Dietary Protein and Fat Intake Affects Diabetes Risk with CDKAL1 Genetic Variants in Korean Adults

Cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1) is one of the strongest diabetes loci identified to date; evidence suggests that it plays an important role in insulin secretion. Dietary factors that affect insulin demand might enhance the risk of diabetes associated with CDKAL1 variants. Our aim was to examine the interactions between dietary protein and fat intake and CDKAL1 genetic variants in relation to the risk of diabetes in Korean adults. Single nucleotide polymorphisms (SNPs) were selected with a genome-wide association study (GWAS) for diabetes after adjustment for age, gender, and examination site. Using data from the Health Examinees (HEXA) Study of the Korean Genome and Epidemiology Study (KoGES), 3988 middle-aged Korean adults between 40–76 years of age (2034 men and 1954 women) were included in the study. Finally, rs7756992 located within the CDKAL1 gene region was selected from GWAS (p-value < 5 × 10−8). Multivariable logistic regression models were used to evaluate the interactions between genotypes and dietary protein and fat intake in relation to diabetes risk after adjustment for age, gender, BMI, waist circumference, physical activity, smoking status, drinking habits, and examination site. Significant interactions between CDKAL1 rs7756992 and dietary protein and fat intake for the risk of diabetes were observed in men (p-value < 0.05). In women, significant interactions between dietary protein and fat intake and CDKAL1 variants (rs7756992) were associated with increased risk of diabetes (p-value < 0.05). Dietary protein and fat intake interacted differently with CDKAL1 variants in relation to the risk of diabetes in Korean adults of both genders. These findings indicate that CDKAL1 variants play a significant role in diabetes and that dietary protein and fat intake could affect these associations.

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Abstract MP50: Serum Metabolomic Profile of Incident Diabetes

Circulation ◽

10.1161/circ.137.suppl_1.mp50 ◽

2018 ◽

Vol 137 (suppl_1) ◽

Author(s):

Casey M Rebholz ◽

Bing Yu ◽

Zihe Zheng ◽

Patrick Chang ◽

Adrienne Tin ◽

...

Keyword(s):

Fasting Glucose ◽

Ultra Performance Liquid Chromatography ◽

Diabetes Risk ◽

Incident Diabetes ◽

P Value ◽

Metabolic Disturbances ◽

Isoleucine Leucine ◽

Metabolomics Data ◽

Metabolomic Profiling ◽

Increased Risk

Background: Metabolomic profiling offers the potential to reveal metabolic pathways relevant to diabetes pathophysiology and to improve diabetes risk prediction. Methods: We prospectively analyzed metabolites and incident diabetes from baseline (1987-1989) through December 31, 2015 in a subset of 2,939 Atherosclerosis Risk in Communities (ARIC) Study participants with metabolomics data and without diabetes at baseline. Metabolomic profiling was conducted in stored serum specimens collected at baseline using a reverse phase, untargeted ultra-performance liquid chromatography tandem mass spectrometry approach. Results: Among the 245 named compounds we identified, 7 metabolites were significantly associated with incident diabetes after Bonferroni correction and covariate adjustment (age, sex, race, center, batch, education, blood pressures, body mass index, lipids, smoking, physical activity, history of cardiovascular disease, eGFR, fasting glucose). These 7 metabolites consisted of a xenobiotic (erythritol) and compounds involved in amino acid metabolism [isoleucine, leucine, valine, asparagine, 3-(4-hydoxyphenyl)lactate] and glucose metabolism (trehalose). Higher levels of the metabolites were associated with an increased risk of incident diabetes, with the exception of asparagine which was associated with a lower risk of diabetes (HR per 1 SD increase: 0.78, 95% CI: 0.71, 0.85; p=4.19x10 -8 ). The 7 metabolites improved the prediction of incident diabetes beyond fasting glucose and established risk factors (C statistic for model with vs. without 7 metabolites, respectively: 0.744 vs. 0.735; p-value for difference in C statistics=0.001). Conclusions: Branched chain amino acids may play a role in diabetes development. Our study is the first to report asparagine as a protective biomarker of diabetes risk. The serum metabolome reflects known and novel metabolic disturbances that improve diabetes prediction.

