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1.
Diabetes Care ; 46(5): 985-992, 2023 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-36809463

RESUMO

OBJECTIVE: The association between FTO rs9939609 and obesity is modified by physical activity (PA) and/or insulin sensitivity (IS). We aimed to assess whether these modifications are independent, to assess whether PA and/or IS modify the association between rs9939609 and cardiometabolic traits, and to elucidate underlying mechanisms. RESEARCH DESIGN AND METHODS: Genetic association analyses comprised up to 19,585 individuals. PA was self-reported, and IS was defined based on inverted HOMA insulin resistance index. Functional analyses were performed in muscle biopsies from 140 men and in cultured muscle cells. RESULTS: The BMI-increasing effect of the FTO rs9939609 A allele was attenuated by 47% with high PA (ß [SE], -0.32 [0.10] kg/m2, P = 0.0013) and by 51% with high IS (-0.31 [0.09] kg/m2, P = 0.00028). Interestingly, these interactions were essentially independent (PA, -0.20 [0.09] kg/m2, P = 0.023; IS, -0.28 [0.09] kg/m2, P = 0.0011). The rs9939609 A allele was also associated with higher all-cause mortality and certain cardiometabolic outcomes (hazard ratio, 1.07-1.20, P > 0.04), and these effects tended to be weakened by greater PA and IS. Moreover, the rs9939609 A allele was associated with higher expression of FTO in skeletal muscle tissue (0.03 [0.01], P = 0.011), and in skeletal muscle cells, we identified a physical interaction between the FTO promoter and an enhancer region encompassing rs9939609. CONCLUSIONS: Greater PA and IS independently reduced the effect of rs9939609 on obesity. These effects might be mediated through altered expression of FTO in skeletal muscle. Our results indicated that PA and/or other means of increasing insulin sensitivity could counteract FTO-related genetic predisposition to obesity.


Assuntos
Doenças Cardiovasculares , Hiperinsulinismo , Resistência à Insulina , Masculino , Humanos , Resistência à Insulina/genética , Índice de Massa Corporal , Obesidade/genética , Obesidade/metabolismo , Exercício Físico , Predisposição Genética para Doença , Insulina/genética , Insulina Regular Humana , Polimorfismo de Nucleotídeo Único , Genótipo , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética
2.
PLoS Genet ; 16(1): e1008544, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31978080

RESUMO

The genetic architecture of the small and isolated Greenlandic population is advantageous for identification of novel genetic variants associated with cardio-metabolic traits. We aimed to identify genetic loci associated with body mass index (BMI), to expand the knowledge of the genetic and biological mechanisms underlying obesity. Stage 1 BMI-association analyses were performed in 4,626 Greenlanders. Stage 2 replication and meta-analysis were performed in additional cohorts comprising 1,058 Yup'ik Alaska Native people, and 1,529 Greenlanders. Obesity-related traits were assessed in the stage 1 study population. We identified a common variant on chromosome 11, rs4936356, where the derived G-allele had a frequency of 24% in the stage 1 study population. The derived allele was genome-wide significantly associated with lower BMI (beta (SE), -0.14 SD (0.03), p = 3.2x10-8), corresponding to 0.64 kg/m2 lower BMI per G allele in the stage 1 study population. We observed a similar effect in the Yup'ik cohort (-0.09 SD, p = 0.038), and a non-significant effect in the same direction in the independent Greenlandic stage 2 cohort (-0.03 SD, p = 0.514). The association remained genome-wide significant in meta-analysis of the Arctic cohorts (-0.10 SD (0.02), p = 4.7x10-8). Moreover, the variant was associated with a leaner body type (weight, -1.68 (0.37) kg; waist circumference, -1.52 (0.33) cm; hip circumference, -0.85 (0.24) cm; lean mass, -0.84 (0.19) kg; fat mass and percent, -1.66 (0.33) kg and -1.39 (0.27) %; visceral adipose tissue, -0.30 (0.07) cm; subcutaneous adipose tissue, -0.16 (0.05) cm, all p<0.0002), lower insulin resistance (HOMA-IR, -0.12 (0.04), p = 0.00021), and favorable lipid levels (triglyceride, -0.05 (0.02) mmol/l, p = 0.025; HDL-cholesterol, 0.04 (0.01) mmol/l, p = 0.0015). In conclusion, we identified a novel variant, where the derived G-allele possibly associated with lower BMI in Arctic populations, and as a consequence also leaner body type, lower insulin resistance, and a favorable lipid profile.


