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1.
Int J Obes (Lond) ; 2018 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-29795460

RESUMO

BACKGROUND: Recent analyses in Greenlandic Inuit identified six genetic polymorphisms (rs74771917, rs3168072, rs12577276, rs7115739, rs174602 and rs174570) in the fatty acid desaturase gene cluster (FADS1-FADS2-FADS3) that are associated with multiple metabolic and anthropometric traits. Our objectives were to systematically assess whether dietary polyunsaturated fatty acid (PUFA) intake modifies the associations between genetic variants in the FADS gene cluster and cardiometabolic traits, and to functionally annotate top-ranking candidates to estimate their regulatory potential. METHODS: Data analyses consisted of the following: interaction analyses between the 6 candidate genetic variants and dietary PUFA intake; gene-centric joint analyses to detect interaction signals in the FADS region; haplotype-centric joint tests across 30 haplotype blocks in the FADS region to refine interaction signals; and functional annotation of top-ranking loci from the previous steps. These analyses were undertaken in Swedish adults from the GLACIER Study (N = 5,160); data on genetic variation and eight cardiometabolic traits were used. RESULTS: Interactions were observed between rs174570 and n-6 PUFA intake on fasting glucose (Pint = 0.005) and between rs174602 and n-3 PUFA intake on total cholesterol (Pint = 0.001). Gene-centric analyses demonstrated a statistically significant interaction effect for FADS and n-3 PUFA on triglycerides (P int = 0.005) considering genetic main effects as random. Haplotype analyses revealed three blocks (Pint < 0.011) that could drive the interaction between FADS and n-3 PUFA on triglycerides; functional annotation of these regions showed that each block harbours a number of highly functional regulatory variants; FADS2 rs5792235 demonstrated the highest functionality score. CONCLUSIONS: The association between FADS variants and triglycerides may be modified by PUFA intake. The intronic FADS2 rs5792235 variant is a potential causal variant in the region, having the highest regulatory potential. However, our results suggest that multiple haplotypes may harbour functional variants in a region, rather than a single causal variant.

2.
Br J Nutr ; 119(12): 1408-1415, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29845900

RESUMO

Potatoes have been a staple food in many countries throughout the years. Potatoes have a high glycaemic index (GI) score, and high GI has been associated with several chronic diseases and cancers. Still, the research on potatoes and health is scarce and contradictive, and we identified no prospective studies that had investigated the association between potatoes as a single food and the risk of pancreatic cancer. The aim of this study was to prospectively investigate the association between potato consumption and pancreatic cancer among 114 240 men and women in the prospective HELGA cohort, using Cox proportional hazard models. Information on diet (validated FFQ's), lifestyle and health was collected by means of a questionnaire, and 221 pancreatic cancer cases were identified through cancer registries. The mean follow-up time was 11·4 (95 % CI 0·3, 16·9) years. High consumption of potatoes showed a non-significantly higher risk of pancreatic cancer in the adjusted model (hazard ratio (HR) 1·44; 95 % CI 0·93, 2·22, P for trend 0·030) when comparing the highest v. the lowest quartile of potato consumption. In the sex-specific analyses, significant associations were found for females (HR 2·00; 95 % CI 1·07, 3·72, P for trend 0·020), but not for males (HR 1·01; 95 % CI 0·56, 1·84, P for trend 0·34). In addition, we explored the associations by spline regression, and the absence of dose-response effects was confirmed. In this study, high potato consumption was not consistently associated with a higher risk of pancreatic cancer. Further studies with larger populations are needed to explore the possible sex difference.