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Genetic Association of ERAP1 and ERAP2 With Eclampsia and Preeclampsia in Northeastern Brazilian Women

10.21203/rs.3.rs-235628/v1 ◽

2021 ◽

Author(s):

LEONARDO CAPISTRANO FERREIRA ◽

CARLOS EDUARDO MAIA GOMES ◽

PRIYA DUGGAL ◽

INGRID DE PAULA HOLANDA ◽

AMANDA SAMARA DE LIMA ◽

...

Keyword(s):

Pregnant Women ◽

Genetic Variants ◽

Antigen Processing ◽

P Value ◽

Chronic Hypertension ◽

Ang Ii ◽

Small Peptides ◽

Increased Risk ◽

Genotype C ◽

Risk Of Preeclampsia

Abstract The clinical spectrum of hypertensive disorders of pregnancy (HDP) is determined by the interplay between environmental and genetic factors, most of which remains unknown. ERAP1, ERAP2 and LNPEP genes code for multifunctional aminopeptidases involved with antigen processing and degradation of small peptides such as angiotensin II (Ang II), vasopressin and oxytocin. We aimed to test for associations between genetic variants in aminopeptidases and HDP. A total of 1282 pregnant women (normotensive controls, n=693; preeclampsia, n=342; chronic hypertension with superimposed preeclampsia, n=61; eclampsia, n=74; and HELLP syndrome, n=112) were genotyped for variants in LNPEP (rs27300, rs38034, rs2303138), ERAP1 (rs27044, rs30187) and ERAP2 (rs2549796 rs2927609 rs11135484). We also evaluated the effect of ERAP1 rs30187 on plasma Ang II levels in an additional cohort of 65 pregnant women. The genotype C/C, in ERAP1 rs30187 variant (c.1583T>C, p.Lys528Arg), was associated with increased risk of eclampsia (OR=1.85, p=0.019) whereas ERAP2 haplotype rs2549796(C)-rs2927609(C)-rs11135484(G) was associated with preeclampsia (OR=1.96, corrected p-value=0.01). Ang II plasma levels did not differ across rs30187 genotypic groups (p=0.895). In conclusion, ERAP1 gene is associated with eclampsia whereas ERAP2 is associated with preeclampsia, although the mechanism by which genetic variants in ERAPs influence the risk of preeclampsia and eclampsia remain to be elucidated.

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Genetic Variants in Lipid Metabolism Pathways Interact with Diet to Influence Blood Lipid Concentrations in Adults with Overweight and Obesity

Lifestyle Genomics ◽

10.1159/000507021 ◽

2020 ◽

Vol 13 (6) ◽

pp. 155-163

Author(s):

Bridget A. Hannon ◽

Caitlyn G. Edwards ◽

Sharon V. Thompson ◽

Sarah K. Burke ◽

Nicholas A. Burd ◽

...

Keyword(s):

