Background: Emerging studies have related circulating glutamine metabolites to various chronic diseases such as cardiovascular disease and cancer; diet is the major source of nutrients involved in glutamine metabolism. However, it remains unknown whether dietary intakes of glutamine, glutamate,and their ratio are related to total and cause-specific mortality. Methods: We followed 74 082 women from the Nurses' Health Study (1984-2012) and 42 303 men from the Health Professionals Follow-up Study (1986-2012), who were free of cardiovascular disease and cancer at baseline. Diet was updated every 2 to 4 years by using validated food frequency questionnaires. The content of glutamine and glutamate in foods was calculated based on protein fractions generated from gene sequencing methods and adjusted for total energy intake. Results: We documented 30 424 deaths during 2 878 344 person-years of follow-up. After adjustment for potential confounders including lifestyle and dietary factors, higher intakes of glutamine and glutamine-to-glutamate ratio were associated with significantly lower risk of total and cause-specific mortality. Compared with people in the lowest quintile of dietary glutamine-to-glutamate ratio, the pooled hazard ratio (HR) in the highest quintile was 0.87 [95% confidence interval (CI): 0.84, 0.91; P for trend < 0.001) for total mortality, 0.81 (95% CI: 0.75, 0.88; P for trend < 0.001) for cardiovascular mortality, and 0.93 (95% CI: 0.87, 0.99; P for trend = 0.01) for cancer mortality. Conclusions: We found dietary glutamine and glutamine-to-glutamate ratio were inversely related to risk of mortality, particularly cardiovascular mortality, independent of other dietary and lifestyle factors, in US men and women.
C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 x 10(-8)). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.
BACKGROUND: Growing evidence has implicated DNA methylation (DNAm) in the regulation of body adiposity; a recent epigenome-wide association study (EWAS) identified a genetic variant determining DNAm at the SREBF1 gene that affected body mass index (BMI). OBJECTIVE: In the present study, we tested interactions between DNAm variant rs752579 and methylation metabolism-related B-vitamins (folate, vitamin B2, vitamin B6, and vitamin B12) on longitudinal change in BMI in the Women's Health Initiative Memory Study (WHIMS). DESIGN: A total of 5687 white women aged 65-79 from WHIMS with genotyping data on SNP rs752579 were included in the analysis. B-vitamins intakes were estimated by a self-report semi-quantitative food frequency questionnaire. BMI was measured at baseline and 6-year follow-up. RESULT: We found significant interactions between the SREBF1 rs752579 genotype and intake of food source B-vitamins on 6-year change in BMI (p interaction <0.01 for all). BMI changes (kg/m(2)) per DNAm-increasing (C) allele were -0.29, 0.06, and 0.11 within subgroups of increasing tertiles of food source folate intake; and the corresponding BMI changes (kg/m(2)) were -0.25, -0.01, and 0.15 for vitamin B2 intake; -0.17, -0.16, and 0.21 for vitamin B6 intake; and -0.12, -0.23, and 0.26 for vitamin B12 intake, respectively. Similar gene-diet interaction patterns were observed on the change in body weight. CONCLUSIONS: Our data suggest that habitual intake of food source B-vitamins may modify the effect of DNAm-related variant on long-term adiposity change.
