Genetic influences on alcohol flushing in East Asian populations.

BACKGROUND: Although it is known that variation in the aldehyde dehydrogenase 2 (ALDH2) gene family influences the East Asian alcohol flushing response, knowledge about other genetic variants that affect flushing symptoms is limited. METHODS: We performed a genome-wide association study meta-analysis and heritability analysis of alcohol flushing in 15,105 males of East Asian ancestry (Koreans and Chinese) to identify genetic associations with alcohol flushing. We also evaluated whether self-reported flushing can be used as an instrumental variable for alcohol intake. RESULTS: We identified variants in the region of ALDH2 strongly associated with alcohol flushing, replicating previous studies conducted in East Asian populations. Additionally, we identified variants in the alcohol dehydrogenase 1B (ADH1B) gene region associated with alcohol flushing. Several novel variants were identified after adjustment for the lead variants (ALDH2-rs671 and ADH1B-rs1229984), which need to be confirmed in larger studies. The estimated SNP-heritability on the liability scale was 13% (S.E. = 4%) for flushing, but the heritability estimate decreased to 6% (S.E. = 4%) when the effects of the lead variants were controlled for. Genetic instrumentation of higher alcohol intake using these variants recapitulated known associations of alcohol intake with hypertension. Using self-reported alcohol flushing as an instrument gave a similar association pattern of higher alcohol intake and cardiovascular disease-related traits (e.g. stroke). CONCLUSION: This study confirms that ALDH2-rs671 and ADH1B-rs1229984 are associated with alcohol flushing in East Asian populations. Our findings also suggest that self-reported alcohol flushing can be used as an instrumental variable in future studies of alcohol consumption.

Proteome-wide Mendelian randomization in global biobank meta-analysis reveals multi-ancestry drug targets for common diseases.

Proteome-wide Mendelian randomization (MR) shows value in prioritizing drug targets in Europeans but with limited evidence in other ancestries. Here, we present a multi-ancestry proteome-wide MR analysis based on cross-population data from the Global Biobank Meta-analysis Initiative (GBMI). We estimated the putative causal effects of 1,545 proteins on eight diseases in African (32,658) and European (1,219,993) ancestries and identified 45 and 7 protein-disease pairs with MR and genetic colocalization evidence in the two ancestries, respectively. A multi-ancestry MR comparison identified two protein-disease pairs with MR evidence in both ancestries and seven pairs with specific effects in the two ancestries separately. Integrating these MR signals with clinical trial evidence, we prioritized 16 pairs for investigation in future drug trials. Our results highlight the value of proteome-wide MR in informing the generalizability of drug targets for disease prevention across ancestries and illustrate the value of meta-analysis of biobanks in drug development.

Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects.

Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.

Childhood body size directly increases type 1 diabetes risk based on a lifecourse Mendelian randomization approach.

The rising prevalence of childhood obesity has been postulated as an explanation for the increasing rate of individuals diagnosed with type 1 diabetes (T1D). In this study, we use Mendelian randomization (MR) to provide evidence that childhood body size has an effect on T1D risk (OR = 2.05 per change in body size category, 95% CI = 1.20 to 3.50, P = 0.008), which remains after accounting for body size at birth and during adulthood using multivariable MR (OR = 2.32, 95% CI = 1.21 to 4.42, P = 0.013). We validate this direct effect of childhood body size using data from a large-scale T1D meta-analysis based on n = 15,573 cases and n = 158,408 controls (OR = 1.94, 95% CI = 1.21 to 3.12, P = 0.006). We also provide evidence that childhood body size influences risk of asthma, eczema and hypothyroidism, although multivariable MR suggested that these effects are mediated by body size in later life. Our findings support a causal role for higher childhood body size on risk of being diagnosed with T1D, whereas its influence on the other immune-associated diseases is likely explained by a long-term effect of remaining overweight for many years over the lifecourse.

Applying Mendelian randomization to appraise causality in relationships between nutrition and cancer.