Lipid Metabolism ◽

Dietary Intake ◽

Dietary Fat ◽

Genetic Variants ◽

Blood Lipid ◽

Overweight And Obesity ◽

Cardiometabolic Health ◽

Fat Intake ◽

Dietary Fat Intake ◽

Increased Risk

Introduction: The effect of various types of dietary fat on cardiometabolic health continues to be debated, due in part to the high heterogeneity of results following clinical trials investigating the effects of saturated (SFA) and unsaturated fat intake. This variability may be due to genetic differences. Individuals with obesity are at an increased risk for adverse cardiometabolic health and dyslipidemia, and often present with the combined phenotype of elevated triglyceride (TG) and decreased high-density lipoprotein (HDL) cholesterol concentrations. Studying genetic variants relevant to lipid and lipoprotein metabolism can elucidate the mechanisms by which diet might interact with genotype to influence these phenotypes. The objective of this study was to determine relationships of genetic variation, dietary fat intake, and blood lipid concentrations in adults with overweight and obesity. Methods: Genomic DNA, blood lipid concentrations (HDL and TG), and 7-day diet records were obtained from 101 adults (25–45 years of age) with overweight or obesity. Resting energy expenditure (REE) was measured using indirect calorimetry and used to determine implausible intakes using a modified Goldberg method (kilocalories/REE). Genetic variants included 23 single-nucleotide polymorphisms (SNPs) from 15 genes in lipid metabolism pathways. Variants were analyzed with dietary fat intake (total fat, SFA, monounsaturated fat [MUFA], and polyunsaturated fat [PUFA]) via regression analyses. All models were adjusted for age, sex, ancestry, visceral adipose tissue mass, and total kilocalorie intake. The Bonferroni correction was applied for multiple comparisons. Results: Two interactions were detected for TG concentrations. Five gene-diet interactions were associated with HDL concentrations. There was a significant interaction detected between the rs5882 variant of cholesterol-esterase transfer protein (CETP) and MUFA intake to associate with TG concentrations (interaction p = 0.004, R2 = 0.306). Among carriers of the CETP-rs5882 major allele (G), TG concentrations were significantly lower in individuals consuming more than the median MUFA intake (31 g/day) than in those with an intake below the median. Total dietary fat intake interacted with the rs13702 polymorphism of lipoprotein lipase (LPL) to associate with HDL concentrations (interaction p = 0.041, R2 = 0.419), by which individuals with the risk allele (G) had significantly higher HDL concentrations when consuming a higher-fat diet (>92 g/day) than those with a lower-fat diet (56 ± 3 vs. 46 ± 2 mg/dL, p = 0.033). Conclusions: Interactions between dietary intake and genes in lipid metabolism pathways were found to be associated with blood lipid concentrations in adults with overweight and obesity. Fatty acid intake may not modulate blood lipid concentrations uniformly across all individuals. Additional research is needed to determine the biological causes of individual variability in response to dietary intake. Understanding the influence of nutrigenetic interactions on dyslipidemia can aid in the development and implementation of personalized dietary strategies to improve health.

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Effects of copper and zinc on ischemic heart disease and myocardial infarction: a Mendelian randomization study

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqy129 ◽

2018 ◽

Vol 108 (2) ◽

pp. 237-242 ◽

Cited By ~ 11

Author(s):

Hanish P Kodali ◽

Brian T Pavilonis ◽

C Mary Schooling

Keyword(s):

Sensitivity Analysis ◽

Heart Disease ◽

Ischemic Heart Disease ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Dietary Factors ◽

Ischemic Heart ◽

P Value ◽

Copper And Zinc ◽

A Genome

ABSTRACTBackgroundDespite great progress in prevention and control, ischemic heart disease (IHD) remains a leading cause of global morbidity and mortality. Diet plays a key role in IHD, but a comprehensive delineation of the role of dietary factors in IHD is not yet quite complete.ObjectiveThe aim of this study was to test the long-standing hypothesis that copper is protective and zinc harmful in IHD.DesignWe used separate-sample instrumental variable analysis with genetic instruments (Mendelian randomization). We obtained single nucleotide polymorphisms (SNPs) from a genome wide association study, strongly (P value < 5 × 10−8) and independently associated with erythrocyte copper and zinc. We applied these genetic predictors of copper and zinc to the largest, most extensively genotyped IHD case (n ≤ 76014)-control (n ≤ 264785) study, based largely on CARDIoGRAMplusC4D 1000 Genomes and the UK Biobank SOFT CAD, to obtain SNP-specific Wald estimates for the effects of copper and zinc on IHD, which were combined through the use of inverse variance weighting. Sensitivity analysis included use of the MR-Egger method, and reanalysis including SNPs independently associated with erythrocyte copper and zinc at P value < 5 × 10−6.ResultsGenetically instrumented copper was negatively associated with IHD (OR: 0.94; 95% CI: 0.90, 0.98). Genetically instrumented zinc was positively associated with IHD (OR: 1.06; 95% CI: 1.02, 1.11). Sensitivity analysis via MR-Egger gave no indication of unknown pleiotropy; less strongly associated SNPs gave similar results for copper.ConclusionGenetic validation of a long-standing hypothesis suggests that further investigation of the effects, particularly of copper, on IHD may provide a practical means of reducing the leading cause of mortality and morbidity.