3.
BMJ Open Diabetes Res Care ; 6(1): e000454, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29527307

RESUMO

Objective: Tight glycemic control and aggressive treatment of additional cardiovascular risk factors can substantially reduce risk of diabetes-related complications. In 2013, the Swiss Society of Endocrinology and Diabetology (SSED) established national criteria on good disease management in diabetes, but little is known about compliance in clinical care. Here we assessed to what extent patients from two tertiary care centers in the German-speaking part of Switzerland enrolled in the Swiss Diabetes (SwissDiab) Registry adhere to the SSED criteria. Research design and methods: SwissDiab is a prospective observational cohort study of patients regularly treated at Swiss tertiary diabetes centers. Data were collected through standardized annual health examinations. Baseline participant descriptive statistics, stratified by diabetes mellitus type 1 (DM1) and type 2 (DM2), were compared with SSED targets for glycemic control, blood pressure, blood lipids, weight maintenance, and ophthalmic examination. Results: By the end of 2016, 604 participants with DM1 (40%) and DM2 (60%) had data available for analyses, 36% and 29% women, respectively. At baseline, all the SSED targets were met with two exceptions: a glycated hemoglobin A1c value <7% was measured in 32% of participants with DM1 (SSED target: ≥40%) and 47% and 56% of overweight or obese participants with DM1 and DM2, respectively, received nutritional counseling in the previous year (SSED target: ≥80%). Conclusions: The SSED targets for good disease management in diabetes were achieved in the majority of participants at the time of enrollment, but results also highlight areas where disease management can be improved, particularly the role of nutrition counseling.

4.
Int J Cancer ; 142(6): 1189-1201, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29114875

RESUMO

Evidence from in vivo, in vitro and ecological studies are suggestive of a protective effect of vitamin D against pancreatic cancer (PC). However, this has not been confirmed by analytical epidemiological studies. We aimed to examine the association between pre-diagnostic circulating vitamin D concentrations and PC incidence in European populations. We conducted a pooled nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Nord-Trøndelag Health Study's second survey (HUNT2) cohorts. In total, 738 primary incident PC cases (EPIC n = 626; HUNT2 n = 112; median follow-up = 6.9 years) were matched to 738 controls. Vitamin D [25(OH)D2 and 25(OH)D3 combined] concentrations were determined using isotope-dilution liquid chromatography-tandem mass spectrometry. Conditional logistic regression models with adjustments for body mass index and smoking habits were used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (95%CI). Compared with a reference category of >50 to 75 nmol/L vitamin D, the IRRs (95% CIs) were 0.71 (0.42-1.20); 0.94 (0.72-1.22); 1.12 (0.82-1.53) and 1.26 (0.79-2.01) for clinically pre-defined categories of ≤25; >25 to 50; >75 to 100; and >100 nmol/L vitamin D, respectively (p for trend = 0.09). Corresponding analyses by quintiles of season-standardized vitamin D concentrations also did not reveal associations with PC risk (p for trend = 0.23). Although these findings among participants from the largest combination of European cohort studies to date show increasing effect estimates of PC risk with increasing pre-diagnostic concentrations of vitamin D, they are not statistically significant.


Assuntos
25-Hidroxivitamina D 2/sangue , Calcifediol/sangue , Neoplasias Pancreáticas/epidemiologia , Idoso , Estudos de Casos e Controles , Europa (Continente) , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/sangue , Estudos Prospectivos , Medição de Risco , Estações do Ano
6.
Am J Clin Nutr ; 105(6): 1502-1511, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28490510

RESUMO

Background: A positive association between nonfermented milk intake and increased all-cause mortality was recently reported, but overall, the association between dairy intake and mortality is inconclusive.Objective: We studied associations between intake of dairy products and all-cause mortality with an emphasis on nonfermented milk and fat content.Design: A total of 103,256 adult participants (women: 51.0%) from Northern Sweden were included (7121 deaths; mean follow-up: 13.7 y). Associations between all-cause mortality and reported intakes of nonfermented milk (total or by fat content), fermented milk, cheese, and butter were tested with the use of Cox proportional hazards models that were adjusted for age, sex, body mass index, smoking status, education, energy intake, examination year, and physical activity. To circumvent confounding, Mendelian randomization was applied in a subsample via the lactase LCT-13910 C/T single nucleotide polymorphism that is associated with lactose tolerance and milk intake.Results: High consumers of nonfermented milk (≥2.5 times/d) had a 32% increased hazard (HR: 1.32; 95% CI: 1.18, 1.48) for all-cause mortality compared with that of subjects who consumed milk ≤1 time/wk. The corresponding value for butter was 11% (HR: 1.11; 95% CI: 1.07, 1.21). All nonfermented milk-fat types were independently associated with increased HRs, but compared with full-fat milk, HRs were lower in consumers of medium- and low-fat milk. Fermented milk intake (HR: 0.90; 95% CI: 0.86, 0.94) and cheese intake (HR: 0.93; 95% CI: 0.91, 0.96) were negatively associated with mortality. Results were slightly attenuated by lifestyle adjustments but were robust in sensitivity analyses. Mortality was not significantly associated with the LCT-13910 C/T genotype in the smaller subsample. The amount and type of milk intake was associated with lifestyle variables.Conclusions: In the present Swedish cohort study, intakes of nonfermented milk and butter are associated with higher all-cause mortality, and fermented milk and cheese intakes are associated with lower all-cause mortality. Residual confounding by lifestyle cannot be excluded, and Mendelian randomization needs to be examined in a larger sample.


