Circulating metabolites may illustrate relationship of alcohol consumption with cardiovascular disease.

BACKGROUND: Metabolite signatures of long-term alcohol consumption are lacking. To better understand the molecular basis linking alcohol drinking and cardiovascular disease (CVD), we investigated circulating metabolites associated with long-term alcohol consumption and examined whether these metabolites were associated with incident CVD. METHODS: Cumulative average alcohol consumption (g/day) was derived from the total consumption of beer, wine, and liquor on average of 19 years in 2428 Framingham Heart Study Offspring participants (mean age 56 years, 52% women). We used linear mixed models to investigate the associations of alcohol consumption with 211 log-transformed plasma metabolites, adjusting for age, sex, batch, smoking, diet, physical activity, BMI, and familial relationship. Cox models were used to test the association of alcohol-related metabolite scores with fatal and nonfatal incident CVD (myocardial infarction, coronary heart disease, stroke, and heart failure). RESULTS: We identified 60 metabolites associated with cumulative average alcohol consumption (p < 0.05/211 ≈ 0.00024). For example, 1 g/day increase of alcohol consumption was associated with higher levels of cholesteryl esters (e.g., CE 16:1, beta = 0.023 ± 0.002, p = 6.3e - 45) and phosphatidylcholine (e.g., PC 32:1, beta = 0.021 ± 0.002, p = 3.1e - 38). Survival analysis identified that 10 alcohol-associated metabolites were also associated with a differential CVD risk after adjusting for age, sex, and batch. Further, we built two alcohol consumption weighted metabolite scores using these 10 metabolites and showed that, with adjustment age, sex, batch, and common CVD risk factors, the two scores had comparable but opposite associations with incident CVD, hazard ratio 1.11 (95% CI = [1.02, 1.21], p = 0.02) vs 0.88 (95% CI = [0.78, 0.98], p = 0.02). CONCLUSIONS: We identified 60 long-term alcohol consumption-associated metabolites. The association analysis with incident CVD suggests a complex metabolic basis between alcohol consumption and CVD.

Circulating Metabolites May Illustrate Relationship of Alcohol Consumption with Cardiovascular Disease.

Background: Metabolite signatures of long-term alcohol consumption are lacking. To better understand the molecular basis linking alcohol drinking and cardiovascular disease (CVD), we investigated circulating metabolites associated with long-term alcohol consumption and examined whether these metabolites were associated with incident CVD. Methods: Cumulative average alcohol consumption (g/day) was derived from the total consumption of beer, wine and liquor on average of 19 years in 2,428 Framingham Heart Study Offspring participants (mean age 56 years, 52% women). We used linear mixed models to investigate the associations of alcohol consumption with 211 log-transformed plasma metabolites, adjusting for age, sex, batch, smoking, diet, physical activity, BMI, and familial relationship. Cox models were used to test the association of alcohol-related metabolite scores with fatal and nonfatal incident CVD (myocardial infarction, coronary heart disease, stroke, and heart failure). Results: We identified 60 metabolites associated with cumulative average alcohol consumption (p<0.05/211≈0.00024). For example, one g/day increase of alcohol consumption was associated with higher levels of cholesteryl esters (e.g., CE 16:1, beta=0.023±0.002, p=6.3e-45) and phosphatidylcholine (e.g., PC 32:1, beta=0.021±0.002, p=3.1e-38). Survival analysis identified that 10 alcohol-associated metabolites were also associated with a differential CVD risk after adjusting for age, sex, and batch. Further, we built two alcohol consumption weighted metabolite scores using these 10 metabolites and showed that, with adjustment age, sex, batch, and common CVD risk factors, the two scores had comparable but opposite associations with incident CVD, hazard ratio 1.11(95% CI=[1.02, 1.21],p=0.02) vs 0.88 (95% CI=[0.78, 0.98], p=0.02). Summary: We identified 60 long-term alcohol consumption-associated metabolites. The association analysis with incident CVD suggests a complex metabolic basis between alcohol consumption and CVD.