AIM: To determine whether weight-loss diets varying in macronutrients modulate the genetic effect of hepatocyte nuclear factor 1alpha (HNF1A) rs7957197 on weight loss and improvement of insulin resistance. MATERIALS AND METHODS: We analysed the interaction between HNF1A rs7957197 and weight-loss diets with regard to weight loss and insulin resistance improvement among 722 overweight/obese adults from a 2-year randomized weight-loss trial, the POUNDS Lost trial. The findings were replicated in another independent 2-year weight-loss trial, the Dietary Intervention Randomized Controlled Trial (DIRECT), in 280 overweight/obese adults. RESULTS: In the POUNDS Lost trial, we found that a high-fat diet significantly modified the genetic effect of HNF1A on weight loss and reduction in waist circumference (P for interaction = .006 and .005, respectively). Borderline significant interactions for fasting insulin and insulin resistance (P for interaction = .07 and .06, respectively) were observed. We replicated the results in DIRECT. Pooled results showed similar significant interactions with weight loss, waist circumference reduction, and improvement in fasting insulin and insulin resistance (P values for interaction = .001, .005, .02 and .03, respectively). Greater decreases in weight, waist circumference, fasting insulin level and insulin resistance were observed in participants with the T allele compared to those without the T allele in the high-fat diet group (P = .04, .03 and .01, respectively). CONCLUSIONS: Our replicable findings provide strong evidence that individuals with the HNF1A rs7957197 T allele might obtain more benefits in weight loss and improvement of insulin resistance by choosing a hypocaloric and high-fat diet.
Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P < 1 x 10(-6)) associated with intake of any macronutrient in 91,114 European ancestry participants. Four loci replicated and reached genome-wide significance in a combined meta-analysis including 123,659 European descent participants, unraveling two novel loci; a common variant in RARB locus for carbohydrate intake and a rare variant in DRAM1 locus for protein intake, and corroborating earlier FGF21 and FTO findings. In additional analysis of 144,770 participants from the UK Biobank, all identified associations from the two-stage analysis were confirmed except for DRAM1. Identified loci might have implications in brain and adipose tissue biology and have clinical impact in obesity-related phenotypes. Our findings provide new insight into biological functions related to macronutrient intake.
PURPOSE: A common variant of the melatonin receptor 1B (MTNR1B) gene has been related to increased signaling of melatonin, a hormone previously associated with body fatness mainly through effects on energy metabolism. We examined whether the MTNR1B variant affects changes of body fatness and composition in response to a dietary weight loss intervention. METHODS: The MTNR1B rs10830963 variant was genotyped for 722 overweight and obese individuals, who were randomly assigned to one of four diets varying in macronutrient composition. Anthropometric and body composition measurements (DXA scan) were collected at baseline and at 6 and 24 months of follow-up. RESULTS: Statistically significant interactions were observed between the MTNR1B genotype and low-/high-fat diet on changes in weight, body mass index (BMI), waist circumference (WC) and total body fat (p interaction = 0.01, 0.02, 0.002 and 0.04, respectively), at 6 months of dietary intervention. In the low-fat diet group, increasing number of the sleep disruption-related G allele was significantly associated with a decrease in weight (p = 0.004), BMI (p = 0.005) and WC (p = 0.001). In the high-fat diet group, carrying the G allele was positively associated with changes in body fat (p = 0.03). At 2 years, the associations remained statistically significant for changes in body weight (p = 0.02), BMI (p = 0.02) and WC (p = 0.048) in the low-fat diet group, although the gene-diet interaction became less significant. CONCLUSIONS: The results suggest that carriers of the G allele of the MTNR1B rs10830963 may have a greater improvement in body adiposity and fat distribution when eating a low-fat diet.
Compelling evidence indicates that lipid metabolism is in partial control of the circadian system. In this context, it has been reported that the melatonin receptor 1B (MTNR1B) genetic variant influences the dynamics of melatonin secretion, which is involved in the circadian system as a chronobiotic. The objective was to analyze whether the MTNR1B rs10830963 genetic variant was related to changes in lipid levels in response to dietary interventions with different macronutrient distribution in 722 overweight/obese subjects from the POUNDS Lost trial. We did not find a significant association between the MTNR1B genotype and changes in lipid metabolism. However, dietary fat intake significantly modified genetic effects on 2 year changes in total and LDL cholesterol (P interaction = 0.006 and 0.001, respectively). In the low-fat diet group, carriers of the sleep disruption G allele (minor allele) showed a greater reduction of total cholesterol (beta +/- SE = -5.78 +/- 2.88 mg/dl, P = 0.04) and LDL cholesterol (beta +/- SE = -7.19 +/- 2.37 mg/dl, P = 0.003). Conversely, in the high-fat diet group, subjects carrying the G allele evidenced a smaller decrease in total cholesterol (beta +/- SE = 5.81 +/- 2.65 mg/dl, P = 0.03) and LDL cholesterol (beta +/- SE = 5.23 +/- 2.21 mg/dl, P = 0.002). Subjects carrying the G allele of the circadian rhythm-related MTNR1B variant may present a bigger impact on total and LDL cholesterol when undertaking an energy-restricted low-fat diet.