Assuntos
Índice de Massa Corporal , Cromossomos Humanos Par 11/genética , Inuíte/genética , Polimorfismo de Nucleotídeo Único , Adiposidade , Colesterol/sangue , DNA Intergênico/genética , Feminino , Groenlândia , Humanos , Resistência à Insulina , Masculino , Metaboloma , Circunferência da Cintura
3.
Obesity (Silver Spring) ; 26(4): 747-754, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29442437

RESUMO

OBJECTIVE: Changes in fat mass depend on adipogenesis and angiogenesis, mechanisms regulated by the inhibitor of differentiation-3 (ID3). Id3 knockout mice showed attenuated increases in BMI and visceral fat mass. We hypothesized that the ID3 missense variant (rs11574-A) would lead to an attenuated increase over time in fat mass, BMI, waist circumference (WC), and waist-hip ratio (WHR) in humans. METHODS: The genotyped study populations included the Obesity Research Group - Genetics (ORGGEN) cohort, a cohort of men with obesity (N = 716) and of randomly selected men (N = 826) from the Danish draft register who were examined at mean ages of 20 and 46 years, and the Inter99 (N = 6,116) and Health2006 (N = 2,761) cohorts, two population-based samples of middle-aged people, followed up after 5 years. RESULTS: In meta-analyses of all data, no association was found between rs11574-A and changes in BMI, WC, WHR, or fat mass. We found an association between rs11574-A and cross-sectional BMI (N = 10,359, ß: -0.16 kg/m2 per allele, 95% CI: -0.30 to -0.01, P = 0.033) and fat mass (N = 4,188, ß: -0.52 kg/m2 per allele, 95% CI: -1.03 to -0.01, P = 0.046). CONCLUSIONS: No consistent impact of the genetic variant on changes in fat mass, BMI, or fat distribution was found in three Danish cohorts.


Assuntos
Proteínas Inibidoras de Diferenciação/genética , Proteínas de Neoplasias/genética , Adulto , Animais , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Proteínas Inibidoras de Diferenciação/metabolismo , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Obesidade/genética , Estudos Prospectivos , Fatores de Risco , Adulto Jovem
4.
Cell Metab ; 25(5): 1045-1053.e6, 2017 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-28467924

RESUMO

The liking and selective ingestion of palatable foods-including sweets-is biologically controlled, and dysfunction of this regulation may promote unhealthy eating, obesity, and disease. The hepatokine fibroblast growth factor 21 (FGF21) reduces sweet consumption in rodents and primates, whereas knockout of Fgf21 increases sugar consumption in mice. To investigate the relevance of these findings in humans, we genotyped variants in the FGF21 locus in participants from the Danish Inter99 cohort (n = 6,514) and examined their relationship with a detailed range of food and ingestive behaviors. This revealed statistically significant associations between FGF21 rs838133 and increased consumption of candy, as well as nominal associations with increased alcohol intake and daily smoking. Moreover, in a separate clinical study, plasma FGF21 levels increased acutely after oral sucrose ingestion and were elevated in fasted sweet-disliking individuals. These data suggest the liver may secrete hormones that influence eating behavior.


Assuntos
Doces , Fatores de Crescimento de Fibroblastos/genética , Preferências Alimentares , Polimorfismo Genético , Açúcares/metabolismo , Adulto , Apetite , Regulação do Apetite , Estudos de Coortes , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Fatores de Crescimento de Fibroblastos/metabolismo , Genótipo , Humanos , Masculino , Obesidade/genética , Obesidade/metabolismo , Paladar , Adulto Jovem
5.
Eur J Epidemiol ; 32(2): 125-134, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27995393