Dietary factors are assumed to play an important role in cancer risk, apparent in consensus recommendations for cancer prevention that promote nutritional changes. However, the evidence in this field has been generated predominantly through observational studies, which may result in biased effect estimates because of confounding, exposure misclassification, and reverse causality. With major geographical differences and rapid changes in cancer incidence over time, it is crucial to establish which of the observational associations reflect causality and to identify novel risk factors as these may be modified to prevent the onset of cancer and reduce its progression. Mendelian randomization (MR) uses the special properties of germline genetic variation to strengthen causal inference regarding potentially modifiable exposures and disease risk. MR can be implemented through instrumental variable (IV) analysis and, when robustly performed, is generally less prone to confounding, reverse causation and measurement error than conventional observational methods and has different sources of bias (discussed in detail below). It is increasingly used to facilitate causal inference in epidemiology and provides an opportunity to explore the effects of nutritional exposures on cancer incidence and progression in a cost-effective and timely manner. Here, we introduce the concept of MR and discuss its current application in understanding the impact of nutritional factors (e.g., any measure of diet and nutritional intake, circulating biomarkers, patterns, preference or behaviour) on cancer aetiology and, thus, opportunities for MR to contribute to the development of nutritional recommendations and policies for cancer prevention. We provide applied examples of MR studies examining the role of nutritional factors in cancer to illustrate how this method can be used to help prioritise or deprioritise the evaluation of specific nutritional factors as intervention targets in randomised controlled trials. We describe possible biases when using MR, and methodological developments aimed at investigating and potentially overcoming these biases when present. Lastly, we consider the use of MR in identifying causally relevant nutritional risk factors for various cancers in different regions across the world, given notable geographical differences in some cancers. We also discuss how MR results could be translated into further research and policy. We conclude that findings from MR studies, which corroborate those from other well-conducted studies with different and orthogonal biases, are poised to substantially improve our understanding of nutritional influences on cancer. For such corroboration, there is a requirement for an interdisciplinary and collaborative approach to investigate risk factors for cancer incidence and progression.

Trans-ethnic Mendelian-randomization study reveals causal relationships between cardiometabolic factors and chronic kidney disease.

BACKGROUND: This study was to systematically test whether previously reported risk factors for chronic kidney disease (CKD) are causally related to CKD in European and East Asian ancestries using Mendelian randomization. METHODS: A total of 45 risk factors with genetic data in European ancestry and 17 risk factors in East Asian participants were identified as exposures from PubMed. We defined the CKD by clinical diagnosis or by estimated glomerular filtration rate of <60 ml/min/1.73 m2. Ultimately, 51 672 CKD cases and 958 102 controls of European ancestry from CKDGen, UK Biobank and HUNT, and 13 093 CKD cases and 238 118 controls of East Asian ancestry from Biobank Japan, China Kadoorie Biobank and Japan-Kidney-Biobank/ToMMo were included. RESULTS: Eight risk factors showed reliable evidence of causal effects on CKD in Europeans, including genetically predicted body mass index (BMI), hypertension, systolic blood pressure, high-density lipoprotein cholesterol, apolipoprotein A-I, lipoprotein(a), type 2 diabetes (T2D) and nephrolithiasis. In East Asians, BMI, T2D and nephrolithiasis showed evidence of causality on CKD. In two independent replication analyses, we observed that increased hypertension risk showed reliable evidence of a causal effect on increasing CKD risk in Europeans but in contrast showed a null effect in East Asians. Although liability to T2D showed consistent effects on CKD, the effects of glycaemic phenotypes on CKD were weak. Non-linear Mendelian randomization indicated a threshold relationship between genetically predicted BMI and CKD, with increased risk at BMI of >25 kg/m2. CONCLUSIONS: Eight cardiometabolic risk factors showed causal effects on CKD in Europeans and three of them showed causality in East Asians, providing insights into the design of future interventions to reduce the burden of CKD.

Avoiding dynastic, assortative mating, and population stratification biases in Mendelian randomization through within-family analyses.