BACKGROUND: Observational studies have illustrated that maternal central obesity is associated with birth size, including of birth weight, birth length and head circumference, but the causal nature of these associations remains unclear. Our study aimed to test the causal effect of maternal central obesity on birth size and puberty height growth using a Mendelian randomization (MR) analysis. METHODS: We performed two-sample MR using summary-level genome-wide public data. Thirty-five single nucleotide polymorphisms (SNPs), 25 SNPs and 41 SNPs were selected as instrumental variables for waist-to-hip ratio adjusted for BMI, waist circumference adjusted for BMI and hip circumference adjusted for BMI, respectively to test the causal effects of maternal central obesity on birth size and puberty height using an inverse-variance-weighted approach. RESULTS: In this MR analysis, we found no evidence of a causal association between waist circumference or waist-to-hip ratio and the outcomes. However, we observed that one standard deviation (SD) increase in hip circumference (HIP) was associated with a 0.392 SD increase in birth length (p = 1.1 x 10(- 6)) and a 0.168 SD increase in birth weight (p = 7.1 x 10(- 5)), respectively at the Bonferroni-adjusted level of significance. In addition, higher genetically predicted maternal HIP was strongly associated with the puberty heights (0.835 SD, p = 8.4 x 10(- 10)). However, HIP was not associated with head circumference (p = 0.172). CONCLUSIONS: A genetic predisposition to higher maternal HIP was causally associated with larger offspring birth size independent of maternal BMI. However, we found no evidence of a causal association between maternal waist circumference, waist-to-hip ratio and birth size.
OBJECTIVE: To test the causal effect of childhood BMI on adult cardiometabolic diseases using a Mendelian randomization analysis. RESEARCH DESIGN AND METHODS: We used 15 single nucleotide polymorphisms as instrumental variables for childhood BMI to test the causal effect of childhood BMI on cardiometabolic diseases using summary-level data from consortia. RESULTS: We found that a 1-SD increase in childhood BMI (kg/m(2)) was associated with an 83% increase in risk of type 2 diabetes (odds ratio [OR] 1.83 [95% CI 1.46, 2.30]; P = 2.5 x 10(-7)) and a 28% increase in risk of coronary artery disease (CAD) (OR 1.28 [95% CI 1.17, 1.39]; P = 2.1 x 10(-8)) at the Bonferroni-adjusted level of significance (P < 0.017) in adults. In addition, a 1-SD increase in childhood BMI was associated with a 0.587-SD increase in adulthood BMI (kg/m(2)), a 0.062-SD increase in hip circumference (cm), a 0.602-SD increase in waist circumference (cm), a 0.111 pmol/L increase in log fasting insulin, a 0.068 increase in log-transformed HOMA of ss-cell function (%), a 0.126 increase in log-transformed HOMA of insulin resistance (%), and a 0.109-SD increase in triglyceride (mg/dL) but a 0.138-SD decrease in HDL (mg/dL) in adults at the Bonferroni-adjusted level of significance (P < 0.0026). CONCLUSIONS: A genetic predisposition to higher childhood BMI was associated with increased risk of type 2 diabetes and CAD in adult life. These results provide evidence supportive of a causal association between childhood BMI and these outcomes.