RESUMO

Lower serum vitamin B12 levels have been related to adverse metabolic health profiles, including adiposity. We used a Mendelian randomization design to test whether this relation might be causal. We included two Danish population-based studies (ntotal = 9311). Linear regression was used to test for associations between (1) serum vitamin B12 levels and body mass index (BMI), (2) genetic variants and serum vitamin B12 levels, and (3) genetic variants and BMI. The effect of a genetically determined decrease in serum vitamin B12 on BMI was estimated by instrumental variable regression. Decreased serum vitamin B12 associated with increased BMI (P < 1 × 10-4). A genetic risk score based on eight vitamin B12 associated variants associated strongly with serum vitamin B12 (P < 2 × 10-43), but not with BMI (P = 0.91). Instrumental variable regression showed that a 20% decrease in serum vitamin B12 was associated with a 0.09 kg/m2 (95% CI 0.05; 0.13) increase in BMI (P = 3 × 10-5), whereas a genetically induced 20% decrease in serum vitamin B12 had no effect on BMI [-0.03 (95% CI -0.22; 0.16) kg/m2] (P = 0.74). Nevertheless, the strongest serum vitamin B12 variant, FUT2 rs602662, which was excluded from the B12 genetic risk score due to potential pleiotropic effects, showed a per allele effect of 0.15 kg/m2 (95% CI 0.01; 0.32) on BMI (P = 0.03). This association was accentuated including two German cohorts (ntotal = 5050), with a combined effect of 0.19 kg/m2 (95% CI 0.08; 0.30) (P = 4 × 10-4). We found no support for a causal role of decreased serum vitamin B12 levels in obesity. However, our study suggests that FUT2, through its regulation of the cross-talk between gut microbes and the human host, might explain a part of the observational association between serum vitamin B12 and BMI.


Assuntos
Índice de Massa Corporal , Vitamina B 12/sangue , Adulto , Fatores Etários , Dinamarca , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
6.
PLoS One ; 11(11): e0166738, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27846319

RESUMO

OBJECTIVES: It has long been discussed whether fitness or fatness is a more important determinant of health status. If the same genetic factors that promote body fat percentage (body fat%) are related to cardiorespiratory fitness (CRF), part of the concurrent associations with health outcomes could reflect a common genetic origin. In this study we aimed to 1) examine genetic correlations between body fat% and CRF; 2) determine whether CRF can be attributed to a genetic risk score (GRS) based on known body fat% increasing loci; and 3) examine whether the fat mass and obesity associated (FTO) locus associates with CRF. METHODS: Genetic correlations based on pedigree information were examined in a family based cohort (n = 230 from 55 families). For the genetic association analyses, we examined two Danish population-based cohorts (ntotal = 3206). The body fat% GRS was created by summing the alleles of twelve independent risk variants known to associate with body fat%. We assessed CRF as maximal oxygen uptake expressed in millilitres of oxygen uptake per kg of body mass (VO2max), per kg fat-free mass (VO2maxFFM), or per kg fat mass (VO2maxFM). All analyses were adjusted for age and sex, and when relevant, for body composition. RESULTS: We found a significant negative genetic correlation between VO2max and body fat% (ρG = -0.72 (SE ±0.13)). The body fat% GRS associated with decreased VO2max (ß = -0.15 mL/kg/min per allele, p = 0.0034, age and sex adjusted). The body fat%-increasing FTO allele was associated with a 0.42 mL/kg/min unit decrease in VO2max per allele (p = 0.0092, age and sex adjusted). Both associations were abolished after additional adjustment for body fat%. The fat% increasing GRS and FTO risk allele were associated with decreased VO2maxFM but not with VO2maxFFM. CONCLUSIONS: Our findings suggest a shared genetic etiology between whole body fat% and CRF.