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Effect of HLA-DRB1 alleles and genetic variants on the development of neutralizing antibodies to interferon beta in the BEYOND and BENEFIT trials

Multiple Sclerosis Journal ◽

10.1177/1352458518763089 ◽

2018 ◽

Vol 25 (4) ◽

pp. 565-573 ◽

Cited By ~ 4

Author(s):

Dorothea Buck ◽

Till FM Andlauer ◽

Wilmar Igl ◽

Eva-Maria Wicklein ◽

Mark Mühlau ◽

...

Keyword(s):

Multiple Sclerosis ◽

Genetic Variants ◽

Neutralizing Antibodies ◽

Genome Wide Association Study ◽

Phase Iii ◽

Interferon Β ◽

Hla Alleles ◽

Genome Wide ◽

A Genome ◽

Increased Risk

Background: Treatment of multiple sclerosis (MS) with interferon β can lead to the development of antibodies directed against interferon β that interfere with treatment efficacy. Several observational studies have proposed different HLA alleles and genetic variants associated with the development of antibodies against interferon β. Objective: To validate the proposed genetic markers and to identify new markers. Methods: Associations of genetic candidate markers with antibody presence and development were examined in a post hoc analysis in 941 patients treated with interferon β-1b in the Betaferon® Efficacy Yielding Outcomes of a New Dose (BEYOND) and BEtaseron®/BEtaferon® in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) prospective phase III trials. All patients were treated with interferon β-1b for at least 6 months. In addition, a genome-wide association study was conducted to identify new genetic variants. Results: We confirmed an increased risk for carriers of HLA-DRB1*04:01 (odds ratio (OR) = 3.3, p = 6.9 × 10−4) and HLA-DRB1*07:01 (OR = 1.8, p = 3.5 × 10−3) for developing neutralizing antibodies (NAbs). Several additional, previously proposed HLA alleles and genetic variants showed nominally significant associations. In the exploratory analysis, variants in the HLA region were associated with NAb development at genome-wide significance (OR = 2.6, p = 2.30 × 10−15). Conclusion: The contribution of HLA alleles and HLA-associated single-nucleotide polymorphisms (SNPs) to the development and titer of antibodies against interferon β was confirmed in the combined analysis of two multi-national, multi-center studies.

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Genetic Variants Correlate With Better Processing Speed

Innovation in Aging ◽

10.1093/geroni/igab046.623 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. 163-164

Author(s):

Anastasia Gurinovich ◽

Kaare Christensen ◽

Marianne Nygaard ◽

Jonas Mengel-From ◽

Stacy Andersen ◽

...

Keyword(s):

Processing Speed ◽

Genetic Variants ◽

Cognitive Aging ◽

Genome Wide Association Study ◽

Brain Aging ◽

P Value ◽

Digit Symbol Substitution Test ◽

Genome Wide ◽

Common Genetic Variants ◽

A Genome

Abstract Some cognitive abilities, such as vocabulary, are resilient to brain aging, while others such as conceptual reasoning, memory, and processing speed, decline with age and their rate of decline is genetically regulated. Despite the strong genetic heritability of processing speed assessed by the digit symbol substitution test (DSST), previous studies have failed to identify robust common genetic variants associated with this test. The Long Life Family Study (LLFS) includes long lived individuals and their family members who maintain good DSST scores as they age and who may carry variants associated with better DSST. We therefore conducted a genome-wide association study (GWAS) of DSST in LLFS using ~15M genetic variants imputed to the HRC panel of 64,940 haplotypes with 39,635,008 sites and replicated the findings using genetic data imputed to the 1000 Genomes phase 3 reference panel combining two Danish cohorts: the Middle Aged Danish Twins and the Longitudinal Study of Aging Danish Twins. The GWAS in LLFS discovered 20 rare genetic variants reaching genome-wide significance (p-value < 5x10-8), including 18 variants associated with better processing speed with large effect size. The genetic associations of rs7623455, rs9821776, rs9821587, rs78704059 in chromosome 3 were replicated in the combined Danish cohort. These genetic variants tagged two hormone receptor related genes, THRB and RARB, both related to cognitive aging. Further gene-based tests in LLFS confirmed that these two genes have protective variants associated with better processing speed.

