Identifying methylation quantitative trait loci (meQTLs) and integrating them with disease-associated variants from genome-wide association studies (GWAS) may illuminate functional mechanisms underlying genetic variant-disease associations. Here, we perform GWAS of >415 thousand CpG methylation sites in whole blood from 4170 individuals and map 4.7 million cis- and 630 thousand trans-meQTL variants targeting >120 thousand CpGs. Independent replication is performed in 1347 participants from two studies. By linking cis-meQTL variants with GWAS results for cardiovascular disease (CVD) traits, we identify 92 putatively causal CpGs for CVD traits by Mendelian randomization analysis. Further integrating gene expression data reveals evidence of cis CpG-transcript pairs causally linked to CVD. In addition, we identify 22 trans-meQTL hotspots each targeting more than 30 CpGs and find that trans-meQTL hotspots appear to act in cis on expression of nearby transcriptional regulatory genes. Our findings provide a powerful meQTL resource and shed light on DNA methylation involvement in human diseases.
Background: Concerns have been raised about the concurrent temporal trend between simple sugar intakes, especially of fructose or high-fructose corn syrup (HFCS), and rates of nonalcoholic fatty liver disease (NAFLD) in the United States.Objective: We examined the effect of different amounts and forms of dietary fructose on the incidence or prevalence of NAFLD and indexes of liver health in humans.Design: We conducted a systematic review of English-language, human studies of any design in children and adults with low to no alcohol intake and that reported at least one predetermined measure of liver health. The strength of the evidence was evaluated by considering risk of bias, consistency, directness, and precision.Results: Six observational studies and 21 intervention studies met the inclusion criteria. The overall strength of evidence for observational studies was rated insufficient because of high risk of biases and inconsistent study findings. Of 21 intervention studies, 19 studies were in adults without NAFLD (predominantly healthy, young men) and 1 study each in adults or children with NAFLD. We found a low level of evidence that a hypercaloric fructose diet (supplemented by pure fructose) increases liver fat and aspartate aminotransferase (AST) concentrations in healthy men compared with the consumption of a weight-maintenance diet. In addition, there was a low level of evidence that hypercaloric fructose and glucose diets have similar effects on liver fat and liver enzymes in healthy adults. There was insufficient evidence to draw a conclusion for effects of HFCS or sucrose on NAFLD.Conclusions: On the basis of indirect comparisons across study findings, the apparent association between indexes of liver health (ie, liver fat, hepatic de novo lipogenesis, alanine aminotransferase, AST, and γ-glutamyl transpeptase) and fructose or sucrose intake appear to be confounded by excessive energy intake. Overall, the available evidence is not sufficiently robust to draw conclusions regarding effects of fructose, HFCS, or sucrose consumption on NAFLD.
Background & Aims The relations of non-alcoholic fatty liver disease to cardiovascular disease (CVD) risk factors are not fully understood. The objective of our study is to explore the bi-directional relationships of fatty liver to CVD risk factors. Methods We prospectively evaluated whether liver fat predicted the development of CVD risk factors and whether CVD risk factors predicted new onset fatty liver during 6 years of follow up in middle- to older-aged Framingham Heart Study participants. We estimated liver fat using multi-detector computed tomography. Results We included 1,051 participants (mean age 45 ± 6 years, 46% women). The prevalence of fatty liver was 18% at baseline. In participants without fatty liver at baseline, 101 participants developed incident fatty liver over approximately 6 years. Baseline liver fat (per standard deviation increase) was associated with increased odds of incident hypertension (OR 1.42; 95% CI 1.15-1.76; p=0.001) and incident type 2 diabetes (OR 1.43; 95% CI 1.09-1.88, p<0.001). In a parallel analysis, individuals with hypertension (OR 3.34; 95% CI 2.04-5.49), hypertriglyceridemia (OR 3.04; 95% CI:1.84-5.02), impaired fasting glucose (OR 2.92; 95% CI 1.76-4.82), or type 2 diabetes (OR 4.15; 95% CI 1.19-14.46) at baseline had higher odds of incident fatty liver compared to individuals without those conditions (all p<0.03). In both analyses, the observed associations remained similar after additional adjustments for measures of adiposity. Conclusions The present study demonstrated bi-directional relationships between fatty liver and CVD risk factors among middle- to older-aged Framingham Heart Study participants.