Assuntos
Tecido Adiposo , Composição Corporal/genética , Aptidão Cardiorrespiratória , Obesidade/genética , Tecido Adiposo/metabolismo , Tecido Adiposo/fisiopatologia , Adulto , Índice de Massa Corporal , Peso Corporal , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Obesidade/fisiopatologia , Consumo de Oxigênio/genética
7.
J Lipid Res ; 57(12): 2193-2199, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27777317

RESUMO

Blood concentrations of triglycerides are influenced by genetic factors as well as a number of environmental factors, including adiposity and glucose homeostasis. The aim was to investigate the association between a serum triglyceride weighted genetic risk score (wGRS) and changes in fasting serum triglyceride level over 5 years and to test whether the effect of the wGRS was modified by 5 year changes of adiposity, insulin resistance, and lifestyle factors. A total of 3,474 nondiabetic individuals from the Danish Inter99 cohort participated in both the baseline and 5 year follow-up physical examinations and had information on the wGRS comprising 39 genetic variants. In a linear regression model adjusted for age, sex, and baseline serum triglyceride, the wGRS was associated with increased serum triglyceride levels over 5 years [per allele effect = 1.3% (1.0-1.6%); P = 1.0 × 10-17]. This triglyceride-increasing effect of the wGRS interacted with changes in insulin resistance (Pinteraction = 1.5 × 10-6). This interaction indicated that the effect of the wGRS was stronger in individuals who became more insulin resistant over 5 years. In conclusion, our findings suggest that increased genetic risk load is associated with a larger increase in fasting serum triglyceride levels in nondiabetic individuals during 5 years of follow-up. This effect of the wGRS is accentuated by increasing insulin resistance.


Assuntos
Resistência à Insulina , Triglicerídeos/sangue , Adiposidade , Adulto , Dislipidemias/sangue , Dislipidemias/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
8.
Obesity (Silver Spring) ; 24(8): 1778-85, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27311925

RESUMO

OBJECTIVE: Forty-nine known single nucleotide polymorphisms (SNPs) associating with body mass index (BMI)-adjusted waist-hip-ratio (WHR) (WHRadjBMI) were recently suggested to cluster into three groups with different associations to cardiometabolic traits. Genetic risk scores of the clusters on the risk of incident diabetes and associations with detailed cardiometabolic phenotypes were tested. METHODS: In a prospective study of 6,121 Inter99 individuals, the risk of incident diabetes using Cox proportional hazards regression was evaluated. Using linear regession, the associations between genetic risk scores and anthropometry and blood samples at fasting and during an oral glucose tolerance test were tested. Analyses were adjusted for age, sex, and BMI. RESULTS: Cluster 1 associated with an increased risk of diabetes (HR = 1.05, P = 2.74 × 10(-) (4) ) and with a poor metabolic profile, including fasting serum triglyceride (ß = 0.98% mmol/L, P = 3.33 × 10(-) (8) ) and Matsuda index (ß = -0.74%, P = 1.29 × 10(-) (4) ). No similar associations for Clusters 2 and 3 were found. The three clusters showed different patterns of association with waist circumference, hip circumference, and height. CONCLUSIONS: Our results suggest that the 49 WHRadjBMI-associated SNPs affect metabolic health differently depending on the cluster of SNPs. The clusters further associate differently with anthropometric measures.


Assuntos
Distribuição da Gordura Corporal , Obesidade/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Antropometria/métodos , Diabetes Mellitus/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Aptidão Física , Estudos Prospectivos , Fatores de Risco , Circunferência da Cintura , Relação Cintura-Quadril
9.
Mol Cell Endocrinol ; 418 Pt 2: 90-100, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26427653

RESUMO

The decade anniversary for genome-wide association studies (GWAS) is approaching, and this experimental approach has commenced a deeper understanding of the genetics underlying complex diseases. In obesity genetics the GIANT (Genetic Investigation of ANthropometric Traits) consortium has played a crucial role, recently with two comprehensive meta-analyses, one focusing on general obesity, analyzing body-mass index (BMI) and the other on fat distribution, focusing on waist-hip ratio adjusted for BMI. With the in silico methods applied in these two studies as the pivot, this review looks into some of the biological knowledge, beginning to emerge from the intricate genomic background behind the genetic determinants of human adiposity. These include synaptic dysfunction, where GWAS pinpoint potential new mechanisms in pathways already known to be linked with obesity.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Obesidade/genética , Sinapses/genética , Distribuição da Gordura Corporal , Índice de Massa Corporal , Humanos , Metanálise como Assunto , Polimorfismo de Nucleotídeo Único , Relação Cintura-Quadril
11.
Circ Cardiovasc Genet ; 8(3): 465-72, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25714099