SCOPE: Effects of dairy consumption on body weight and body composition have been inconsistently observed in randomized control trials (RCTs). Our meta-analysis aims to systematically evaluate the effects of dairy consumption on body weight and body composition among the adults. METHODS AND RESULTS: We conducted a comprehensive search of the Cochrane Library, PubMed, and Embase databases of the relevant studies from 1966 to Mar 2017 regarding dairy consumption on body weight and body composition including body fat, lean mass, and waist circumference (WC). The summary results are pooled by using a random-effects meta-analysis. Thirty-seven RCTs with 184 802 participants are included in this meta-analysis. High dairy intervention increased body weight (0.01, 95% CI: -0.25, 0.26, I(2) = 78.3%) and lean mass (0.37, 95% CI: 0.11, 0.62, I(2) = 83.4%); decreased body fat (-0.23, 95% CI: -0.48, 0.02, I(2) = 78.2%) and WC (-1.37, 95% CI: -2.28, -0.46, I(2) = 98.9%) overall. In the subgroup analysis, we found that consumption of dairy products increases body weight (0.36, 95% CI: 0.01, 0.70, I(2) = 83.1%) among participants without energy restriction. Dairy consumption decreases body weight (-0.64, 95% CI: -1.05, -0.24, I(2) = 60.2%), body fat (-0.56, 95%CI: -0.95, -0.17, I(2) = 66.6%), and waist circumference (-2.18, 95%CI: -4.30, -0.06, I(2) = 99.0%) among the adults with energy restriction. CONCLUSIONS: This meta-analysis suggests a beneficial effect of energy-restricted dairy consumption on body weight and body composition. However, high dairy consumption in the absence of caloric restriction may increase body weight.
BACKGROUND: Observational studies have demonstrated diet/lifestyle play roles in development of type 2 diabetes (T2DM); however, it remains unclear whether these relationships are causal. METHODS: A two-sample MR approach was used to examine the causal effect of diet/lifestyle upon risk of T2DM and glycemic traits. RESULTS: The protein intake-increasing allele C of FTO was significant associated with higher risk of T2DM (Beta +/- SE = 0.104 +/- 0.014, P = 4.40 x 10(- 11)), higher level of HOMA-IR (Beta +/- SE = 0.016 +/- 0.004, P = 9.55 x 10(- 5)), HOMA-B (Beta +/- SE = 0.008 +/- 0.003, P = 0.020). Using MR analyses, increased protein intake was causally associated with an increased risk of T2DM (Beta +/- SE = 0.806 +/- 0.260, P = 0.002). In addition, smoking cessation was causally associated with increased levels of glycemic traits such as HOMA-IR (Beta +/- SE = 0.165 +/- 0.072, P = 0.021), fasting insulin (Beta +/- SE = 0.132 +/- 0.066, P = 0.047) and fasting glucose (Beta +/- SE = 0.132 +/- 0.064, P = 0.039). CONCLUSIONS: These results provide evidence supporting a causal role for higher protein intake and smoking cession in T2DM. Our study provides further rationale for individuals at risk for diabetes to keep healthy lifestyle.
Background: It is unknown whether dietary quality modifies genetic association with body mass index (BMI). Objective: This study examined whether dietary quality modifies genetic association with BMI. Design: We calculated 3 diet quality scores including the Alternative Healthy Eating Index 2010 (AHEI-2010), the Alternative Mediterranean Diet score (AMED), and the Dietary Approach to Stop Hypertension (DASH) diet score. We examined the interactions of a genetic risk score (GRS) based on 97 BMI-associated variants with the 3 diet quality scores on BMI in 30,904 participants from 3 large cohorts. Results: We found significant interactions between total GRS and all 3 diet scores on BMI assessed after 2-3 y, with an attenuated genetic effect observed in individuals with healthier diets (AHEI: P-interaction = 0.003; AMED: P = 0.001; DASH: P = 0.004). For example, the difference in BMI (kg/m2) per 10-unit increment of the GRS was smaller among participants in the highest tertile of AHEI score compared with those in the lowest tertile (0.84; 95% CI: 0.72, 0.96 compared with 1.14; 95% CI: 0.99, 1.29). Results were consistent across the 3 cohorts with no significant heterogeneity. The interactions with diet scores on BMI appeared more significant for central nervous system GRSs (P < 0.01 for 3 diet scores) than for non-central nervous system GRSs (P > 0.05 for 3 diet scores). Conclusions: A higher diet quality attenuated genetic predisposition to obesity. These findings underscore the importance of maintaining a healthful diet for the prevention of obesity, particularly for those individuals with a strong genetic predisposition to obesity. This trial was registered with the Clinical Trial Registry as NCT03577639.
