SD Increase In Genetic Risk Score Research Articles

Maternal GDM Status, Genetically Determined Blood Glucose, and Offspring Obesity Risk: An Observational Study.

The purpose of this study was to estimate the associations of genetically determined maternal blood glucose levels with obesity-related outcomes among children from pregnancies with and without gestational diabetes mellitus (GDM). A total of 1,114 mothers with (N = 560) and without (N = 554) GDM and their children were included in the present study. A maternal genetic risk score (GRS) for blood glucose was constructed on the basis of 17 single-nucleotide polymorphisms identified from a recent genome-wide association study. It was found that maternal GRS for blood glucose showed different associations with offspring risk of overweight and obesity, as well as adiposity measures (all P for interaction < 0.05). Among mothers without GDM, genetically determined maternal blood glucose levels were associated with an 89% higher risk of overweight in their children (95% CI: 42%-152% per SD increase in GRS, P = 1.40 × 10-5 ) and a 120% higher risk of obesity (44%-235%, P = 2.61 × 10-4 ) after adjustment for covariates. In addition, higher maternal GRS for blood glucose was associated with children's increased obesity-related traits (all P < 0.05). However, no significant associations were observed among children of mothers with GDM. This study indicates that GDM status may modify the relation between genetically determined glucose levels and obesity risk among children.

Active Cigarette Smoking Is Associated With an Exacerbation of Genetic Susceptibility to Diabetes.

The heritability levels of two traits for diabetes diagnosis, serum fasting glucose (FG) and glycated hemoglobin (HbA1c), were estimated to be 51-62%. Studies have shown that cigarette smoking is a modifiable risk factor for diabetes. It is important to uncover whether smoking may modify the genetic risk of diabetes. This study included unrelated Taiwan Biobank subjects in a discovery cohort (TWB1) of 25,460 subjects and a replication cohort (TWB2) of 58,774 subjects. Genetic risk score (GRS) of each TWB2 subject was calculated with weights retrieved from the TWB1 analyses. We then assessed the significance of GRS-smoking interactions on FG, HbA1c, and diabetes while adjusting for covariates. A total of five smoking measurements were investigated, including active smoking status, pack-years, years as a smoker, packs smoked per day, and hours as a passive smoker per week. Except for passive smoking, all smoking measurements were associated with FG, HbA1c, and diabetes (P < 0.0033) and were associated with an exacerbation of the genetic risk of FG and HbA1c (P Interaction < 0.0033). For example, each 1 SD increase in GRS is associated with a 1.68% higher FG in subjects consuming one more pack of cigarettes per day (P Interaction = 1.9 × 10-7). Smoking cessation is especially important for people who are more genetically predisposed to diabetes.

A Comprehensive Type 1 Diabetes Genetic Risk Score Is Associated with Type 2 Diabetes in the Framingham Heart Study

It is often difficult to distinguish between type 1 (T1D) and type 2 diabetes (T2D), particularly in young adulthood. Both T1D and T2D have significant genetic contributions to risk and understanding their genetic overlap may offer clinical insight. We examined whether a T1D genetic risk score (GRS) is associated with clinical features and diagnosis of T2D in the Framingham Heart Study (FHS). We constructed a T1D GRS based on 79 SNPs from fine mapping results, with SNPs weighted by published effect sizes. The GRS included both HLA (27 SNPs) and non-HLA (52 SNPs) regions, and was applied to 1503 participants with T2D. Multivariable regression models assessed the association of the GRS with age of T2D onset, BMI, HbA1C, HOMA-β and HOMA-IR at the exam of diagnosis. Case-control analysis of 1503 cases and 5649 controls was done using multivariate generalized estimating equations (GEE) logistic models to determine the association between the T1D GRS and T2D risk with age and sex as covariates. In FHS participants, the mean age was 57.2 y, BMI was 30 kg/m2, and HbA1c 6.05%. The T1D GRS was not associated with T2D age of onset, or BMI, HbA1c, HOMA-β and HOMA-IR after excluding participants on medications for T2D. There was a trend towards lower HOMA-β and HOMA-IR values in the top quintile of the GRS (n=244, mean=2.47, SD= 0.7 for ln(HOMA-β) and mean=2.88, SD=0.8 for ln(HOMA-IR)) when compared to the lowest quintile of the GRS (n=260, mean= 2.53, SD=0.8 for ln(HOMA-β) and mean=2.92, SD=0.8 for ln(HOMA-IR)). The T1D GRS was associated with T2D (β = 0.per SD increase in GRS, SE= 0.03, OR =1.1, P = 0.04). When the non-HLA and HLA components of the GRS were tested separately, the results remained significant only for the non-HLA T1D GRS (β = 0.per SD increase in GRS, SE= 0.03, OR=1.1, P= 0.02). A T1D GRS of non-HLA SNPs is associated with T2D in the FHS participants. Our further analysis with increased sample size in multi-ethnic populations may refine the impact of the T1D GRS to characterize individuals with T2D. Disclosure S. Srinivasan: None. A. Leong: None. M. Udler: None. B.C. Porneala: None. J.B. Meigs: None. S.S. Rich: None. J. Dupuis: None.

