No Interaction with Alcohol Consumption, but Independent Effect of C12orf51 (HECTD4) on Type 2 Diabetes Mellitus in Korean Adults Aged 40-69 Years: The KoGES_Ansan and Ansung Study.
ABSTRACT: Previously, genetic polymorphisms of C12orf51 (HECTD4) (rs2074356 and/or rs11066280) have been shown to be related to alcohol consumption and type 2 diabetes (T2D). This study aimed to prospectively examine whether C12orf51 had an interaction with or independent effect on alcohol consumption and the risk of T2D. The present study included 3,244 men and 3,629 women aged 40 to 69 years who participated in the Korean Genome and Epidemiology Study (KoGES)_Ansan and Ansung Study. Cox proportional hazards models were used to estimate HRs and 95% CIs for T2D. rs2074356 and rs11066280 were associated with the risk of T2D after adjusting for alcohol consumption (rs2074356 for AA: HR = 0.39 and 95% CI = 0.17-0.87 in men, and HR = 0.36 and 95% CI = 0.13-0.96 in women; rs11066280 for AA: HR = 0.44 and 95% CI = 0.23-0.86 in men, and HR = 0.39 and 95% CI = 0.16-0.94 in women). We identified that the association of each variant (rs2074356 and rs11065756) in C12orf51 was nearly unchanged after adjusted for alcohol consumption. Therefore, the association of 2 SNPs in C12orf51 with diabetes may not be mediated by alcohol use. There was no interaction effect between alcohol consumption and the SNPs with T2D. However, even in never-drinkers, minor allele homozygote strongly influenced T2D risk reduction (rs2074356 for AA: HR = 0.35, 95% CI = 0.14-0.90, and p-trend = 0.0035 in men and HR = 0.34, 95% CI = 0.13-0.93, and p-trend = 0.2348 in women; rs11066280 for AA: HR = 0.36, 95% CI = 0.16-0.82, and p-trend = 0.0014 in men and HR = 0.39, 95% CI = 0.16-0.95, and p-trend = 0.3790 in women), while alcohol consumption did not influence the risk of T2D within each genotype. rs2074356 and rs11066280 in or near C12orf51, which is related to alcohol drinking behavior, may longitudinally decrease the risk of T2D, but not through regulation of alcohol consumption.
Project description:BACKGROUND:Lead (Pb) is a ubiquitous toxic metal present in the environment that poses adverse health effects to humans. Inter-individual variation in blood Pb levels is affected by various factors, including genetic makeup. However, limited data are available on the association between genetic variation and blood Pb levels. The purpose of this study was to identify the genetic markers associated with blood Pb levels in the Korean population. METHODS:The study subjects consisted of 1,483 healthy adults with no history of occupational exposure to Pb. We measured blood Pb levels and calculated probable daily intake of Pb according to dietary data collected using 24-hour recall. We conducted exome-wide association screening using Illumina Human Exome-12v1.2 platform (n?=?500) and a replication analysis using VeraCode Goldengate assay (n?=?1,483). RESULTS:Among the 244,770 single nucleotide polymorphisms (SNPs) tested, 12 SNPs associated with blood Pb level were identified, with suggestive significance level (P?<?1?×?10-4). In the Goldengate assay for replication, three SNPs (C12orf51 rs11066280, MYL2 rs12229654, and ALDH2 rs671) were associated with statistically suggestively significant differences in blood Pb levels. When stratified by drinking status, a potential association of C12orf51 rs11066280, MYL2 rs12229654, and ALDH2 rs671 with blood Pb level was observed only in drinkers. A marginally significant gene-environment interaction between ALDH2 rs671 and alcohol consumption was observed in relation to blood Pb levels. The effects of the three suggestively significant SNPs on blood Pb levels was dependent on daily calcium intake amounts. CONCLUSIONS:This exome-wide association study indicated that C12orf51 rs11066280, MYL2 rs12229654, and ALDH2 rs671 polymorphisms are linked to blood Pb levels in the Korean population. Our results suggest that these three SNPs are involved in the determination of Pb levels in Koreans via the regulation of alcohol drinking behavior, and that their negative effects may be compensated by appropriate calcium intake.