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GWAS of Post-Orthodontic Aggressive External Apical Root Resorption Identified Multiple Putative Loci at X-Y Chromosomes

Journal of Personalized Medicine ◽

10.3390/jpm10040169 ◽

2020 ◽

Vol 10 (4) ◽

pp. 169

Author(s):

Paula Iber-Díaz ◽

Raquel Senen-Carramolino ◽

Alejandro Iglesias-Linares ◽

Pablo Fernández-Navarro ◽

Carlos Flores-Mir ◽

...

Keyword(s):

Logistic Regression ◽

Genetic Variants ◽

Genome Wide Association Study ◽

Root Resorption ◽

Genetic Model ◽

Nucleotide Polymorphisms ◽

Apical Root Resorption ◽

A Genome ◽

Increased Risk ◽

External Apical Root Resorption

Personalized dental medicine requires from precise and customized genomic diagnostic. To conduct an association analysis over multiple putative loci and genes located at chromosomes 2, 4, 8, 12, 18, X, and Y, potentially implicated in an extreme type of external apical root resorption secondary to orthodontic forces (aEARR). A genome-wide association study of aEARR was conducted with 480 patients [ratio~1:3 case/control]. Genomic DNA was extracted and analyzed using the high-throughput Axiom platform with the GeneTitan® MC Instrument. Up to 14,377 single nucleotide polymorphisms (SNPs) were selected at candidate regions and clinical/diagnostic data were recorded. A descriptive analysis of the data along with a backward conditional binary logistic regression was used to calculate odds ratios, with 95% confidence intervals [p < 0.05]. To select the best SNP candidates, a logistic regression model was fitted assuming a log-additive genetic model using R software [p < 0.0001]. In this sample the top lead genetic variants associated with aEARR were two novel putative genes located in the X chromosome, specifically, STAG 2 gene, rs151184635 and RP1-30E17.2 gene, rs55839915. These variants were found to be associated with an increased risk of aEARR, particularly restricted to men [OR: 6.09; 95%CI: 2.6–14.23 and OR: 6.86; 95%CI: 2.65–17.81, respectively]. Marginal associations were found at previously studied variants such as SSP1: rs11730582 [OR: 0.54; 95%CI: 0.34–0.86; p = 0.008], P2RX7: rs1718119 [OR: 0.6; 95%CI: 0.36–1.01; p = 0.047], and TNFRSF11A: rs8086340 [OR: 0.6; 95%CI: 0.38–0.95; p = 0.024]), found solely in females. Multiple putative genetic variants located at chromosomes X and Y are potentially implicated in an extreme phenotype of aEARR. A gender-linked association was noted.

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Dietary fat in relation to overall and progression-free survival among patients (pts) with advanced or metastatic colorectal cancer (CRC): Data from CALGB 80405 (Alliance).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3588 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3588-3588

Author(s):

Erin Van Blarigan ◽

Chao Ma ◽

Fang-Shu Ou ◽

Alan P. Venook ◽

Kimmie Ng ◽

...