Observational studies are prone to bias due to confounding either measured or unmeasured. While measured confounding can be controlled for with a variety of sophisticated methods such as propensity score-based matching, stratification and multivariable regression model, the unmeasured confounding is usually cumbersome, leading to biased estimates. In econometrics, instrumental variable (IV) is widely used to control for unmeasured confounding. However, its use in clinical researches is generally less employed. In some subspecialties of clinical medicine such as pharmacoepidemiological research, IV analysis is increasingly used in recent years. With the development of electronic healthcare records, more and more healthcare data are available to clinical investigators. Such kind of data are observational in nature, thus estimates based on these data are subject to confounding. This article aims to review several methods for implementing IV analysis for binary and continuous outcomes. R code for these analyses are provided and explained in the main text.
BACKGROUND AND AIMS: Considerable attention is given nowadays to the presence of cardiovascular diseases risk factors in children. The current blood lipid classification system for Chinese children was based on the United States National Cholesterol Education Program (NCEP) cutpoints, which did not take the age, gender and race differences into consideration. This study aimed to develop gender- and age-specific lipid cutpoints for dyslipidemia screening in Chinese children and compare the ability of new cutpoints and NCEP pediatric cutpoints to predict obesity and unfavorable blood pressure (BP) levels. METHODS: Data were obtained from a nationwide multicenter cross-sectional study: The China Child and Adolescent Cardiovascular Health Study, comprising 12,875 Chinese children aged 6-18 years. We calculated cutpoints for abnormal levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) that were linked to Chinese adult abnormal lipid thresholds using the General Additive Model for Location Scale and Shape method. RESULTS: Borderline-high and high cutpoints (TC, LDL-C and TG) as well as low cutpoints (HDL-C) were developed to classify the abnormal blood lipid levels in Chinese children. Better performance for prediction of obesity, elevated BP, and hypertension were found with the proposed cutpoints in comparison with the NCEP pediatric cutpoints (AUC for obesity: 0.612 vs. 0.597, p=0.017; AUC for elevated BP: 0.529 vs. 0.521, p=0.017; AUC for hypertension: 0.536 vs. 0.527, p=0.016). CONCLUSIONS: The gender- and age-specific cutpoints should improve the accuracy of dyslipidemia screening in China and be more reasonable in practice.
OBJECTIVE: To investigate whether improving adherence to healthy dietary patterns interacts with the genetic predisposition to obesity in relation to long term changes in body mass index and body weight. DESIGN: Prospective cohort study. SETTING: Health professionals in the United States. PARTICIPANTS: 8828 women from the Nurses' Health Study and 5218 men from the Health Professionals Follow-up Study. EXPOSURE: Genetic predisposition score was calculated on the basis of 77 variants associated with body mass index. Dietary patterns were assessed by the Alternate Healthy Eating Index 2010 (AHEI-2010), Dietary Approach to Stop Hypertension (DASH), and Alternate Mediterranean Diet (AMED). MAIN OUTCOME MEASURES: Five repeated measurements of four year changes in body mass index and body weight over follow-up (1986 to 2006). RESULTS: During a 20 year follow-up, genetic association with change in body mass index was significantly attenuated with increasing adherence to the AHEI-2010 in the Nurses' Health Study (P=0.001 for interaction) and Health Professionals Follow-up Study (P=0.005 for interaction). In the combined cohorts, four year changes in body mass index per 10 risk allele increment were 0.07 (SE 0.02) among participants with decreased AHEI-2010 score and -0.01 (0.02) among those with increased AHEI-2010 score, corresponding to 0.16 (0.05) kg versus -0.02 (0.05) kg weight change every four years (P<0.001 for interaction). Viewed differently, changes in body mass index per 1 SD increment of AHEI-2010 score were -0.12 (0.01), -0.14 (0.01), and -0.18 (0.01) (weight change: -0.35 (0.03), -0.36 (0.04), and -0.50 (0.04) kg) among participants with low, intermediate, and high genetic risk, respectively. Similar interaction was also found for DASH but not for AMED. CONCLUSIONS: These data indicate that improving adherence to healthy dietary patterns could attenuate the genetic association with weight gain. Moreover, the beneficial effect of improved diet quality on weight management was particularly pronounced in people at high genetic risk for obesity.