Smoking, blood DNA methylation sites and lung cancer risk.

Altered DNA methylation (DNAm) might be a biological intermediary in the pathway from smoking to lung cancer. In this study, we investigated the contribution of differential blood DNAm to explain the association between smoking and lung cancer incidence. Blood DNAm was measured in 2321 Strong Heart Study (SHS) participants. Incident lung cancer was assessed as time to event diagnoses. We conducted mediation analysis, including validation with DNAm and paired gene expression data from the Framingham Heart Study (FHS). In the SHS, current versus never smoking and pack-years single-mediator models showed, respectively, 29 and 21 differentially methylated positions (DMPs) for lung cancer with statistically significant mediated effects (14 of 20 available, and five of 14 available, positions, replicated, respectively, in FHS). In FHS, replicated DMPs showed gene expression downregulation largely in trans, and were related to biological pathways in cancer. The multimediator model identified that DMPs annotated to the genes AHRR and IER3 jointly explained a substantial proportion of lung cancer. Thus, the association of smoking with lung cancer was partly explained by differences in baseline blood DNAm at few relevant sites. Experimental studies are needed to confirm the biological role of identified eQTMs and to evaluate potential implications for early detection and control of lung cancer.

Dietary and supplemental intake of vitamins C and E is associated with altered DNA methylation in an epigenome-wide association study meta-analysis.

BACKGROUND: Dietary intake of antioxidants such as vitamins C and E protect against oxidative stress, and may also be associated with altered DNA methylation patterns. METHODS: We meta-analysed epigenome-wide association study (EWAS) results from 11,866 participants across eight population-based cohorts to evaluate the association between self-reported dietary and supplemental intake of vitamins C and E with DNA methylation. EWAS were adjusted for age, sex, BMI, caloric intake, blood cell type proportion, smoking status, alcohol consumption, and technical covariates. Significant results of the meta-analysis were subsequently evaluated in gene set enrichment analysis (GSEA) and expression quantitative trait methylation (eQTM) analysis. RESULTS: In meta-analysis, methylation at 4,656 CpG sites was significantly associated with vitamin C intake at FDR ≤ 0.05. The most significant CpG sites associated with vitamin C (at FDR ≤ 0.01) were enriched for pathways associated with systems development and cell signalling in GSEA, and were associated with downstream expression of genes enriched in the immune response in eQTM analysis. Furthermore, methylation at 160 CpG sites was significantly associated with vitamin E intake at FDR ≤ 0.05, but GSEA and eQTM analysis of the top most significant CpG sites associated with vitamin E did not identify significant enrichment of any biological pathways investigated. CONCLUSIONS: We identified significant associations of many CpG sites with vitamin C and E intake, and our results suggest that vitamin C intake may be associated with systems development and the immune response.

Body mass index trajectories, weight gain and risks of liver and biliary tract cancers.

BACKGROUND: Little is known about the role of early obesity or weight change during adulthood in the development of liver cancer and biliary tract cancer (BTC). METHODS: We investigated the associations of body mass index (BMI) and weight trajectories with the risk of liver cancer and BTC in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). BMI was self-reported at ages 20, 50, and at enrollment. BMI trajectories were determined using latent class growth models. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: During a median follow-up of 15.9 years among 138,922 participants, 170 liver cancer and 143 BTC cases were identified. Compared with those whose BMI does not exceed 25 kg/m2, participants with BMI exceeding 25 kg/m2 at age 20 had increased risks of liver cancer (HR = 2.03, 95% CI: 1.26-3.28) and BTC (HR = 1.99, 95% CI: 1.16-3.39). Compared to participants maintaining normal BMI until enrollment, trajectory of normal weight at age 20 to obesity at enrollment was associated with increased risk for liver cancer (HR = 2.50, 95% CI: 1.55-4.04) and BTC (HR = 1.83, 95% CI: 1.03-3.22). Compared to adults with stable weight (+/-5kg) between age 20 to 50 years, weight gain ≥20 kg between ages 20 to 50 years had higher HRs of 2.24 (95%CI: 1.40-3.58) for liver cancer and 1.86 (95% CI: 1.12-3.09) for BTC. CONCLUSIONS: Being overweight/obese at age 20, and BMI trajectories that result in being overweight and/or obese, may increase risk for both liver cancer and BTC.