A 45-SNP genetic risk score is increased in early-onset coronary artery disease but independent of familial disease clustering

Background and aimsCommon genetic risk variants may contribute to the heritability of early-onset coronary artery disease (CAD). We aimed to investigate the association of a genetic risk score (GRS) with age upon CAD-onset and to test the association between the GRS, familial clustering, and CAD severity in early-onset CAD. Methods134 early-onset CAD patients (<40 years), 446 late-onset CAD patients (male >55 years/female >65 years), and 89 healthy controls were genotyped for 45 CAD-associated SNPs and a GRS was created. In early-onset CAD patients, family pedigrees with information on 1585 1st and 2nd degree relatives were used to calculate a stratified log-rank family score (SLFS) as a measure of familial clustering. ResultsEarly-onset patients had a higher mean GRS than late-onset CAD patients (p = 0.02) and healthy controls (p < 0.0001). In the adjusted model, a GRS increase of one SD was associated with 1.2 years (95% CI 0.1–2.2) earlier onset. The GRS was not associated with the SLFS in the regression model (p = 0.41) and did not differ between SLFS tertiles (p = 0.98). The SLFS predicted the number of affected coronary vessels (OR [95% CI] per SD increase in SLFS: 2.0 [1.4–3.0]), whereas the association between the GRS and CAD severity was not statistically significant (OR [95% CI] per SD increase in GRS: 1.3 [0.9–1.9]). ConclusionsThe GRS was increased in early-onset CAD patients, but not associated with the SLFS, suggesting that these common genetic variants are of minor importance in familial clustering of early-onset CAD. Furthermore, family pedigree analysis may predict CAD severity more precisely than common variants.

Prospective association of a genetic risk score and lifestyle intervention with cardiovascular morbidity and mortality among individuals with type 2 diabetes: the Look AHEAD randomised controlled trial.

Both obesity and genetics contribute to cardiovascular disease (CVD). We examined whether a genetic risk score (GRS) prospectively predicted cardiovascular morbidity and mortality among overweight/obese individuals with type 2 diabetes and whether behavioural weight loss could diminish this association. Look AHEAD (Action for Health in Diabetes) is a randomised controlled trial to determine the effects of intensive lifestyle intervention (ILI), including weight loss and physical activity, relative to diabetes support and education, on cardiovascular outcomes among overweight/obese individuals with type 2 diabetes. Of the participants, 4,016 provided consent for genetic analyses and had DNA samples passing quality control procedures. These secondary data analyses focused on whether a GRS derived from 153 single nucleotide polymorphisms (SNPs) associated with coronary artery disease in the most recent genome-wide association study predicted cardiovascular morbidity and mortality over a median of 9.6 years of follow-up, and whether ILI would diminish this association. The GRS significantly predicted the primary composite endpoint of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalisation for angina in the full sample (HR, 95% CI per 1 SD increase in GRS: 1.19 [1.10, 1.28]) and among individuals with no known history of CVD at baseline (HR 1.18 [95% CI 1.07, 1.30]). In no case did ILI significantly alter this association. A GRS comprised of SNPs significantly predicts cardiovascular morbidity and mortality over 9.6 years of follow-up in Look AHEAD. Lifestyle intervention did not alter the genetic association. NCT00017953; NCT01270763.

Common sequence variants associated with coronary artery disease correlate with the extent of coronary atherosclerosis.

Single-nucleotide polymorphisms predisposing to coronary artery disease (CAD) have been shown to predict cardiovascular risk in healthy individuals when combined into a genetic risk score (GRS). We examined whether the cumulative burden of known genetic risk variants associated with risk of CAD influences the development and progression of coronary atherosclerosis. We investigated the combined effects of all known CAD variants in a cross-sectional study of 8622 Icelandic patients with angiographically significant CAD (≥ 50% diameter stenosis). We constructed a GRS based on 50 CAD variants and tested for association with the number of diseased coronary arteries on angiography. In models adjusted for traditional cardiovascular risk factors, the GRS associated significantly with CAD extent (difference per SD increase in GRS, 0.076; P=7.3 × 10(-17)). When compared with the bottom GRS quintile, patients in the top GRS quintile were roughly 1.67× more likely to have multivessel disease (odds ratio, 1.67; 95% confidence interval, 1.45-1.94). The GRS significantly improved prediction of multivessel disease over traditional cardiovascular risk factors (χ(2) likelihood ratio 48.1; P<0.0001) and modestly improved discrimination, as estimated by the C-statistic (without GRS versus with GRS, 64.0% versus 64.8%) and the integrated discrimination improvement (0.52%). Furthermore, the GRS associated with an earlier age at diagnosis of angiographic CAD. These findings were replicated in an independent sample from the Emory Biobank study (n=1853). When combined into a single GRS, known genetic risk variants for CAD contribute significantly to the extent of coronary atherosclerosis in patients with significant angiographic disease.