Estimates from Mendelian randomization studies of unrelated individuals can be biased due to uncontrolled confounding from familial effects. Here we describe methods for within-family Mendelian randomization analyses and use simulation studies to show that family-based analyses can reduce such biases. We illustrate empirically how familial effects can affect estimates using data from 61,008 siblings from the Nord-Trøndelag Health Study and UK Biobank and replicated our findings using 222,368 siblings from 23andMe. Both Mendelian randomization estimates using unrelated individuals and within family methods reproduced established effects of lower BMI reducing risk of diabetes and high blood pressure. However, while Mendelian randomization estimates from samples of unrelated individuals suggested that taller height and lower BMI increase educational attainment, these effects were strongly attenuated in within-family Mendelian randomization analyses. Our findings indicate the necessity of controlling for population structure and familial effects in Mendelian randomization studies.

The Dysfunctional Autonomic Function and "Dysfunctional" Fatigue in Drug Naïve Parkinson's Disease.

BACKGROUND: Fatigue is a common and disabling non-motor symptom in Parkinson's disease (PD). Autonomic dysfunction is suggested as the possible pathophysiology of fatigue, but it has not been investigated in drug-naïve PD patients. OBJECTIVE: In the present study, the relationship between fatigue and autonomic dysfunction in drug-naïve PD patients was investigated. METHODS: In the present study, 89 drug-naïve PD patients were analyzed. The Parkinson's disease fatigue scale (PFS) was used to divide the patients into fatigue (mean PFS≥3.3) and non-fatigue groups (mean PFS < 3.3). The autonomic function test (AFT), Scale for Outcomes in Parkinson's Disease-Autonomic (SCOPA-AUT), Unified Parkinson's Disease Rating Scale (UPDRS)-I, -II, -III, modified Hoehn and Yahr (H&Y) scale, Montreal Cognitive Assessment (MoCA), Parkinson's Disease Questionnaire-39 (PDQ-39), Parkinson's Disease Sleep Scale (PDSS), and Beck Depress Index (BDI) were performed in all the participants. The AFT results and clinical scales were compared using multiple logistic regression analysis. RESULTS: The prevalence of fatigue was 23.6% (n = 21) in drug-naïve PD patients. Total SCOPA-AUT score was higher in the fatigue group than in the non-fatigue group. The fatigue group had lower inspiratory:expiratory (I:E) ratio and Valsalva ratio. The prevalence of abnormal sympathetic skin response and orthostatic hypotension (OH) was 19% and 38.1%, respectively, in the fatigue group. Regression model analysis revealed that SCOPA-AUT and OH were the most related factor of fatigue in drug-naïve PD patients. CONCLUSION: Autonomic dysfunction in drug-naïve PD patients was investigated using a subjective scale as well as objective tests. The results indicated that fatigue is associated with autonomic dysfunction, especially OH, in drug-naïve PD patients.

Exploiting horizontal pleiotropy to search for causal pathways within a Mendelian randomization framework.

In Mendelian randomization (MR) analysis, variants that exert horizontal pleiotropy are typically treated as a nuisance. However, they could be valuable in identifying alternative pathways to the traits under investigation. Here, we develop MR-TRYX, a framework that exploits horizontal pleiotropy to discover putative risk factors for disease. We begin by detecting outliers in a single exposure-outcome MR analysis, hypothesising they are due to horizontal pleiotropy. We search across hundreds of complete GWAS summary datasets to systematically identify other (candidate) traits that associate with the outliers. We develop a multi-trait pleiotropy model of the heterogeneity in the exposure-outcome analysis due to pathways through candidate traits. Through detailed investigation of several causal relationships, many pleiotropic pathways are uncovered with already established causal effects, validating the approach, but also alternative putative causal pathways. Adjustment for pleiotropic pathways reduces the heterogeneity across the analyses.

Association of circulating 25-hydroxyvitamin D levels with hypertension and blood pressure values in Korean adults: A Mendelian randomization study on a subset of the Korea National Health and Nutrition Survey 2011-2012 population.