BACKGROUND/OBJECTIVES: Prenatal growth, which is widely marked by birthweight, may have a pivotal role in affecting the lifelong risk of cardiometabolic disorders; however, comprehensive evaluation of its relations with childhood cardiometabolic risk patterns and the ethnic and gender disparities in national representative populations is still lacking. The aim of this study was to evaluate the associations between birthweight and comprehensive patterns of cardiometabolic risk in a nationally representative sample of children and adolescents. SUBJECTS/METHODS: Prospective analyses were performed using data from 28 153 children 0 to 15 years in the National Health and Nutrition Examination Survey from 1999 through 2014. We defined childhood cardiometabolic disorders using standard definitions for obesity, high blood pressure, hyperglycemia and dyslipidemia. RESULTS: Five birthweight categories <2.5, 2.5-3.0, 3.0-3.5, 3.5-4.2 and 4.2 kg accounted for 8.2%, 17.9%, 35.7%, 27.9% and 10.4% of the population, respectively. In all children, with increasing birthweight, we observed significantly increasing trends of the risk of general and central obesity (P for trend <0.01) and significantly decreasing trends of the risk of high systolic blood pressure (SBP), high HbA1c and low high-density lipoprotein cholesterol (HDL-C) (P for trend <0.05). The associations were independent of current body mass index (BMI). In addition, we found that the relations of birthweight with high waist circumference in Black children showed U-shape, as well as high SBP in Mexican and Hispanic children. Moreover, we found that the associations of low birthweight with high SBP and low HDL-C appeared to more prominent significant in boys, whereas the inverse association with high HbA1c was more evident in girls. CONCLUSIONS: Our data indicate that birthweight is significantly related to childhood cardiometabolic risk, independent of current BMI, and the associations exhibit race and gender-specific patterns.
Background: The meta-analyses of genome-wide association studies identified several waist-hip ratio (WHR) related loci in individuals of European ancestry. Since the pattern of fat distribution and the relationship between fat distribution and glucose metabolism disturbance in Chinese are different from those in Europeans, the present study aimed to explore the individual and cumulative effects of WHR-related loci on glycemic phenotypes in Chinese children. Methods: A total of 2030 children were recruited from two independent studies. Eleven single nucleotide polymorphisms (SNPs) were selected and genotyped using matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS). Logistic regression and linear regression model were used to examine the association of 11 SNPs and genetic risk score (GRS) with impaired fasting glucose (IFG) and fasting plasma glucose (FPG), respectively. Results: Three SNPs (rs6795735, rs984222 and rs1011731) were nominally associated with IFG (all P < 0.05). Each WHR-increasing (C) allele of rs6795735 (ADAMTS9) was associated with a 40.1% increased risk of IFG (OR = 1.401, 95% CI = 1.131-1.735, P = 0.002), which remained significant after Bonferroni correction. We observed no association of both weighted and unweighted GRS with FPG and IFG (all P > 0.05). Conclusions: We identified individual effects of rs6795735 (ADAMTS9), rs984222 (TBX15-WARS2), and rs1011731 (DNM3-PIGC) on glycemic phenotypes in Chinese children for the first time. The study suggests that genetic predisposition to central obesity is associated with impaired fasting glucose, providing more evidence for the pathogenesis of diabetes.