Assuntos
Manteiga/efeitos adversos , Causas de Morte , Dieta , Gorduras na Dieta/efeitos adversos , Comportamento Alimentar , Leite/efeitos adversos , Adulto , Animais , Laticínios , Ingestão de Energia , Feminino , Humanos , Intolerância à Lactose/genética , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Suécia/epidemiologia
7.
Nat Commun ; 8: 14977, 2017 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-28443625

RESUMO

Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Obesidade/genética , Locos de Características Quantitativas/genética , Fumar/genética , Adiposidade/genética , Adulto , Distribuição da Gordura Corporal , Índice de Massa Corporal , Epistasia Genética , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Circunferência da Cintura/genética , Relação Cintura-Quadril
8.
PLoS Genet ; 13(4): e1006528, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28448500

RESUMO

Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.


Assuntos
Adiposidade/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Exercício , Obesidade/genética , Adiposidade/fisiologia , Índice de Massa Corporal , Epigenômica , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Obesidade/fisiopatologia , Circunferência da Cintura , Relação Cintura-Quadril
9.
Nutr J ; 16(1): 20, 2017 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-28351404

RESUMO

BACKGROUND: Dietary risks today constitute the largest proportion of disability-adjusted life years (DALYs) globally and in Sweden. An increasing number of people today consume highly processed foods high in saturated fat, refined sugar and salt and low in dietary fiber, vitamins and minerals. It is important that dietary trends over time are monitored to predict changes in disease risk. METHODS: In total, 15,995 individuals with two visits 10 (±1) years apart in the population-based Västerbotten Intervention Programme 1996-2014 were included. Dietary intake was captured with a 64-item food frequency questionnaire. Percent changes in intake of dietary components, Healthy Diet Score and Dietary Inflammatory Index were calculated and related to body mass index (BMI), serum cholesterol and triglyceride levels and blood pressure at the second visit in multivariable regression analyses. RESULTS: For both sexes, on group level, proportion of energy intake (E%) from carbohydrates and sucrose decreased (largest carbohydrate decrease among 40 year-olds) and E% protein and total fat as well as saturated and poly-unsaturated fatty acids (PUFA) increased (highest protein increase among 30 year-olds and highest fat increase among 60 year-olds) over the 10-year period. Also, E% trans-fatty acids decreased. On individual basis, for both sexes decreases in intake of cholesterol and trans-fatty acids were associated with lower BMI and serum cholesterol at second visit (all P < 0.05). For men, increases in intake of whole grain and Healthy Diet Score were associated with lower BMI and serum cholesterol at second visit (all P < 0.05). Also for men, decreases in intake of trans-fatty acids and increases in Healthy Diet Score were associated with lower systolic blood pressure at second visit (P = 0.002 and P < 0.000). For women, increases in intake of PUFA and Healthy Diet Score were associated with lower BMI at second visit (P = 0.01 and P < 0.05). Surprisingly, increases in intake of sucrose among women were associated with lower BMI at second visit (P = 0.02). CONCLUSIONS: In this large population-based sample, dietary changes over 10 years towards less carbohydrates and more protein and fat were noted. Individual changes towards the Nordic dietary recommendations were associated with healthier cardio-metabolic risk factor profile at second visit.