Keyword(s):

Dietary Fat ◽

Controlled Trial ◽

Saturated Fat ◽

Dietary Factors ◽

P Value ◽

Fat Intake ◽

Total N ◽

Long Chain ◽

Vegetable Fat

3588 Background: Growing data suggest dietary factors are associated with survival among pts with non-metastatic CRC. However, data on diet and survival among pts with advanced or metastatic disease are very limited. Methods: We prospectively examined dietary fat intake assessed at initiation of treatment for advanced or metastatic CRC in relation to OS and PFS. This analysis was conducted among 1,149 pts in the CALGB 80405 randomized controlled trial who completed a validated food frequency questionnaire. We examined intakes of saturated, monounsaturated, and polyunsaturated (total n-3, long-chain n-3, and total n-6) fats as well as animal and vegetable fats. Based on data from non-metastatic CRC and other cancers, we hypothesized that higher intakes of long-chain n-3 fatty acids and vegetable fats would be associated with longer OS and PFS and higher intakes of saturated fat and animal fat would be associated with shorter OS and PFS. We used Cox proportional hazards regression to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI). Results: Over a median follow-up of 6.1 years [y; interquartile range (IQR): 5.3, 7.2 y], we observed 974 deaths and 103 events of progression without death during follow-up. Participants in this analysis had a median age of 59 y (IQR: 51 to 67 y); 41% were female and 86% identified as white. We observed no statistically significant associations between any type of dietary fat and OS. However, vegetable fat was non-linearly associated with longer PFS (HR comparing 4th to 1st quartile: 0.78; 95% CI: 0.64, 0.96; p-trend: 0.10). We also observed a linear association between continuous saturated fat and PFS (HR per 5% kcal/d: 1.21; 95% CI: 1.03, 1.42; p-value: 0.02), perhaps driven by pts with high saturated fat intake. Conclusions: We observed no statistically significant associations between types of dietary fat and OS among pts with advanced or metastatic CRC. However, a healthy diet that includes vegetable fat and is modest in saturated fat may be associated with longer PFS. Future studies to replicate these findings and examine diet in relation to cancer survival in racially/ethnically diverse populations are needed. Support: K07CA197077, U10CA180821, U10CA180882, https://acknowledgments.alliancefound.org . Clinical trial information: NCT00265850.

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Increased Risk of High Body Fat and Altered Lipid Metabolism Associated to Suboptimal Consumption of Vitamin A Is Modulated by Genetic Variants rs5888 (SCARB1), rs1800629 (UCP1) and rs659366 (UCP2)

Nutrients ◽

10.3390/nu12092588 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2588

Author(s):

Sebastià Galmés ◽

Andreu Palou ◽

Francisca Serra

Keyword(s):

Gene Expression ◽

Lipid Metabolism ◽

Vitamin A ◽

Body Fat ◽

Genetic Variants ◽

Mononuclear Cells ◽

Metabolic Response ◽

Ex Vivo ◽

P Value ◽

Increased Risk

Obesity is characterized by an excessive body fat percentage (BF%). Animal and cell studies have shown benefits of vitamin A (VA) on BF% and lipid metabolism, but it is still controversial in humans. Furthermore, although some genetic variants may explain heterogeneity in VA plasma levels, their role in VA metabolic response is still scarcely characterized. This study was designed as a combination of an observational study involving 158 male subjects followed by a study with a well-balanced genotype–phenotype protocol, including in the design an ex vivo intervention study performed on isolated peripheral blood mononuclear cells (PBMCs) of the 41 former males. This is a strategy to accurately identify the delivery of Precision Nutrition recommendations to targeted subjects. The study assesses the influence of rs5888 (SCARB1), rs659366 (UCP2), and rs1800629 (UCP1) variants on higher BF% associated with suboptimal VA consumption and underlines the cellular mechanisms involved by analyzing basal and retinoic acid (RA) response on PBMC gene expression. Data show that male carriers with the major allele combinations and following suboptimal-VA diet show higher BF% (adjusted ANOVA test p-value = 0.006). Genotype–BF% interaction is observed on oxidative/inflammatory gene expression and also influences lipid related gene expression in response to RA. Data indicate that under suboptimal consumption of VA, carriers of VA responsive variants and with high-BF% show a gene expression profile consistent with an impaired basal metabolic state. The results show the relevance of consuming VA within the required amounts, its impact on metabolism and energy balance, and consequently, on men’s adiposity with a clear influence of genetic variants SCARB1, UCP2 and UCP1.

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