Integrative analysis of clinical and epigenetic biomarkers of mortality.

DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n = 15,013). During a mean follow-up of 10 years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p < 1 × 10-7 , of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm-based prediction models for all-cause mortality that predicted mortality risk after adjusting for clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed an improvement in prediction of cancer death with 5% increase in the C-index in a replication cohort, compared with the model including clinical risk factors alone. Mendelian randomization identified 15 putatively causal CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta = 1.2, PMR  = 4.1 × 10-4 ) and negatively associated with longevity (Beta = -1.9, PMR  = 0.02). Pathway analysis revealed that genes associated with mortality-related CpGs are enriched for immune- and cancer-related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk.

Higher diet quality relates to decelerated epigenetic aging.

BACKGROUND: DNA methylation-based epigenetic age measures have been used as biological aging markers and are associated with a healthy lifespan. Few population-based studies have examined the relation between diet and epigenetic age acceleration. OBJECTIVES: We aimed to investigate the relation between diet quality and epigenetic age acceleration. METHODS: We analyzed data from 1995 participants (mean age, 67 years; 55% women) of the Framingham Heart Study Offspring Cohort. Cross-sectional associations between the Dietary Approaches to Stop Hypertension (DASH) score and 3 whole-blood DNA methylation-derived epigenetic age acceleration measures-Dunedin Pace of Aging Methylation (DunedinPoAm), GrimAge acceleration (GrimAA), and PhenoAge acceleration (PhenoAA)-were examined. A mediation analysis was conducted to assess the mediating role of epigenetic age acceleration in relation to DASH and all-cause mortality. RESULTS: A higher DASH score was associated with lower levels of DunedinPoAm (ß = -0.05; SE = 0.02; P = 0.007), GrimAA (ß = -0.09; SE = 0.02; P < 0.001), and PhenoAA (ß = -0.07; SE = 0.02; P = 0.001). All 3 epigenetic measures mediated the association between the DASH score and all-cause mortality, with mean proportions of 22.1% for DunedinPoAm (Pmediation = 0.04), 45.1% for GrimAA (Pmediation = 0.001), and 22.9% for PhenoAA (Pmediation = 0.03). An interaction was observed between the DASH score and smoking status in relation to the epigenetic aging markers. The association between the DASH score and epigenetic aging markers tended to be stronger in "ever-smokers" (former and current smokers) compared to "never-smokers." The proportions of mediation were 31.3% for DunedinPoAm, 46.8% for GrimAA, and 10.3% for PhenoAA in ever-smokers, whereas no significant mediation was observed in never-smokers. CONCLUSIONS: Higher diet quality is associated with slower epigenetic age acceleration, which partially explains the beneficial effect of diet quality on the lifespan. Our findings emphasize that adopting a healthy diet is crucial for maintaining healthy aging.

Diet Quality Scores Are Positively Associated with Whole Blood-Derived Mitochondrial DNA Copy Number in the Framingham Heart Study.