BACKGROUND/OBJECTIVES: Lower circulating 25-hydroxyvitamin D [25(OH)D] levels are associated with a higher risk of hypertension (HTN); however, it remains unclear whether the relationship is causal. We aimed to evaluate the causal effects of circulating 25(OH)D levels on the prevalence of HTN in the Korean population using the Mendelian randomization (MR) approach. SUBJECTS/METHODS: Epidemiological data, serum 25(OH)D data, and genomic DNA biospecimens were obtained from 2,591 participants, a subset of the study population in the Korea National Health and Nutrition Survey 2011-2012. Five 25(OH)D-related single nucleotide polymorphisms (SNPs; DHCR7 rs12785878, CYP2R1 rs10741657, CYP2R1 rs12794714, CYP24A1 rs6013897, and GC rs2282679), identified a priori from genome-wide association studies, were used as instrument variables (IVs) for serum 25(OH)D levels. In the MR analysis, we performed IV analyses using the two-stage least squares method. RESULTS: In the observational analysis, circulating 25(OH)D levels were found to be inversely associated with the HTN prevalence in ordinary least squares models (odds ratio: 0.97, 95% confidence interval: 0.96, 0.99) after adjusting for the potential confounders. There were differences in the circulating 25(OH)D levels across genotypes of individual SNPs. In the MR analysis, using individual SNPs as IVs, 25(OH)D levels were not associated with the HTN prevalence. CONCLUSIONS: We found no association between genetically determined circulating 25(OH)D levels and HTN in Korean adults. Our results are listed owing to the relatively small sample size and possible weak instrument bias; therefore, further studies are needed to confirm these results.

Differential value of brain magnetic resonance imaging in multiple system atrophy cerebellar phenotype and spinocerebellar ataxias.

Clinically differentiating multiple system atrophy cerebellar (MSA-C) phenotype and spinocerebellar ataxias (SCAs) is challenging especially in the early stage. We assessed diagnostic value of brain magnetic resonance imaging (MRI) in differentiating MSA-C and SCAs based at different disease stages (<3, 3-7, and >7 years of disease duration). Overall, 186 patients with probable MSA-C and 117 with genetically confirmed SCAs were included. Hot cross bun (HCB) signs and middle cerebellar peduncle (MCP) hyperintensities were exclusively prevalent in MSA-C compared to SCAs at <3 years (HCB, 44.6% versus 0.9%; MCP hyperintensities, 38.3% versus 0.9%, respectively). Sensitivity, specificity, and positive predictive value (PPV) for HCB signs to differentiate MSA-C from SCAs were 45%, 99%, and 99% and those for MCP hyperintensities were 68%, 99%, and 99%, respectively; considering both HCB signs and MCP hyperintensities, specificity and PPV were 100%. However, the differential value of MRI signs decreased over time. MCP widths were smaller and showed more significant decrease in MSA-C than in SCAs. In conclusion, pontine and MCP changes were exclusively prominent in early stage MSA-C rather than in SCAs. Therefore, we should consider disease duration when interpreting pontine and MCP changes in brain MRIs, which will help better differentiate MSA-C and SCAs.

Exploring the utility of alcohol flushing as an instrumental variable for alcohol intake in Koreans.

Previous studies have indicated an association of higher alcohol intake with cardiovascular disease and related traits, but causation has not been definitively established. In this study, the causal effect of alcohol intake on hypertension in 2,011 men and women from the Ansan-Ansung cohort was estimated using an instrumental variable (IV) approach, with both a phenotypic and genotypic instrument for alcohol intake: alcohol flushing and the rs671 genotype (in the alcohol dehydrogenase 2 [ALDH2] gene), respectively. Both alcohol flushing and the rs671 genotype were associated with alcohol intake (difference in alcohol intake with alcohol flushers vs. non-flushers: -9.07 g/day; 95% confidence interval [CI]: -11.12, -7.02; P-value: 8.3 × 10-18 and with the rs671 GA + AA vs. GG genotype: -7.94 g/day; 95% CI: -10.20, -5.69; P-value: 6.1 × 10-12). An increase in alcohol intake, as predicted by both the absence of alcohol flushing and the presence of the rs671 GG genotype in the IV analyses, was associated with an increase in blood pressure in men from this Korean population. In conclusion, this study supports a causal effect of alcohol intake on hypertension and indicated that alcohol flushing may be a valid proxy for the ALDH2 rs671 polymorphism, which influences alcohol intake in this Korean population.