Assuntos
Doenças Cardiovasculares/epidemiologia , Dieta Saudável , Síndrome Metabólica/epidemiologia , Adulto , Pressão Sanguínea , Índice de Massa Corporal , Doenças Cardiovasculares/prevenção & controle , Colesterol/sangue , Exercício , Feminino , Seguimentos , Humanos , Estilo de Vida , Estudos Longitudinais , Masculino , Síndrome Metabólica/prevenção & controle , Pessoa de Meia-Idade , Fatores de Risco , Fatores Socioeconômicos , Inquéritos e Questionários , Suécia/epidemiologia , Triglicerídeos/sangue
10.
Diabetologia ; 60(3): 442-452, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28004149

RESUMO

AIMS/HYPOTHESIS: Little is known about the heritable basis of gene-environment interactions in humans. We therefore screened multiple cardiometabolic traits to assess the probability that they are influenced by genotype-environment interactions. METHODS: Fourteen established environmental risk exposures and 11 cardiometabolic traits were analysed in the VIKING study, a cohort of 16,430 Swedish adults from 1682 extended pedigrees with available detailed genealogical, phenotypic and demographic information, using a maximum likelihood variance decomposition method in Sequential Oligogenic Linkage Analysis Routines software. RESULTS: All cardiometabolic traits had statistically significant heritability estimates, with narrow-sense heritabilities (h 2) ranging from 24% to 47%. Genotype-environment interactions were detected for age and sex (for the majority of traits), physical activity (for triacylglycerols, 2 h glucose and diastolic BP), smoking (for weight), alcohol intake (for weight, BMI and 2 h glucose) and diet pattern (for weight, BMI, glycaemic traits and systolic BP). Genotype-age interactions for weight and systolic BP, genotype-sex interactions for BMI and triacylglycerols and genotype-alcohol intake interactions for weight remained significant after multiple test correction. CONCLUSIONS/INTERPRETATION: Age, sex and alcohol intake are likely to be major modifiers of genetic effects for a range of cardiometabolic traits. This information may prove valuable for studies that seek to identify specific loci that modify the effects of lifestyle in cardiometabolic disease.


Assuntos
Interação Gene-Ambiente , Glicemia/metabolismo , Pressão Sanguínea/fisiologia , Peso Corporal/fisiologia , Ingestão de Alimentos/fisiologia , Exercício/fisiologia , Jejum/sangue , Feminino , Ligação Genética/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Modelos Teóricos , Linhagem , Fenótipo , Fatores Sexuais , Fumar/fisiopatologia , Circunferência da Cintura/fisiologia
11.
Int J Epidemiol ; 46(4): 1211-1222, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27864399

RESUMO

Background: Cross-sectional genome-wide association studies have identified hundreds of loci associated with blood lipids and related cardiovascular traits, but few genetic association studies have focused on long-term changes in blood lipids. Methods: Participants from the GLACIER Study (Nmax = 3492) were genotyped with the MetaboChip array, from which 29 387 SNPs (single nucleotide polymorphisms; replication, fine-mapping regions and wildcard SNPs for lipid traits) were extracted for association tests with 10-year change in total cholesterol (ΔTC) and triglycerides (ΔTG). Four additional prospective cohort studies (MDC, PIVUS, ULSAM, MRC Ely; Nmax = 8263 participants) were used for replication. We conducted an in silico look-up for association with coronary artery disease (CAD) in the Coronary ARtery DIsease Genome-wide Replication and Meta-analysis (CARDIoGRAMplusC4D) Consortium (N ∼ 190 000) and functional annotation for the top ranking variants. Results: In total, 956 variants were associated (P < 0.01) with either ΔTC or ΔTG in GLACIER. In GLACIER, chr19:50121999 at APOE was associated with ΔTG and multiple SNPs in the APOA1/A4/C3/A5 region at genome-wide significance (P < 5 × 10-8), whereas variants in four loci, DOCK7, BRE, SYNE1 and KCNIP1, reached study-wide significance (P < 1.7 × 10-6). The rs7412 variant at APOE was associated with ΔTC in GLACIER (P < 1.7 × 10-6). In pooled analyses of all cohorts, 139 SNPs at six and five loci were associated with ΔTC and for ΔTG, respectively (P < 10-3). Of these, a variant at CAPN3 (P = 1.2 × 10-4), multiple variants at HPR (Pmin = 1.5 × 10-6) and a variant at SIX5 (P = 1.9 × 10-4) showed evidence for association with CAD. Conclusions: We identified seven novel genomic regions associated with long-term changes in blood lipids, of which three also raise CAD risk.