BACKGROUND: The association between diet quality and mitochondrial DNA copy number (mtDNA-CN) remains to be examined. OBJECTIVES: We aimed to study the relation between diet quality and mtDNA-CN. METHODS: We analyzed data from 2931 Framingham Heart Study (FHS) participants (mean age of 57 y, 55% females). Whole-genome sequencing was used to calculate mtDNA-CN from whole-blood samples. We examined the cross-sectional associations between 3 diet quality scores, the Dietary Approaches to Stop Hypertension (DASH) score, the Alternative Healthy Eating Index (AHEI), and the Mediterranean diet score (MDS), and mtDNA-CN. Linear mixed models were used to account for maternal lineage. RESULTS: We observed that a higher DASH score was positively associated with mtDNA-CN after adjusting for sex, age, energy intake, smoking status, alcohol intake, and physical activity level. A 1-SD increase in the DASH score was associated with a 0.042-SD greater mtDNA-CN (95% CI: 0.007, 0.077; P = 0.02). Similarly, for each SD increase in AHEI and MDS, the mtDNA-CN SD increased by 0.056 (95% CI: 0.019, 0.092; P = 0.003) and 0.047 (95% CI: 0.01, 0.083; P = 0.01), respectively. Diet quality scores were associated with neutrophil and lymphocyte counts but not platelet counts, e.g., for a 1-SD increase in the DASH, neutrophils decreased by 0.8% (95% CI: 0.5%, 1.1%; P = 4.1 × 10-6), lymphocytes increased by 0.7% (95% CI: 0.4%, 1%, P = 1.2 × 10-5), and there was no significant change in platelet number (0.1 × 1000/µL; 95% CI: -1.6, 1.9; P = 0.89). Further adjustment for neutrophil, lymphocyte, and platelet counts and the associations between diet quality scores and mtDNA-CN were completely attenuated to nonsignificant (P = 0.95, 0.54, and 0.91, respectively). CONCLUSIONS: We observed that higher diet quality is associated with a greater whole-blood derived mtDNA-CN in middle-aged to older adult FHS participants, and that blood cell composition, particularly neutrophil counts, attenuated the association between diet quality and mtDNA-CN.

Cardiovascular Biomarkers of Obesity and Overlap With Cardiometabolic Dysfunction.

Background Obesity may be associated with a range of cardiometabolic manifestations. We hypothesized that proteomic profiling may provide insights into the biological pathways that contribute to various obesity-associated cardiometabolic traits. We sought to identify proteomic signatures of obesity and examine overlap with related cardiometabolic traits, including abdominal adiposity, insulin resistance, and adipose depots. Methods and Results We measured 71 circulating cardiovascular disease protein biomarkers in 6981 participants (54% women; mean age, 49 years). We examined the associations of obesity, computed tomography measures of adiposity, cardiometabolic traits, and incident metabolic syndrome with biomarkers using multivariable regression models. Of the 71 biomarkers examined, 45 were significantly associated with obesity, of which 32 were positively associated and 13 were negatively associated with obesity (false discovery rate q<0.05 for all). There was significant overlap of biomarker profiles of obesity and cardiometabolic traits, but 23 biomarkers, including melanoma cell adhesion molecule (MCAM), growth differentiation factor-15 (GDF15), and lipoprotein(a) (LPA) were unique to metabolic traits only. Using hierarchical clustering, we found that the protein biomarkers clustered along 3 main trait axes: adipose, metabolic, and lipid traits. In longitudinal analyses, 6 biomarkers were significantly associated with incident metabolic syndrome: apolipoprotein B (apoB), insulin-like growth factor-binding protein 2 (IGFBP2), plasma kallikrein (KLKB1), complement C2 (C2), fibrinogen (FBN), and N-terminal pro-B-type natriuretic peptide (NT-proBNP); false discovery rate q<0.05 for all. Conclusions We found that the proteomic architecture of obesity overlaps considerably with associated cardiometabolic traits, implying shared pathways. Despite overlap, hierarchical clustering of proteomic profiles identified 3 distinct clusters of cardiometabolic traits: adipose, metabolic, and lipid. Further exploration of these novel protein targets and associated pathways may provide insight into the mechanisms responsible for the progression from obesity to cardiometabolic disease.

Dietary Patterns, Ceramide Ratios, and Risk of All-Cause and Cause-Specific Mortality: The Framingham Offspring Study.