Project description:Abstract <h4>Objectives</h4> Epidemiological studies suggested the evidence that coffee consumption decreased risk of type 2 diabetes. Recently, Japanese genome-wide association studies (GWAS) of coffee consumption has identified rs2074356 (G > A) at 12q24.12–13 in HECTD4. This study aims to examine the associations of habitual coffee consumption with prediabetes and type 2 diabetes, and whether this association is modified by rs2074356 variant in Korean adults. <h4>Methods</h4> A total of 4010 participants (1890 men and 2120 women) who had genetic information from Korea Association REsource (KARE) study were included. Habitual coffee consumption was assessed through a food frequency questionnaire and categorized into five categories (non-consumers, <1 cup/day and ?1 cups/day of black coffee, and <1 cup/day and ?1 cups/day of sugared coffee). Incident prediabetes or type 2 diabetes were defined according to the self-report of physician-diagnosis, oral glucose tolerance test (OGTT) or hemoglobin A1c (HbA1c) test. Multivariable logistic regression models were used to calculate odds ratio (OR)s and 95% confidence interval (CI)s. <h4>Results</h4> A total of 2916 participants (72.7%) have developed prediabetes during a follow-up of 15 years. We found that black coffee consumption lowered risk of prediabetes and type 2 diabetes combined among men and women combined (OR = 0.63; 95% CI = 0.44–0.91 for ?1 cups/day black coffee vs. non-consumers). When we separated men and women, compared with non-consumers, ORs (95% CIs) for ?1 cups/day of black coffee were 0.50 (0.27–0.93) among men and 0.72 (0.45–1.14) among women and ORs (95% CIs) for ?1 cups/day of sugared coffee were 1.41 (0.91–2.18) among men and 1.12 (0.80–1.58) among women. We observed a suggestive difference by rs2074356 (GG vs. AG + AA). Compared with non-consumers, participants with AG + AA genotypes consumed ? 1 cups/day of black coffee had a 60% lower risk of prediabetes and type 2 diabetes combined (95% CI 0.20–0.78), but we found a weaker association among those with GG genotype (OR = 0.81; 95% CI = 0.51–1.28). <h4>Conclusions</h4> We observed an inverse association between black coffee consumption and prediabetes and type 2 diabetes combined in Korean population. This association was more pronounced among carriers of minor allele of HECTD4 rs2074356 (AG/AA). <h4>Funding Sources</h4> None.
Project description:BACKGROUND:We previously showed that human papillomavirus (HPV) serostatus was not an independent risk factor for esophageal squamous cell carcinoma(ESCC) in nonsmokers and nondrinkers; however, HPV increased the risk in smokers. METHODS:Here we investigated possible interactions between HPV16 serostatus and three susceptibility loci identified in GWASs at apoptosis associated genes with regard to risk of ESCC in a case-control study of 313 patients with ESCC and 314 healthy controls. The loci (CHK2 rs738722, C12orf51 rs2074356, and PLCE1 rs2274223) were genotyped, and the presence or absence of HPV16 in serum was measured by ELISA. Multivariable logistic regression was used to evaluate possible interactions of HPV16 serostatus and the three loci on the risk of ESCC. RESULTS:A significant interaction was found between HPV16 serology and rs2074356 (P = 0.005, odds ratio [OR] 1.40, 95% confidence interval [CI] 1.11-1.77) or rs2274223 (P < 0.001, OR 1.53, 95% CI 1.23-1.91), but not for rs738722. For rs2074356, risk of ESCC was increased substantially in smokers (P < 0.001, OR 8.25, 95% CI 3.84-17.71) and drinkers (OR4.04, P = 0.001, 95% CI 1.79-9.10) who carried risk alleles (TT or TC genotype) and were HPV16-seropositive. Similar results were observed for rs2274223 in smokers (P < 0.001, OR6.06, 95% CI 2.85-12.88) and drinkers (P < 0.001, OR 5.43, 95% CI 2.51-11.76), but not for rs738722. CONCLUSION:Consistent with the previous study, loci at rs2074356 and rs2274223 could increase the risk of ESCC, furthermore, there were significant interactions between HPV sero-status and the susceptibility loci on the risk of ESCC. This effect could be modified obviously by smoking and drinking.