Alcohol Consumption, Aldehyde Dehydrogenase 2 Gene Polymorphisms, and Cardiovascular Health in Korea.

Alcohol consumption is a serious health issue in Korea in terms of the amount consumed and the behavior related to its consumption. Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme in alcohol metabolism that degrades acetaldehyde to nontoxic acetic acid. The enzyme is coded by the ALDH2 gene, which is commonly polymorphic in East Asian populations. A point mutation in the ALDH2 gene (the rs671 allele) yields an inactive form of ALDH2 that causes acetaldehyde accumulation in the body after alcohol consumption, thereby inhibiting normal alcohol metabolism. Individuals who are homozygous for polymorphism in ALDH2 tend to refrain from drinking alcohol, decreasing their chances of developing alcoholism and exposure to the associated risks. Mendelian randomization (MR) studies have demonstrated that alcohol consumption predicted by ALDH2 genotype is causally related to cardiovascular risks. Moreover, recent MR studies suggest that the ALDH2 variant has mechanistic effects on some disease outcomes or mortality through increased blood levels of acetaldehyde, showing differences therein between heterozygotes (ALDH2*2*2) and homozygotes (ALDH2*1*2) in those who consume alcohol. Accordingly, consideration of ALDH2 genotype in alcohol prevention programs is warranted. In conclusion, strategies that incorporate genetic information and provide an evidential basis from which to help people make informed decisions on alcohol consumption are urgently required.

Burdens of Cardiometabolic Diseases Attributable to Dietary and Metabolic Risks in Korean Adults 2012-2013.

PURPOSE: In line with epidemiological and sociocultural changes in Korea over the past decades, reliable estimation of diseases as a result of dietary and metabolic risks is required. In this study, we aimed to evaluate the contributions of dietary and metabolic factors to cardiometabolic diseases (CMDs) in Korean adults (25-64 years old) during 2012-2013. MATERIALS AND METHODS: Distribution of risk factors and cause-specific mortality by gender and age per year was obtained from the Korea National Health and Nutrition Examination Survey and Statistics Korea, respectively. The association between the two was obtained from published meta-analyses. The population-attributable fraction attributable to the risk factors was calculated across gender and age strata (male and female, age groups 25-34, 35-44, 45-54, and 55-64) in 2012 and 2013. RESULTS: The results showed that during the period studied, high body mass index [5628 deaths; uncertainty intervals (UIs): 5473-5781] and blood pressure (4202 deaths; UIs: 3992-4410) were major metabolic risks for CMD deaths, followed by dietary risks such as low intake of whole grain (4107 deaths; UIs: 3275-4870) and fruits (3886 deaths; UIs: 3227-4508), as well as high intake of sodium (2911 deaths, UIs: 2406-3425). Also, males and the younger population were seen more prone to be exposed to harmful dietary risk than their female and older counterparts. CONCLUSION: The findings provide the necessary information to develop targeted government interventions to improve cardiometabolic health at the population level.

Household Food Insecurity Is Associated with Adverse Mental Health Indicators and Lower Quality of Life among Koreans: Results from the Korea National Health and Nutrition Examination Survey 2012-2013.

Food insecurity is an ongoing public health issue and contributes to mental health status. We investigated whether food insecurity is associated with inadequate nutrient intake and whether it affects mental health indicators (perceived stress/experience of depressive symptom/suicidal ideation) and quality of life (QOL) among Koreans (n = 5862, 20-64 years) using data from the Korea National Health and Nutritional Examination Survey (2012-2013). Household food security status was categorized as "food-secure household", "food-insecure household without hunger", and "food-insecure household with hunger". Data on food insecurity, sociodemographic factors, nutrient intake, mental health indicators, and QOL were used. A logistic regression model was conducted to determine odds ratios (ORs) for psychological health. A greater proportion of food-insecure participants were nutritionally deficient compared with expectations of the 2015 Korean Dietary Reference Intakes. These deficiencies were generally higher in both "food-insecure household" groups. Both "food-insecure household" groups, particularly the "food-insecure household with hunger" group showed significantly adverse mental health status (ORs: 1.52-3.83) and lower QOL (ORs: 1.49-3.92) than did the "food-secure household" group before and after adjusting for sex, age, education, household income, smoking/alcohol consumption, physical activity, marital status, and receiving food assistance. In conclusion, food insecurity may be significantly associated with adverse mental health indicators and decreased QOL in young/middle-aged Koreans.

