HDL over time. Materials and Methods: Data of 329 participants of 3 phases of Tehran Lipid and Glucose Study (TLGS) was analyzed using marginal transition model. This model has a formulation which allows first and second order Markov dependence to take into account the correlation among successive observations of the same individual in longitudinal binary response for which the marginal probability of success is modelled via a form of logistic regression. Results...
Atherosclerosis, 2011
Several genes that influence HDL-C, LDL-C, and triglyceride levels have been identified. The effects of genetic polymorphisms on lipid levels may be age dependent. We replicated 17 of these previously identified associations and then used cross-sectional and longitudinal analysis to investigate age-SNP interaction effects. The rs646776 SNP at the SORT1 locus showed an age interaction that was significant in cross-sectional analyses of 1350 individuals from Utah (p = 0.0003) and in 2977 individuals from the NHLBI Family Heart Study (p = 0.007) as well as in longitudinal analysis of a subsample of 1099 individuals from the Utah cohort that had been followed for over 20 years (p = 0.0001). The rs646776 genotype-specific difference in LDL-C levels was significantly greater for younger individuals than for older individuals. These findings may help elucidate the mode of action of the SORT1 gene and impact potential therapeutic interventions targeting this pathway.
Cardiovascular health, genetic predisposition, and lifetime risk of type 2 diabetes
European Journal of Preventive Cardiology, 2021
Aims Data on the lifetime risk of type 2 diabetes (T2D) incidence across different cardiovascular health (CVH) categories are scarce. Moreover, it remains unclear whether a genetic predisposition modifies this association. Methods and results Using data from the prospective population-based Rotterdam Study, a CVH score (body mass index, blood pressure, total cholesterol, smoking status, diet, and physical activity) was calculated and further categorized at baseline. Genetic predisposition to T2D was assessed and divided into tertiles by creating a genetic risk score (GRS). We estimated the lifetime risk for T2D within different CVH and GRS categories. Among 5993 individuals free of T2D at baseline [mean (standard deviation) age, 69.1 (8.5) years; 58% female], 869 individuals developed T2D during follow-up. At age 55 years, the remaining lifetime risk of T2D was 22.6% (95% CI: 19.4–25.8) for ideal, 28.3% (25.8–30.8) for intermediate, and 32.6% (29.0–36.2) for poor CVH. After further ...
Scientific reports, 2017
Patients with heterozygous familial hypercholesterolemia (HeFH) have been reported to be less vulnerable to type 2 diabetes mellitus (T2DM), although the mechanism is unknown. The aims of the present study were to assess the effects of low density lipoprotein (LDL) cholesterol concentration and the presence of FH-causing mutations on T2DM prevalence in HeFH. Data were collected from the Dyslipidemia Registry of the Spanish Arteriosclerosis Society. Inclusion criteria were definite or probable HeFH in patients aged ≥18 years. T2DM prevalence in HeFH patients was compared with data of the general population. 1732 patients were included. The prevalence of T2DM was lower in patients with HeFH compared with the general population (5.94% vs 9.44%; OR: 0.606, 95% CI 0.486-0.755, p < 0.001). Risk factors for developing T2DM were male sex, age, body mass index, hypertension, baseline triglyceride levels and years on statin therapy. The prevalence of T2DM in HeFH patients was 40% lower tha...
Atherosclerosis, 2002
Background: Molecular variations in the gene coding for the cholesteryl ester transfer protein (CETP) such as the TaqIB polymorphism are associated with higher plasma high-density lipoprotein (HDL) concentration. However, whether this polymorphism is associated with risk of myocardial infarction (MI) is uncertain. Methods and results: In a prospective cohort of 14 916 apparently healthy men enrolled in the Physicians' Health Study, allelic status for the TaqIB polymorphism in the CETP gene was determined among 384 participants who subsequently developed a first MI (cases) and among an equal number of age and smoking-matched participants who remained free of cardiovascular disease during follow-up (controls). Overall, the B2B2 genotype was present in 17% of the study participants and was associated with higher HDL cholesterol levels (mean mg/dl [ 9S.D.], 45 9 11 for the B1B1 genotype, 48 9 13 for the B1B2 genotype and 50 9 12 for the B2B2 genotype; P= 0.01). However, the risk of developing MI did not differ significantly across these three genotypes. After adjustment for coronary risk factors (but not HDL), the relative risks for future MI were 1.12(95% CI 0.74 −1.70) for the B1B2 genotype and 0.95(95% CI 0.54-1.66) for the B2B2 genotype, compared with the B1B1 genotype. In subgroup analysis of individuals with low HDL levels, B2B2 genotype appeared to have a lower risk of MI compared with the B1B1 genotype. However, participants with high HDL were at lower risk of developing MI regardless of their CETP genotype. Conclusions: In this prospective study of apparently healthy middle-aged US men, carriers of the B2 allele of the TaqIB in the CETP gene had higher HDL concentrations, but did not have lower risk of MI. Condensed abstract: In a cohort of apparently healthy middle-aged US men, the relation between CETP genotype and MI risk was prospectively examined in a nested case-control study. Afier adjusting for coronary risk factors (but not HDL), the 9-year risk of developing MI did not differ significantly by genotype. Comparing to the B1B1 genotype, the relative risks for future MI were 1.12 (95% CI 0.74 −1.70) for the B1B2 genotype and 0.95 (95% CI 0.54-1.66) for the B2B2 genotype.
Triglyceride-Increasing Alleles Associated with Protection against Type-2 Diabetes
PLOS Genetics, 2015
Elevated plasma triglyceride (TG) levels are an established risk factor for type-2 diabetes (T2D). However, recent studies have hinted at the possibility that genetic risk for TG may paradoxically protect against T2D. In this study, we examined the association of genetic risk for TG with incident T2D, and the interaction of baseline TG with TG genetic risk on incident T2D in 13,247 European-Americans (EA) and 3,238 African-Americans (AA) from three prospective cohort studies. A TG genetic risk score (GRS) was calculated based on 31 validated single nucleotide polymorphisms (SNPs). We considered several baseline covariates, including body-mass index (BMI) and lipid traits. Among EA and AA, we find, as expected, that baseline levels of TG are strongly positively associated with incident T2D (p<2 x 10-10). However, the TG GRS is negatively associated with T2D (p=0.013), upon adjusting for only race, in the full dataset. Upon additionally adjusting for age, sex, BMI, high-density lipoprotein cholesterol and TG, the TG GRS is significantly and negatively associated with T2D incidence (p=7.0 x 10-8), with similar trends among both EA and AA. No single SNP appears to be driving this association. We also find a significant statistical interaction of the TG GRS with TG (p interaction =3.3 x 10-4), whereby the association of TG with incident T2D is strongest among those with low genetic risk for TG. Further research is needed to understand the likely pleiotropic mechanisms underlying these findings, and to clarify the causal relationship between T2D and TG.