BACKGROUND: Prior evidence suggests that diet modifies the association of blood ceramides with the risk of incident cardiovascular disease (CVD). It remains unknown if diet quality modifies the association of very long-chain-to-long-chain ceramide ratios with mortality in the community. OBJECTIVES: Our objectives were to determine how healthy dietary patterns associate with blood ceramide concentrations and to examine if healthy dietary patterns modify associations of ceramide ratios (C22:0/C16:0 and C24:0/C16:0) with all-cause and cause-specific mortality. METHODS: We examined 2157 participants of the Framingham Offspring Study (mean age = 66 y, 55% women). Blood ceramides were quantified using a validated assay. We evaluated prospective associations of the Dietary Guidelines Adherence Index (DGAI) and Mediterranean-style Diet Score (MDS) with incidence of all-cause and cause-specific mortality using Cox proportional hazards models. Cross-sectional associations of the DGAI and MDS with ceramides were evaluated using multivariable linear regression models. RESULTS: The C22:0/C16:0 and C24:0/C16:0 ceramide ratios were inversely associated with all-cause, CVD, and cancer mortality; multivariable-adjusted HRs (95% CIs) were 0.73 (0.67, 0.80) and 0.70 (0.63, 0.77) for all-cause mortality, 0.74 (0.60, 0.90) and 0.69 (0.55, 0.86) for CVD mortality, and 0.75 (0.65, 0.87) and 0.75 (0.64, 0.88) for cancer mortality, respectively. Inverse associations of the C22:0/C16:0 and C24:0/C16:0 ceramide ratios with cancer mortality were attenuated among individuals with a higher diet quality (DGAI or MDS above the median, all P-interaction ≤0.1). The DGAI and MDS had distinct associations with ceramide ratios (DGAI: lower C22:0/C16:0 across quartiles; MDS: higher C24:0/C16:0 across quartiles; all P-trend ≤0.01). CONCLUSION: In our community-based sample, ceramide ratios (C22:0/C16:0 and C24:0/C16:0) were associated with a lower risk of all-cause and cause-specific mortality. Further, we observed that a higher overall diet quality attenuates the association between blood ceramide ratios and cancer mortality and that dietary patterns have distinct relations with ceramide ratios.

Structural insights to heterodimeric cis-prenyltransferases through yeast dehydrodolichyl diphosphate synthase subunit Nus1.

The polyprenoid glycan carriers are produced by cis-prenyltransferases (cis-PTs), which function as heterodimers in metazoa and fungi or homodimers in bacteria, but both are found in plants, protista and archaea. Heterodimeric cis-PTs comprise catalytic and non-catalytic subunits while homodimeric enzymes contain two catalytic subunits. The non-catalytic subunits of cis-PT shows low sequence similarity to known cis-PTs and their structure information is of great interests. Here we report the crystal structure of Nus1, the non-catalytic subunit of cis-PT from Saccharomyces cerevisiae. We also investigate the heterodimer formation and active site conformation by constructing a homology model of Nus1 and its catalytic subunit. Nus1 does not contain an active site, but its C-terminus may participate in catalysis by interacting with the substrates bound to the catalytic subunit. These results provide important basis for further investigation of heterodimeric cis-PTs.

Genetic risk score and risk of stage 3 chronic kidney disease.

BACKGROUND: We developed a genetic risk score (GRS) and examined whether the GRS may predict incident stage 3 chronic kidney disease (CKD) independent of common clinical risk factors. METHOD: The present study included 2,698 individuals who attended the 15th (1977 to 1979) and the 24th exams (1995 to 1998) in the Framingham Original cohort or the 6th (1995 to 1998) and the 8th exams (2005 to 2008) in the Framingham Offspring cohort. A weighted GRS was constructed combining 53 single nucleotide polymorphisms (SNPs) associated with lower creatinine-based estimated glomerular filtration rate (eGFR). Stage 3 CKD was defined as eGFR <60 mL/min/1.73 m2, and incident cases were identified at follow-up after excluding prevalent cases at baseline. RESULTS: A total of 292 incident cases and 2,406 non-cases were identified over, on average, 11 years of follow-up. After adjustment for sex, age, cohort, baseline eGFR, hypertension, diabetes, and dipstick proteinuria, the odds ratio of incident stage 3 CKD was 1.37 (95%CI: 1.02-1.83) per 10 alleles of the GRS (P = 0.04). There was no statistically significant difference between the C-statistic without and with inclusion of the GRS (0.783 and 0.785, respectively; P = 0.39). CONCLUSIONS: A GRS developed based on 53 SNPs associated with reduced eGFR was prospectively associated with incident stage 3 CKD. However, this score did not substantially improve discrimination of stage 3 CKD beyond the common clinical risk factors.