Estimating change in cardiovascular disease and diabetes burdens due to dietary and metabolic factors in Korea 1998-2011: a comparative risk assessment analysis.

OBJECTIVES: Over the past 10 years, the burden of chronic diseases in Korea has increased. However, there are currently no quantitative estimates of how changes in diet and metabolic factors have contributed to these shifting burdens. This study aims to evaluate the contributions of dietary and metabolic risk factors to death from cardiometabolic diseases (CMDs) such as cardiovascular conditions, strokes and diabetes in Korea, and to estimate how these contributions have changed over the past 10 years (1998-2011). DESIGN AND METHODS: We used data on 6 dietary and 4 metabolic risk factors by sex, age and year from the Korea National Health and Nutrition Examination Survey. The relative risks for the effects of the risk factors on CMD mortality were obtained from meta-analyses. The population-attributable fraction attributable to the risk factors was calculated by using a comparative risk assessment approach across sex and age strata (males and females, age groups 25-34, 35-44, 45-54, 55-64, 65-74 and 75+ years) from 1998 to 2011. RESULTS: The results showed that a suboptimal diet and high blood pressure were the main risk factors for CMD mortality in Korea. High blood pressure accounted for 127 096 (95% uncertainty interval (UI): 121 907 to 132 218) deaths from CMD. Among the individual dietary risk factors, a high intake of sodium (42 387 deaths; 95% UI: 42 387 to 65 094) and a low intake of fruit (50 244 deaths; 95% UI: 40 981 to 59 178) and whole grains (54 248 deaths; 95% UI: 47 020 to 61 343) were responsible for the highest number of CMD deaths in Korea. CONCLUSIONS: Indicating the relative importance of risk factors in Korea, the results suggest that metabolic and dietary risk factors were major contributors to CMD mortality.

Association between Genetic Variations Affecting Mean Telomere Length and the Prevalence of Hypertension and Coronary Heart Disease in Koreans.

In this study, we investigated whether the single nucleotide polymorphisms (SNPs) associated with telomere length (TL) were associated with the incidence of hypertension (HTN)/coronary heart disease (CHD) and cardiovascular risk factors in the Korean population. Data from 5,705 (ages 39-70) participants in the Korean Genome Epidemiology Study (rural Ansung and urban Ansan cohorts) were studied. Twelve SNPs known to be associated with telomere biology were tested for an association with HTN/CHD. As results, no significant associations were found between the selected TL-related SNPs and prevalence of HTN and CHD. Among non-alcohol users, subjects with minor alleles in rs1269304 and rs10936601 (TERC and LRRC34, respectively) exhibited a higher rate of CHD occurrence (odds ratio [OR], 1.862; 95% confidence intervals [CIs], 1.137, 3.049; OR, 1.855; 95% CIs, 1.111, 2.985; respectively). However, alcohol users with minor alleles in rs398652 (PELI2) were significantly associated with higher HTN prevalence (OR, 1.179; 95% CIs, 1.040, 1.336). Of the 3 SNPs related to disease outcomes, rs1296304 was significantly associated with increased levels of diastolic blood pressure (ß estimate, 0.470; 95% CIs, 0.013, 0.926). The minor allele in rs398652 was significantly associated with higher levels of body mass index (OR, 0.128; 95% CIs, 0.010, 0.246) and γ-glutamyl transpeptidase (OR, 0.013; 95% CIs, 0.001, 0.024). In conclusion, there were no significant associations between the selected TL-related SNPs and the occurrence of HTN/CHD in Koreans. However, the results suggest the presence of a possible interaction between related SNPs and alcohol behavior associated with HTN/CHD occurrence.

Association of dietary intakes of total and subtypes of fat substituted for carbohydrate with metabolic syndrome in Koreans.