RESUMO

BACKGROUND: There are several well-established lifestyle factors influencing dyslipidemia and currently; 157 genetic susceptibility loci have been reported to be associated with serum lipid levels at genome-wide statistical significance. However, the interplay between lifestyle risk factors and these susceptibility loci has not been fully elucidated. We tested whether genetic risk scores (GRS) of lipid-associated single nucleotide polymorphisms associate with fasting serum lipid traits and whether the effects are modulated by lifestyle factors or estimates of metabolic health. METHODS AND RESULTS: The single nucleotide polymorphisms were genotyped in 2 Danish cohorts: inter99 (n=5961) for discovery analyses and Health2006 (n=2565) for replication. On the basis of published effect sizes of single nucleotide polymorphisms associated with circulating fasting levels of total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, or triglyceride, 4 weighted GRS were constructed. In a cross-sectional design, we investigated whether the effect of these weighted GRSs on lipid levels were modulated by diet, alcohol consumption, physical activity, and smoking or the individual metabolic health status as estimated from body mass index, waist circumference, and insulin resistance assessed using homeostasis model assessment of insulin resistance. All 4 lipid weighted GRSs associated strongly with their respective trait (from P=3.3×10(-69) to P=1.1×10(-123)). We found interactions between the triglyceride weighted GRS and body mass index and waist circumference on fasting triglyceride levels in Inter99 and replicated these findings in Health2006 (P(interaction)=9.8×10(-5) and 2.0×10(-5), respectively, in combined analysis). CONCLUSIONS: Our findings suggest that individuals who are obese may be more susceptible to the cumulative genetic burden of triglyceride single nucleotide polymorphisms. Therefore, it is suggested that especially these genetically at-risk individuals may benefit more from targeted interventions aiming at obesity prevention.


Assuntos
HDL-Colesterol/sangue , LDL-Colesterol/sangue , Colesterol/sangue , Estudo de Associação Genômica Ampla , Triglicerídeos/sangue , Idoso , Índice de Massa Corporal , Estudos de Coortes , Estudos Transversais , Dinamarca , Feminino , Loci Gênicos , Genótipo , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/patologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco
12.
Diabetologia ; 58(3): 523-33, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25501261

RESUMO

AIMS/HYPOTHESIS: Elevated serum ferritin levels are associated with an increased risk of type 2 diabetes, but the nature of this association remains elusive. The aim of this study was to test the hypothesis that an elevated fasting serum ferritin level is associated with an increased risk of type 2 diabetes due to its association with impaired beta cell function and decreased insulin sensitivity. METHODS: We investigated 6,392 individuals from the Danish general population. Surrogate measures of beta cell function and insulin sensitivity were calculated for approximately 6,100 individuals based on OGTT examinations. RESULTS: The ORs for type 2 diabetes were 4.2 (95% CI 2.4, 7.2) for the highest vs the lowest quintile of serum ferritin, and 17 (95% CI 8.9, 33) for serum ferritin levels ≥97.5th percentile vs <20th percentile. Elevated serum ferritin levels were associated with elevated plasma glucose levels at 0, 30 and 120 min (p < 0.001), elevated serum insulin levels at 0 and 120 min (p = 0.02 and p < 0.001), decreased beta cell function estimated as the insulinogenic index and corrected insulin response (p < 0.001), and decreased insulin sensitivity estimated by the Matsuda index of insulin sensitivity and HOMA-IR (p < 0.001). Whereas the association with impaired beta cell function was present in both men and women, the association with decreased insulin sensitivity was observed among men and older women but not among younger women. CONCLUSIONS/INTERPRETATION: Elevated fasting serum ferritin levels are associated with surrogate measures of both impaired beta cell function and decreased insulin sensitivity. Menopause seems to modify the association with insulin sensitivity.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Ferritinas/sangue , Células Secretoras de Insulina/metabolismo , Adulto , Jejum/sangue , Feminino , Humanos , Resistência à Insulina/fisiologia , Masculino , Pessoa de Meia-Idade
13.
Diabetologia ; 57(8): 1528-41, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24859358