Project description:Excessive alcohol intake is an important cause of major public health problem in East Asian countries. Growing evidence suggests that genetic factors are associated with alcohol consumption and the risk for alcohol-associated disease, and these factors contribute to the risk of developing chronic diseases, including diabetes. This study aims to investigate the association of type 2 diabetes with genetic polymorphisms within HECTD4 based on alcohol exposure. We performed a genome-wide association study involving the cohorts of the KoGES-HEXA study (n = 50,028) and Ansan and Ansung study (n = 7,980), both of which are prospective cohort studies in Korea. The top three single-nucleotide polymorphisms (SNPs) of the HECTD4 gene, specifically rs77768175, rs2074356 and rs11066280, were found to be significantly associated with alcohol consumption. We found that individuals carrying the variant allele in these SNPs had lower fasting blood glucose, triglyceride, and GGT levels than those with the wild-type allele. Multiple logistic regression showed that statistically significant associations of HECTD4 gene polymorphisms with an increased risk of type 2 diabetes were found in drinkers. Namely, these SNPs were associated with decreased odds of diabetes in the presence of alcohol consumption. As a result of examining the effect of alcohol on the expression of the HECTD4 gene, ethanol increased the expression of HECTD4 in cells, but the level was decreased by NAC treatment. Similar results were obtained from liver samples of mice treated with alcohol. Moreover, a loss of HECTD4 resulted in reduced levels of CYP2E1 and lipogenic gene expression in ethanol-treated cells, while the level of ALDH2 expression increased, indicating a reduction in ethanol-induced hepatotoxicity.
Project description:BACKGROUND:Organic food (OF) consumption has substantially increased in high income countries, mostly driven by environmental concerns and health beliefs. Lower exposure to synthetic pesticides has been systematically documented among consumers of organic products compared to non-consumers. While experimental studies suggest that pesticides currently used in food production may be associated with type 2 diabetes (T2D), no well-conducted prospective studies have investigated the potential association between consumption of organic products and the risk of T2D, controlling for potential confounding factors. The objective of this prospective study was to estimate the association between OF consumption and the risk of T2D. METHODS:A total of 33,256 participants (76% women, mean (SD) age: 53?years (14)) of the French NutriNet-Santé prospective cohort study who completed the organic food frequency questionnaire were included (2014-2019). The proportion of OF in the diet (as weight without drinking water) was computed. The associations between the proportion of OF in the diet (as 5% increment and as quintiles) and the risk of T2D were estimated using multivariable Hazard Ratio (HR) and 95% confidence interval (95% CI) derived from proportional hazards models adjusted for confounders (sociodemographic, anthropometric, lifestyle, medical and nutritional factors). RESULTS:During follow-up (mean?=?4.05 y, SD?=?1.03 y, 134,990 person-years), 293 incident cases of T2D were identified. After adjustment for confounders including lifestyle (physical activity, smoking status, alcohol consumption) and nutritional quality of the diet assessed by the adherence to the French food-based dietary guidelines, OF consumption was associated with a lower risk of T2D. Participants with the highest quintile of OF consumption, compared with those with the lowest quintile, had 35% lower risk of T2D (95% CI?=?0.43-0.97). Each increment of 5% in the proportion of OF in the diet was associated with 3% lower risk of T2D (HR 0.97, 95% CI?=?0.95-0.99). CONCLUSIONS:In this large prospective cohort study, OF consumption was inversely associated with the risk of T2D. Further experimental and prospective studies should be conducted to confirm these observations. CLINICAL TRIAL REGISTRY:The study was registered at ClinicalTrials.gov ( NCT03335644 ).
Project description:<h4>Background</h4>Alcohol consumption is a leading contributor to death and disability worldwide, but previous research has not examined the effects of different patterns of alcohol consumption. The study objective was to understand the relationship between different alcohol consumption patterns and adverse health outcomes risk, adjusting for average amount consumed among regular drinkers.<h4>Methods</h4>This was a prospective cohort study of UK Biobank (UKB) participants. Abstainers, infrequent alcohol consumers or those with previous cancer, myocardial infarction (MI), stroke or liver cirrhosis were excluded. We used beverage type, consumption with food and consumption frequency as exposures and adjusted for potential confounding. All-cause mortality, major cardiovascular events-MACE (MI/stroke/cardiovascular death), accidents/injuries, liver cirrhosis, all-cause and alcohol-related cancer incidence over 9-year median follow-up period were outcomes of interest.<h4>Results</h4>The final sample size for analysis was N =?309,123 (61.5% of UKB sample). Spirit drinking was associated with higher adjusted mortality (hazard ratio (HR) 1.25; 95% confidence intervals (CI) 1.14-1.38), MACE (HR 1.31; 95% CI 1.15-1.50), cirrhosis (HR 1.48; 95% CI 1.08-2.03) and accident/injuries (HR 1.10; 95% CI 1.03-1.19) risk compared to red wine drinking, after adjusting for the average weekly alcohol consumption amounts. Beer/cider drinkers were also at a higher risk of mortality (HR 1.18; 95% CI 1.10-1.27), MACE (HR 1.16; 95% CI 1.05-1.27), cirrhosis (HR 1.36; 95% CI 1.06-1.74) and accidents/injuries (HR 1.11; 95% CI 1.06-1.17). Alcohol consumption without food was associated with higher adjusted mortality (HR 1.10; 95% CI 1.02-1.17) risk, compared to consumption with food. Alcohol consumption over 1-2 times/week had higher adjusted mortality (HR 1.09; 95% CI 1.03-1.16) and MACE (HR 1.14; 95% CI 1.06-1.23) risk, compared to 3-4 times/week, adjusting for the amount of alcohol consumed.<h4>Conclusion</h4>Red wine drinking, consumption with food and spreading alcohol intake over 3-4?days were associated with lower risk of mortality and vascular events among regular alcohol drinkers, after adjusting for the effects of average amount consumed. Selection bias and residual confounding are important possible limitations. These findings, if replicated and validated, have the potential to influence policy and practice advice on less harmful patterns of alcohol consumption.