Assuntos
Doença da Artéria Coronariana/genética , Grupo com Ancestrais do Continente Europeu/genética , Loci Gênicos , Lipídeos/sangue , Adulto , Idoso , Estudos Transversais , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Suécia
13.
J Am Heart Assoc ; 5(11)2016 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-27799235

RESUMO

BACKGROUND: Bicycling to work may be a viable approach for achieving physical activity that provides cardiovascular health benefits. In this study we investigated the relationship of bicycling to work with incidence of obesity, hypertension, hypertriglyceridemia, and impaired glucose tolerance across a decade of follow-up in middle-aged men and women. METHODS AND RESULTS: We followed 23 732 Swedish men and women with a mean age of 43.5 years at baseline who attended a health examination twice during a 10-year period (1990-2011). In multivariable adjusted models we calculated the odds of incident obesity, hypertension, hypertriglyceridemia, and impaired glucose tolerance, comparing individuals who commuted to work by bicycle with those who used passive modes of transportation. We also examined the relationship of change in commuting mode with incidence of these clinical risk factors. Cycling to work at baseline was associated with lower odds of incident obesity (odds ratio [OR]=0.85, 95% CI 0.73-0.99), hypertension (OR=0.87, 95% CI 0.79-0.95), hypertriglyceridemia (OR=0.85, 95% CI 0.76-0.94), and impaired glucose tolerance (OR=0.88, 95% CI 0.80-0.96) compared with passive travel after adjusting for putative confounding factors. Participants who maintained or began bicycling to work during follow-up had lower odds of obesity (OR=0.61, 95% CI 0.50-0.73), hypertension (OR=0.89, 95% CI 0.80-0.98), hypertriglyceridemia (OR=0.80, 95% CI 0.70-0.90), and impaired glucose tolerance (OR=0.82, 95% CI 0.74-0.91) compared with participants not cycling to work at both times points or who switched from cycling to other modes of transport during follow-up. CONCLUSIONS: These data suggest that commuting by bicycle to work is an important strategy for primordial prevention of clinical cardiovascular risk factors among middle-aged men and women.


Assuntos
Ciclismo , Doenças Cardiovasculares/prevenção & controle , Adulto , Doenças Cardiovasculares/epidemiologia , Estudos de Coortes , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Intolerância à Glucose/epidemiologia , Humanos , Hipertensão/epidemiologia , Hipertrigliceridemia/epidemiologia , Incidência , Masculino , Obesidade/epidemiologia , Fatores de Risco , Suécia/epidemiologia
14.
Circ Cardiovasc Genet ; 9(6): 495-503, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27784733

RESUMO

BACKGROUND: We assessed whether 234 established dyslipidemia-associated loci modify the effects of metformin treatment and lifestyle intervention (versus placebo control) on lipid and lipid subfraction levels in the Diabetes Prevention Program randomized controlled trial. METHODS AND RESULTS: We tested gene treatment interactions in relation to baseline-adjusted follow-up blood lipid concentrations (high-density lipoprotein [HDL] and low-density lipoprotein-cholesterol, total cholesterol, and triglycerides) and lipoprotein subfraction particle concentrations and size in 2993 participants with pre-diabetes. Of the previously reported single-nucleotide polymorphism associations, 32.5% replicated at P<0.05 with baseline lipid traits. Trait-specific genetic risk scores were robustly associated (3×10-4>P>1.1×10-16) with their respective baseline traits for all but 2 traits. Lifestyle modified the effect of the genetic risk score for large HDL particle numbers, such that each risk allele of the genetic risk scores was associated with lower concentrations of large HDL particles at follow-up in the lifestyle arm (ß=-0.11 µmol/L per genetic risk scores risk allele; 95% confidence interval, -0.188 to -0.033; P=5×10-3; Pinteraction=1×10-3 for lifestyle versus placebo), but not in the metformin or placebo arms (P>0.05). In the lifestyle arm, participants with high genetic risk had more favorable or similar trait levels at 1-year compared with participants at lower genetic risk at baseline for 17 of the 20 traits. CONCLUSIONS: Improvements in large HDL particle concentrations conferred by lifestyle may be diminished by genetic factors. Lifestyle intervention, however, was successful in offsetting unfavorable genetic loading for most lipid traits. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique Identifier: NCT00004992.