RESUMO

During the past 7 years, genome-wide association studies have shed light on the contribution of common genomic variants to the genetic architecture of type 2 diabetes, obesity and related intermediate phenotypes. The discoveries have firmly established more than 175 genomic loci associated with these phenotypes. Despite the tight correlation between type 2 diabetes and obesity, these conditions do not appear to share a common genetic background, since they have few genetic risk loci in common. The recent genetic discoveries do however highlight specific details of the interplay between the pathogenesis of type 2 diabetes, insulin resistance and obesity. The focus is currently shifting towards investigations of data from targeted array-based genotyping and exome and genome sequencing to study the individual and combined effect of low-frequency and rare variants in metabolic disease. Here we review recent progress as regards the concepts, methodologies and derived outcomes of studies of the genetics of type 2 diabetes and obesity, and discuss avenues to be investigated in the future within this research field.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Variação Genética , Resistência à Insulina/genética , Obesidade/genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Genótipo , Humanos
14.
Eur J Nutr ; 53(7): 1549-59, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24458267

RESUMO

PURPOSE: Meta-analyses have suggested an effect of MTHFR C677T genotype (rs1801133), a proxy for blood total homocysteine, on cardiovascular disease (CVD) in populations with low population dietary folate. The aim was to examine the association and effect modification by serum folate and vitamin B12 levels between MTHFR and CVD-related outcomes in a general population with no mandatory folic acid fortification policy. METHODS: The study population included 13,748 adults retrieved from pooling of four population-based studies conducted in Denmark. MTHFR genotype, serum folate (measured in approximately 9,356 individuals), and serum vitamin B12 (9,215 individuals), hypertension, and dyslipidemia were measured at baseline, and participants were followed for a mean of 10.5-11.7 years in central registries for diagnoses of stroke (623 incidents), ischaemic heart disease (IHD) (835 incidents), and all-cause mortality (1,272 incidents). RESULTS: The MTHFR genotype (TT vs. CC/CT) was not associated with hypertension [OR (95% CI) 1.09 (0.95-1.25)], dyslipidemia [OR (95% CI) 0.97 (0.84-1.11)], stroke [HR (95% CI) 0.92 (0.69-1.23)], and all-cause mortality [HR (95% CI) 0.94 (0.77-1.14)], either overall, or in participants with low serum folate or B12 status (P values for interactions 0.15-0.94). Individuals with the MTHFR TT genotype had a higher risk of IHD (HR (95% CI) 1.38 (1.11-1.71)), but this association was not modified by folate status (P value for interaction 0.45). CONCLUSIONS: Our results do not support a causal relationship between homocysteine and CVD. However, we cannot exclude a direct causal effect of MTHFR C677T genotype on IHD.


Assuntos
Doenças Cardiovasculares/genética , Ácido Fólico/sangue , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Adolescente , Adulto , Idoso , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Estudos de Coortes , Dinamarca , Dislipidemias/sangue , Dislipidemias/genética , Feminino , Ácido Fólico/administração & dosagem , Seguimentos , Genótipo , Técnicas de Genotipagem , Homocisteína/sangue , Humanos , Hipertensão/sangue , Hipertensão/genética , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Pessoa de Meia-Idade , Polimorfismo Genético , Fatores de Risco , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/genética , Triglicerídeos/sangue , Vitamina B 12/administração & dosagem , Vitamina B 12/sangue , Adulto Jovem
15.
PLoS Genet ; 9(7): e1003607, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23935507