Project description:BACKGROUND:Epidemiological evidence has demonstrated a positive association between artificially sweetened beverage (ASB) and sugar-sweetened beverage (SSB) consumption and type 2 diabetes (T2D) risk. However, research informing this topic in young adults is limited. OBJECTIVE:This study examined the association between ASB, SSB, and total sweetened beverage (TSB; combined ASB and SSB) consumption and T2D risk in young adults. METHODS:A prospective analysis of 4719 Black and White men and women aged 18-30 y at baseline was conducted from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Each participant's beverage intake was assessed using the CARDIA Diet History at baseline and at study Years 7 and 20. Multivariable Cox proportional hazards regression models were used to examine cumulative average ASB, SSB, and TSB intakes and risk of T2D. RESULTS:During the 30-y follow-up period, 680 participants developed T2D. ASB consumption was associated with a 12% greater risk of T2D per serving/day (HR 1.12, 95% CI 1.04-1.20) in a model adjusted for lifestyle factors, diet quality, and dieting behavior. Further adjustments for baseline BMI (HR 1.07, 95% CI 0.99-1.14) and weight change during follow-up (HR 1.04, 95% CI 0.97-1.12) attenuated the association. SSB and TSB consumption as continuous variables per 1 serving/day of intake were associated with 6% and 5% increased risks of T2D, respectively (HRSSB 1.06, 95% CI 1.01-1.10; HRTSB 1.05, 95% CI 1.01-1.09), in the model accounting for lifestyle factors, dieting behavior, baseline BMI, and weight change. Results were consistent when the exposures were modeled in categories of consumption and quintiles. CONCLUSIONS:In young adults, long-term ASB, SSB, and TSB consumption were associated with increased risks of T2D. However, the estimates for ASB were attenuated when accounting for weight changes.
Project description:Importance:Evidence on alcohol consumption as a risk factor for dementia usually relates to overall consumption. The role of alcohol-induced loss of consciousness is uncertain. Objective:To examine the risk of future dementia associated with overall alcohol consumption and alcohol-induced loss of consciousness in a population of current drinkers. Design, Setting, and Participants:Seven cohort studies from the UK, France, Sweden, and Finland (IPD-Work consortium) including 131?415 participants were examined. At baseline (1986-2012), participants were aged 18 to 77 years, reported alcohol consumption, and were free of diagnosed dementia. Dementia was examined during a mean follow-up of 14.4 years (range, 12.3-30.1). Data analysis was conducted from November 17, 2019, to May 23, 2020. Exposures:Self-reported overall consumption and loss of consciousness due to alcohol consumption were assessed at baseline. Two thresholds were used to define heavy overall consumption: greater than 14 units (U) (UK definition) and greater than 21 U (US definition) per week. Main Outcomes and Measures:Dementia and alcohol-related disorders to 2016 were ascertained from linked electronic health records. Results:Of the 131?415 participants (mean [SD] age, 43.0 [10.4] years; 80?344 [61.1%] women), 1081 individuals (0.8%) developed dementia. After adjustment for potential confounders, the hazard ratio (HR) was 1.16 (95% CI, 0.98-1.37) for consuming greater than 14 vs 1 to 14 U of alcohol per week and 1.22 (95% CI, 1.01-1.48) for greater than 21 vs 1 to 21 U/wk. Of the 96?591 participants with data on loss of consciousness, 10?004 individuals (10.4%) reported having lost consciousness due to alcohol consumption in the past 12 months. The association between loss of consciousness and dementia was observed in men (HR, 2.86; 95% CI, 1.77-4.63) and women (HR, 2.09; 95% CI, 1.34-3.25) during the first 10 years of follow-up (HR, 2.72; 95% CI, 1.78-4.15), after excluding the first 10 years of follow-up (HR, 1.86; 95% CI, 1.16-2.99), and for early-onset (<65 y: HR, 2.21; 95% CI, 1.46-3.34) and late-onset (?65 y: HR, 2.25; 95% CI, 1.38-3.66) dementia, Alzheimer disease (HR, 1.98; 95% CI, 1.28-3.07), and