Assuntos
Dislipidemias/genética , Dislipidemias/terapia , Loci Gênicos , Hipoglicemiantes/uso terapêutico , Lipídeos/sangue , Metformina/uso terapêutico , Polimorfismo de Nucleotídeo Único , Estado Pré-Diabético/terapia , Comportamento de Redução do Risco , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Dislipidemias/sangue , Dislipidemias/epidemiologia , Interação Gene-Ambiente , Marcadores Genéticos , Predisposição Genética para Doença , Hereditariedade , Humanos , Tamanho da Partícula , Fenótipo , Estado Pré-Diabético/sangue , Estado Pré-Diabético/epidemiologia , Medição de Risco , Fatores de Risco , Triglicerídeos/sangue , Estados Unidos/epidemiologia
15.
Am J Clin Nutr ; 104(3): 809-15, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27465381

RESUMO

BACKGROUND: The consumption of sugar-sweetened beverages (SSBs), which has increased substantially during the last decades, has been associated with obesity and weight gain. OBJECTIVE: Common genetic susceptibility to obesity has been shown to modify the association between SSB intake and obesity risk in 3 prospective cohorts from the United States. We aimed to replicate these findings in 2 large Swedish cohorts. DESIGN: Data were available for 21,824 healthy participants from the Malmö Diet and Cancer study and 4902 healthy participants from the Gene-Lifestyle Interactions and Complex Traits Involved in Elevated Disease Risk Study. Self-reported SSB intake was categorized into 4 levels (seldom, low, medium, and high). Unweighted and weighted genetic risk scores (GRSs) were constructed based on 30 body mass index [(BMI) in kg/m(2)]-associated loci, and effect modification was assessed in linear regression equations by modeling the product and marginal effects of the GRS and SSB intake adjusted for age-, sex-, and cohort-specific covariates, with BMI as the outcome. In a secondary analysis, models were additionally adjusted for putative confounders (total energy intake, alcohol consumption, smoking status, and physical activity). RESULTS: In an inverse variance-weighted fixed-effects meta-analysis, each SSB intake category increment was associated with a 0.18 higher BMI (SE = 0.02; P = 1.7 × 10(-20); n = 26,726). In the fully adjusted model, a nominal significant interaction between SSB intake category and the unweighted GRS was observed (P-interaction = 0.03). Comparing the participants within the top and bottom quartiles of the GRS to each increment in SSB intake was associated with 0.24 (SE = 0.04; P = 2.9 × 10(-8); n = 6766) and 0.15 (SE = 0.04; P = 1.3 × 10(-4); n = 6835) higher BMIs, respectively. CONCLUSIONS: The interaction observed in the Swedish cohorts is similar in magnitude to the previous analysis in US cohorts and indicates that the relation of SSB intake and BMI is stronger in people genetically predisposed to obesity.


Assuntos
Bebidas/efeitos adversos , Carboidratos da Dieta/efeitos adversos , Loci Gênicos , Predisposição Genética para Doença , Obesidade/genética , Sobrepeso/genética , Polimorfismo de Nucleotídeo Único , Índice de Massa Corporal , Bebidas Gaseificadas/efeitos adversos , Estudos de Coortes , Fatores de Confusão (Epidemiologia) , Estudos Transversais , Registros de Dieta , Carboidratos da Dieta/administração & dosagem , Feminino , Sucos de Frutas e Vegetais/efeitos adversos , Estudos de Associação Genética , Predisposição Genética para Doença/etnologia , Humanos , Masculino , Pessoa de Meia-Idade , Nutrigenômica/métodos , Inquéritos Nutricionais , Obesidade/epidemiologia , Obesidade/etnologia , Obesidade/etiologia , Sobrepeso/epidemiologia , Sobrepeso/etnologia , Sobrepeso/etiologia , Estudos Prospectivos , Autorrelato , Suécia/epidemiologia
16.
Hum Mol Genet ; 25(18): 4094-4106, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27466198