Amount of fat consumption has gradually increased among Koreans, which is relatively lower than western countries. In the current study, we examined the association between dietary fat and metabolic syndrome (MetS) prevalence among Korean adults. 3,212 participants who are aged 30-74 years from the Korea National Health and Nutritional Examination Survey (KNHANES) VI (2013) were included for cross-sectional analyses. Dietary intake data was assessed using 24-hour recall method, and MetS was defined using guideline of the National Cholesterol Education Program Adult Treatment panel III (NCEP-ATP III). Multivariate logistic regression analysis was used to estimate MetS odds ratios, using nutrient density model, according to 5% percent unit of dietary fat intake. The prevalence of MetS was significantly associated with dietary intake of total fat and saturated fatty acid (SFA) after adjustment (odds ratio [OR] 0.984 95% confidence interval [CI] 0.972-0.996; OR 0.946 95% CI 0.915-0.979). When dietary intake of total fat and SFA were substituted for carbohydrate (CHO), ORs for MetS were 0.985 (95% CI 0.972-0.998) and 0.948 (95% CI 0.907-0.990), respectively, after adjusting for potential covariates. In summary, MetS was significantly associated with dietary intakes of total fat and SFA, and when substituting dietary fat for carbohydrate among Koreans.

Serum gamma-glutamyl transferase and risk of type 2 diabetes in the general Korean population: a Mendelian randomization study.

Elevated gamma-glutamyl transferase (GGT) levels are associated with higher risk of type 2 diabetes in observational studies, but the underlying causal relationship is still unclear. Here, we tested a hypothesis that GGT levels have a causal effect on type 2 diabetes risk using Mendelian randomization. Data were collected from 7640 participants in a South Korean population. In a single instrumental variable (IV) analysis using two stage least squares regression with the rs4820599 in the GGT1 gene region as an instrument, one unit of GGT levels (IU/L) was associated with 11% higher risk of type 2 diabetes (odds ratio (OR) = 1.11, 95% confidence interval (CI): 1.04 to 1.19). In a multiple IV analysis using seven genetic variants that have previously been demonstrated to be associated with GGT at a genome-wide level of significance, the corresponding estimate suggested a 2.6% increase in risk (OR = 1.026, 95% CI: 1.001 to 1.052). In a two-sample Mendelian randomization analysis using genetic associations with type 2 diabetes taken from a trans-ethnic GWAS study of 110 452 independent samples, the single IV analysis confirmed an association between the rs4820599 and type 2 diabetes risk (P-value = 0.04); however, the estimate from the multiple IV analysis was compatible with the null (OR = 1.007, 95% CI: 0.993 to 1.022) with considerable heterogeneity between the causal effects estimated using different genetic variants. Overall, there is weak genetic evidence that GGT levels may have a causal role in the development of type 2 diabetes.

Beneficial effects of voglibose administration on body weight and lipid metabolism via gastrointestinal bile acid modification.

This study was designed with the goal of examining the effects of voglibose administration on body weight and lipid metabolism and underlying mechanism high fat diet-induced obese mice. Male C57BL/6 mice were randomly assigned to one of four groups: a control diet (CTL), high-fat diet (HF), high-fat diet supplemented with voglibose (VO), and high fat diet pair-fed group (PF). After 12 weeks, the following characteristics were investigated: serum lipid and glucose levels, serum polar metabolite profiles, and expression levels of genes involved in lipid and bile acid metabolism. In addition, pyrosequencing was used to analyze the composition of gut microbiota found in feces. Total body weight gain was significantly lower in the VO group than in the CTL, HF, and PF groups. The VO group exhibited improved metabolic profiles including those of blood glucose, triglyceride, and total cholesterol levels. The 12-week voglibose administration decreased the ratio of Firmicutes to Bacteroidetes found in feces. Circulating levels of taurocholic and cholic acid were significantly higher in the VO group than in the HF and CTL groups. Deoxycholic acid levels tended to be higher in the VO group than in the HF group. Voglibose administration downregulated expression levels of CYP8B1 and HNF4α genes and upregulated those of PGC1α, whereas FXRα was not affected. Voglibose administration elicits changes in the composition of the intestinal microbiota and circulating metabolites, which ultimately has systemic effects on body weight and lipid metabolism in mice.