Background & Aims Non-alcoholic fatty liver disease affects ~30% of US adults, yet the role of sugar-sweetened beverages and diet soda on these diseases remains unknown. We examined the cross-sectional association between intake of sugar-sweetened beverages or diet soda and fatty liver disease in participants of the Framingham Offspring and Third Generation cohorts. Methods Fatty liver disease was defined using liver attenuation measurements generated from computed tomography in 2634 participants. Alanine transaminase concentration, a crude marker of fatty liver disease, was measured in 5908 participants. Sugar-sweetened beverage and diet soda intake were estimated using a food frequency questionnaire. Participants were categorized as either non-consumers or consumers (3 categories: 1 serving/month to <1 serving/week, 1 serving/week to <1 serving/-day, and ⩾1 serving/day) of sugar-sweetened beverages or diet soda. Results After adjustment for age, sex, smoking status, Framingham cohort, energy intake, alcohol, dietary fiber, fat (% energy), protein (% energy), diet soda intake, and body mass index, the odds ratios of fatty liver disease were 1, 1.16 (0.88, 1.54), 1.32 (0.93, 1.86), and 1.61 (1.04, 2.49) across sugar-sweetened beverage consumption categories (p trend = 0.04). Sugar-sweetened beverage consumption was also positively associated with alanine transaminase levels (p trend = 0.007). We observed no significant association between diet soda intake and measures of fatty liver disease. Conclusion In conclusion, we observed that regular sugar-sweetened beverage consumption was associated with greater risk of fatty liver disease, particularly in overweight and obese individuals, whereas diet soda intake was not associated with measures of fatty liver disease.
In an analysis of participants in the Framingham Heart Study, increasing diet quality, determined based on MDS and AHEI scores, is associated with less liver fat accumulation and reduced risk for new-onset fatty liver. An improved diet is particularly important for individuals with a high genetic risk for NAFLD.
Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury1–4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries5. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.
Inconsistent evidence describes the association between dietary intake of dairy and milk-based products and type 2 diabetes (T2D) risk. Our objective was to assess associations between consumption of milk-based products, incident prediabetes, and progression to T2D in the Framingham Heart Study Offspring Cohort. Total dairy and milk-based product consumption was assessed by ≤4 food-frequency questionnaires across a mean of 12 y of follow-up in 2809 participants [mean ± SD age: 54.0 ± 9.7 y; body mass index (in kg/m): 27.1 ± 4.7; 54% female]. Prediabetes was defined as the first occurrence of fasting plasma glucose ≥5.6 to <7.0 mmol/L (≥100 to <126 mg/dL), and T2D was defined as the first occurrence of fasting plasma glucose ≥7.0 mmol/L (≥126 mg/dL) or diabetes treatment. Proportional hazards models were used to estimate the risk of incident outcomes relative to dairy product intake in subsets of the cohort who were at risk of developing the outcomes. Spline regressions were used to examine potential nonlinear relations. Of 1867 participants free of prediabetes at baseline, 902 (48%) developed prediabetes. Total, low-fat, and high-fat dairy consumptions were associated with a 39%, 32%, and 25% lower risk of incident prediabetes, respectively, in the highest compared with the lowest intakes (≥14 compared with <4 servings/wk). Total, low-fat and skim milk, whole-milk, and yogurt intakes were associated nonlinearly with incident prediabetes; moderate intake was associated with the greatest relative risk reduction. Neither cheese nor cream and butter was associated with prediabetes. Of 925 participants with prediabetes at baseline, 196 (21%) developed T2D. Only high-fat dairy and cheese showed evidence of dose-response, inverse associations with incident T2D, with 70% and 63% lower risk, respectively, of incident T2D between the highest and lowest intake categories (≥14 compared with <1 serving/wk for high-fat dairy, ≥4 compared with <1 serving/wk for cheese). Associations of dairy with incident prediabetes or diabetes varied both by dairy product and type and by baseline glycemic status in this middle-aged US population. Baseline glycemic status may partially underlie prior equivocal evidence regarding the role of dairy intake in diabetes.
Background Genome-wide association studies (GWAS) have identified loci associated with coronary heart disease (CHD) in Caucasians of European ancestry. This study evaluated whether genetic markers previously identified in Caucasians associated with nonfatal acute myocardial infarction (MI) in Hispanics. Methods and Results Cases (n=1,989) with a first nonfatal acute MI and population-based controls (n=2,096) living in Costa Rica were studied. Fourteen SNPs were genotyped. Seven SNPs at three independent loci showed significant associations with MI. The odds ratios (ORs) and 95% confidence interval (CI) for the loci with the strongest associations were 1.16 (1.05-1.27) for rs4977574 (CDKN2A/2B), 1.15 (1.03-1.29) for rs646776 (CELSR2-PSRC1-SORT1), and 1.22 (1.08-1.38) for rs501120 (CXCL12); and the corresponding population attributable risk (PAR) were 6.8%, 10.5%, and 15.2%; respectively. We developed a genetic risk score (GRS) by summing the number of the top three associated risk alleles. The OR for MI per GRS unit was 1.18 (95% CI 1.11- 1.25; P = 4.83*10-8). Discrimination of MI was significantly improved (P =0.02) when the GRS was added to a model including clinical predictors. However, the increment in the area under the receiver-operating characteristic curve (AUC) after adding GRS was moderate, from 0.67 (95% CI, 0.65 to 0.69) to 0.68 (95% CI, 0.66 to 0.70). Conclusions These results indicate both the consistency and disparity of genetic effects on risk of MI between Hispanic and Caucasian populations. The improvement of the identified genetic markers on discrimination of MI in Hispanics was modest.
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