RESUMO

It has been hypothesized that low frequency (1-5% minor allele frequency (MAF)) and rare (<1% MAF) variants with large effect sizes may contribute to the missing heritability in complex traits. Here, we report an association analysis of lipid traits (total cholesterol, LDL-cholesterol, HDL-cholesterol triglycerides) in up to 27 312 individuals with a comprehensive set of low frequency coding variants (ExomeChip), combined with conditional analysis in the known lipid loci. No new locus reached genome-wide significance. However, we found a new lead variant in 26 known lipid association regions of which 16 were >1000-fold more significant than the previous sentinel variant and not in close LD (six had MAF <5%). Furthermore, conditional analysis revealed multiple independent signals (ranging from 1 to 5) in a third of the 98 lipid loci tested, including rare variants. Addition of our novel associations resulted in between 1.5- and 2.5-fold increase in the proportion of heritability explained for the different lipid traits. Our findings suggest that rare coding variants contribute to the genetic architecture of lipid traits.


Assuntos
HDL-Colesterol/genética , LDL-Colesterol/genética , Metabolismo dos Lipídeos/genética , Lipídeos/genética , Adolescente , Adulto , Idoso , Criança , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Grupo com Ancestrais do Continente Europeu , Exoma/genética , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Lipídeos/sangue , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Triglicerídeos/sangue , Triglicerídeos/genética
17.
PLoS One ; 11(7): e0159025, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27409582

RESUMO

Scores of overall diet quality have received increasing attention in relation to disease aetiology; however, their value in risk prediction has been little examined. The objective was to assess and compare the association and predictive performance of 10 diet quality scores on 10-year risk of all-cause, CVD and cancer mortality in 451,256 healthy participants to the European Prospective Investigation into Cancer and Nutrition, followed-up for a median of 12.8y. All dietary scores studied showed significant inverse associations with all outcomes. The range of HRs (95% CI) in the top vs. lowest quartile of dietary scores in a composite model including non-invasive factors (age, sex, smoking, body mass index, education, physical activity and study centre) was 0.75 (0.72-0.79) to 0.88 (0.84-0.92) for all-cause, 0.76 (0.69-0.83) to 0.84 (0.76-0.92) for CVD and 0.78 (0.73-0.83) to 0.91 (0.85-0.97) for cancer mortality. Models with dietary scores alone showed low discrimination, but composite models also including age, sex and other non-invasive factors showed good discrimination and calibration, which varied little between different diet scores examined. Mean C-statistic of full models was 0.73, 0.80 and 0.71 for all-cause, CVD and cancer mortality. Dietary scores have poor predictive performance for 10-year mortality risk when used in isolation but display good predictive ability in combination with other non-invasive common risk factors.


Assuntos
Doenças Cardiovasculares/mortalidade , Dieta , Grupo com Ancestrais do Continente Europeu , Neoplasias/mortalidade , Distribuição por Idade , Estudos de Coortes , Feminino , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Distribuição por Sexo
18.
Cancer Causes Control ; 27(7): 919-27, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27294726