dementia with features of atherosclerotic cardiovascular disease (HR, 4.18; 95% CI, 1.86-9.37). The association with dementia was not explained by 14 other alcohol-related conditions. With moderate drinkers (1-14 U/wk) who had not lost consciousness as the reference group, the HR for dementia was twice as high in participants who reported having lost consciousness, whether their mean weekly consumption was moderate (HR, 2.19; 95% CI, 1.42-3.37) or heavy (HR, 2.36; 95% CI, 1.57-3.54). Conclusions and Relevance:The findings of this study suggest that alcohol-induced loss of consciousness, irrespective of overall alcohol consumption, is associated with a subsequent increase in the risk of dementia.
Project description:<h4>Objective</h4>We aimed to elucidate whether potato consumption is associated with a higher risk of type 2 diabetes (T2D).<h4>Research design and methods</h4>We analyzed data in three cohorts consisting of U.S. male and female health professionals without diabetes, cardiovascular disease, and cancer at baseline: 70,773 women from the Nurses' Health Study (1984-2010), 87,739 women from Nurses' Health Study II (1991-2011), and 40,669 men from the Health Professionals Follow-up Study (1986-2010). Potato consumption was assessed quadrennially using validated food frequency questionnaires (FFQs), and we calculated 4-year change in potato consumption from consecutive FFQs. Self-reported T2D diagnosis was confirmed using a validated supplementary questionnaire.<h4>Results</h4>During 3,988,007 person-years of follow-up, 15,362 new cases of T2D were identified. Higher consumption of total potatoes (including baked, boiled, or mashed potatoes and french fries) was significantly associated with an elevated risk for T2D: the pooled hazard ratio (HR) of T2D compared with <1 serving/week was 1.07 (95% CI 0.97-1.18) for 2-4 servings/week and 1.33 (95% CI 1.17-1.52) for ?7 servings/week after adjustment for demographic, lifestyle, and dietary factors. In addition, the pooled HRs of T2D for every 3 servings/week were 1.04 (95% CI 1.01-1.08) for baked, boiled, or mashed potatoes, and 1.19 (95% CI 1.13-1.25) for french fries. We further estimated that the HR of T2D was 0.88 (95% CI 0.84-0.91) for replacing 3 servings/week of total potatoes with the same amount of whole grains. Last, in comparison with stable potato consumption, every 3-servings/week increment of potato consumption in 4 years was associated with a 4% (95% CI 0-8%) higher T2D risk.<h4>Conclusions</h4>Greater consumption of potatoes, especially french fries, was associated with a higher T2D risk, independent of BMI and other risk factors. Replacement of potatoes with whole grains was associated with a lower T2D risk.
Project description:The objective of this review was to provide a summary of the literature on the dose-response relationship between alcohol consumption and risk of type 2 diabetes (T2D) in Asian populations, particularly men. The present study was recorded in PROSPERO as CRD 42019121073. We searched the PubMed-Medline, Web of Science, and Cochrane Library for studies published in any language since the database inception to January 2019. Prospective cohort studies were included in the meta-analysis. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated for random-effects models and dose-response meta-analyses. In total, 8 prospective cohort studies were included. High alcohol intake was significantly associated with increased risk of T2D (RR = 1.16, 95% CI: 1.04-1.29; Q statistic p = 0.326) compared to the lowest category of alcohol intake. Nonlinear association was observed between alcohol consumption and T2D risk in men (p = 0.003). Dose-wise, consuming ?57?g/day of alcohol was not associated with the risk of T2D in this study; however, alcohol intake >57?g/day was associated with increased risk of T2D in men. Overall, the association between alcohol consumption and T2D among Asian men was J-shaped. Lifestyle recommendations for prevention of T2D should include advice on limiting alcohol intake. This trial is registered with Prospero registration: CRD 42019121073.