Potential link between excess added sugar intake and ectopic fat: a systematic review of randomized controlled trials.

CONTEXT: The effect of added sugar intake on ectopic fat accumulation is a subject of debate. OBJECTIVE: A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to examine the potential effect of added sugar intake on ectopic fat depots. DATA SOURCES: MEDLINE, CAB Abstracts, CAB Global Health, and EBM (Evidence-Based Medicine) Reviews - Cochrane Central Register of Controlled Trials databases were searched for studies published from 1973 to September 2014. DATA EXTRACTION: RCTs with a minimum of 6 days' duration of added sugar exposure in the intervention group were selected. The dosage of added sugar intake as a percentage of total energy was extracted or calculated. Means and standard deviations of pre- and post-test measurements or changes in ectopic fat depots were collected. DATA SYNTHESIS: Fourteen RCTs were included. Most of the studies had a medium to high risk of bias. Meta-analysis showed that, compared with eucaloric controls, subjects who consumed added sugar under hypercaloric conditions likely increased ectopic fat, particularly in the liver (pooled standardized mean difference = 0.9 [95%CI, 0.6-1.2], n = 6) and muscles (pooled SMD = 0.6 [95%CI, 0.2-1.0], n = 4). No significant difference was observed in liver fat, visceral adipose tissue, or muscle fat when isocaloric intakes of different sources of added sugars were compared. CONCLUSIONS: Data from a limited number of RCTs suggest that excess added sugar intake under hypercaloric diet conditions likely increases ectopic fat depots, particularly in the liver and in muscle fat. There are insufficient data to compare the effect of different sources of added sugars on ectopic fat deposition or to compare intake of added sugar with intakes of other macronutrients. Future well-designed RCTs with sufficient power and duration are needed to address the role of sugars on ectopic fat deposition.

Sugar-sweetened beverage, diet soda, and fatty liver disease in the Framingham Heart Study cohorts.

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.

Fructose, high-fructose corn syrup, sucrose, and nonalcoholic fatty liver disease or indexes of liver health: a systematic review and meta-analysis.

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.

Genetic risk score and risk of myocardial infarction in Hispanics.

BACKGROUND: Genome-wide association studies have identified loci associated with coronary heart disease in whites of European ancestry. This study evaluated whether genetic markers previously identified in whites are associated with nonfatal acute myocardial infarction (MI) in Hispanics. METHODS AND RESULTS: Cases (n=1989) with a first nonfatal acute MI and population-based controls (n=2096) living in Costa Rica were studied. Fourteen single-nucleotide polymorphisms were genotyped. Seven single-nucleotide polymorphisms at 3 independent loci showed significant associations with MI. The odds ratios for the loci with the strongest associations were 1.16 (95 confidence interval [CI], 1.05 to 1.27) for rs4977574 (CDKN2A/2B), 1.15 (95 CI, 1.03 to 1.29) for rs646776 (CELSR2-PSRC1-SORT1), and 1.22 (95 CI, 1.08 to 1.38) for rs501120 (CXCL12); the corresponding PARs were 6.8, 10.5, and 15.2; respectively. We developed a genetic risk score by summing the number of the top 3 associated risk alleles. The OR for MI per genetic risk score unit was 1.18 (95 CI, 1.11 to 1.25; P=4.83 × 10(-8)). Discrimination of MI was significantly improved (P=0.02) when the genetic risk score was added to a model including clinical predictors. However, the increase in the area under the receiver-operating characteristic curve after the genetic risk score was added 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 white populations. The improvement in the identified genetic markers on discrimination of MI in Hispanics was modest.