RESUMO

BACKGROUND: The etiology of small intestinal cancer (SIC) is largely unknown, and there are very few epidemiological studies published to date. No studies have investigated abdominal adiposity in relation to SIC. METHODS: We investigated overall obesity and abdominal adiposity in relation to SIC in the European Prospective Investigation into Cancer and Nutrition (EPIC), a large prospective cohort of approximately half a million men and women from ten European countries. Overall obesity and abdominal obesity were assessed by body mass index (BMI), waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR). Multivariate Cox proportional hazards regression modeling was performed to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs). Stratified analyses were conducted by sex, BMI, and smoking status. RESULTS: During an average of 13.9 years of follow-up, 131 incident cases of SIC (including 41 adenocarcinomas, 44 malignant carcinoid tumors, 15 sarcomas and 10 lymphomas, and 21 unknown histology) were identified. WC was positively associated with SIC in a crude model that also included BMI (HR per 5-cm increase = 1.20, 95 % CI 1.04, 1.39), but this association attenuated in the multivariable model (HR 1.18, 95 % CI 0.98, 1.42). However, the association between WC and SIC was strengthened when the analysis was restricted to adenocarcinoma of the small intestine (multivariable HR adjusted for BMI = 1.56, 95 % CI 1.11, 2.17). There were no other significant associations. CONCLUSION: WC, rather than BMI, may be positively associated with adenocarcinomas but not carcinoid tumors of the small intestine. IMPACT: Abdominal obesity is a potential risk factor for adenocarcinoma in the small intestine.


Assuntos
Adenocarcinoma/epidemiologia , Adiposidade , Neoplasias Intestinais/epidemiologia , Obesidade/complicações , Adulto , Idoso , Estatura , Índice de Massa Corporal , Europa (Continente)/epidemiologia , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Circunferência da Cintura , Relação Cintura-Quadril
19.
Circ Cardiovasc Genet ; 9(2): 162-71, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26865658

RESUMO

BACKGROUND: Obesity is a major risk factor for dyslipidemia, but this relationship is highly variable. Recently published data from 2 Danish cohorts suggest that genetic factors may underlie some of this variability. METHODS AND RESULTS: We tested whether established triglyceride-associated loci modify the relationship of body mass index (BMI) and triglyceride concentrations in 2 Swedish cohorts (the Gene-Lifestyle Interactions and Complex Traits Involved in Elevated Disease Risk [GLACIER Study; N=4312] and the Malmö Diet and Cancer Study [N=5352]). The genetic loci were amalgamated into a weighted genetic risk score (WGRSTG) by summing the triglyceride-elevating alleles (weighted by their established marginal effects) for all loci. Both BMI and the WGRSTG were strongly associated with triglyceride concentrations in GLACIER, with each additional BMI unit (kg/m(2)) associated with 2.8% (P=8.4×10(-84)) higher triglyceride concentration and each additional WGRSTG unit with 2% (P=7.6×10(-48)) higher triglyceride concentration. Each unit of the WGRSTG was associated with 1.5% higher triglyceride concentrations in normal weight and 2.4% higher concentrations in overweight/obese participants (Pinteraction=0.056). Meta-analyses of results from the Swedish cohorts yielded a statistically significant WGRSTG×BMI interaction effect (Pinteraction=6.0×10(-4)), which was strengthened by including data from the Danish cohorts (Pinteraction=6.5×10(-7)). In the meta-analysis of the Swedish cohorts, nominal evidence of a 3-way interaction (WGRSTG×BMI×sex) was observed (Pinteraction=0.03), where the WGRSTG×BMI interaction was only statistically significant in females. Using protein-protein interaction network analyses, we identified molecular interactions and pathways elucidating the metabolic relationships between BMI and triglyceride-associated loci. CONCLUSIONS: Our findings provide evidence that body fatness accentuates the effects of genetic susceptibility variants in hypertriglyceridemia, effects that are most evident in females.


Assuntos
Predisposição Genética para Doença , Hipertrigliceridemia/complicações , Hipertrigliceridemia/genética , Obesidade/complicações , Obesidade/genética , Índice de Massa Corporal , Feminino , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla , Humanos , Hipertrigliceridemia/sangue , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Caracteres Sexuais , Triglicerídeos/sangue
20.
Nat Commun ; 7: 10494, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26833098

RESUMO

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.


Assuntos
Regulação da Expressão Gênica/fisiologia , Estudo de Associação Genômica Ampla , Leptina/sangue , Leptina/metabolismo , Tecido Adiposo/metabolismo , Animais , Técnicas de Silenciamento de Genes , Leptina/genética , Masculino , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Técnicas de Cultura de Tecidos
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