RESUMO

Numerous obesity loci have been identified using genome-wide association studies. A UK study indicated that physical activity may attenuate the cumulative effect of 12 of these loci, but replication studies are lacking. Therefore, we tested whether the aggregate effect of these loci is diminished in adults of European ancestry reporting high levels of physical activity. Twelve obesity-susceptibility loci were genotyped or imputed in 111,421 participants. A genetic risk score (GRS) was calculated by summing the BMI-associated alleles of each genetic variant. Physical activity was assessed using self-administered questionnaires. Multiplicative interactions between the GRS and physical activity on BMI were tested in linear and logistic regression models in each cohort, with adjustment for age, age(2), sex, study center (for multicenter studies), and the marginal terms for physical activity and the GRS. These results were combined using meta-analysis weighted by cohort sample size. The meta-analysis yielded a statistically significant GRS × physical activity interaction effect estimate (Pinteraction  = 0.015). However, a statistically significant interaction effect was only apparent in North American cohorts (n = 39,810, Pinteraction  = 0.014 vs. n = 71,611, Pinteraction  = 0.275 for Europeans). In secondary analyses, both the FTO rs1121980 (Pinteraction  = 0.003) and the SEC16B rs10913469 (Pinteraction  = 0.025) variants showed evidence of SNP × physical activity interactions. This meta-analysis of 111,421 individuals provides further support for an interaction between physical activity and a GRS in obesity disposition, although these findings hinge on the inclusion of cohorts from North America, indicating that these results are either population-specific or non-causal.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Atividade Motora/genética , Obesidade/genética , Adulto , Alelos , Índice de Massa Corporal , Feminino , Humanos , Modelos Logísticos , Masculino , Obesidade/epidemiologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Inquéritos e Questionários , População Branca/genética
16.
Diabetes ; 62(10): 3610-7, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23835328

RESUMO

More than 40 genetic risk variants for type 2 diabetes have been validated. We aimed to test whether a genetic risk score associates with the incidence of type 2 diabetes and with 5-year changes in glycemic traits and whether the effects were modulated by changes in BMI and lifestyle. The Inter99 study population was genotyped for 46 variants, and a genetic risk score was constructed. During a median follow-up of 11 years, 327 of 5,850 individuals developed diabetes. Physical examinations and oral glucose tolerance tests were performed at baseline and after 5 years (n = 3,727). The risk of incident type 2 diabetes was increased with a hazard ratio of 1.06 (95% CI 1.03-1.08) per risk allele. While the population in general had improved glucose regulation during the 5-year follow-up period, each additional allele in the genetic risk score was associated with a relative increase in fasting, 30-min, and 120-min plasma glucose values and a relative decrease in measures of ß-cell function over the 5-year period, whereas indices of insulin sensitivity were unaffected. The effect of the genetic risk score on 5-year changes in fasting plasma glucose was stronger in individuals who increased their BMI. In conclusion, a genetic risk score based on 46 variants associated strongly with incident type 2 diabetes and 5-year changes in plasma glucose and ß-cell function. Individuals who gain weight may be more susceptible to the cumulative impact of type 2 diabetes risk variants on fasting plasma glucose.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Hemoglobinas Glicadas/metabolismo , Células Secretoras de Insulina/metabolismo , Polimorfismo de Nucleotídeo Único , Adulto , Glicemia/genética , Índice de Massa Corporal , Dinamarca/epidemiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Seguimentos , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Teste de Tolerância a Glucose , Hemoglobinas Glicadas/genética , Humanos , Incidência , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores de Tempo
17.
PLoS Genet ; 9(6): e1003530, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23754956

RESUMO

Genome-wide association studies have mainly relied on common HapMap sequence variations. Recently, sequencing approaches have allowed analysis of low frequency and rare variants in conjunction with common variants, thereby improving the search for functional variants and thus the understanding of the underlying biology of human traits and diseases. Here, we used a large Icelandic whole genome sequence dataset combined with Danish exome sequence data to gain insight into the genetic architecture of serum levels of vitamin B(12) (B12) and folate. Up to 22.9 million sequence variants were analyzed in combined samples of 45,576 and 37,341 individuals with serum B(12) and folate measurements, respectively. We found six novel loci associating with serum B(12) (CD320, TCN2, ABCD4, MMAA, MMACHC) or folate levels (FOLR3) and confirmed seven loci for these traits (TCN1, FUT6, FUT2, CUBN, CLYBL, MUT, MTHFR). Conditional analyses established that four loci contain additional independent signals. Interestingly, 13 of the 18 identified variants were coding and 11 of the 13 target genes have known functions related to B(12) and folate pathways. Contrary to epidemiological studies we did not find consistent association of the variants with cardiovascular diseases, cancers or Alzheimer's disease although some variants demonstrated pleiotropic effects. Although to some degree impeded by low statistical power for some of these conditions, these data suggest that sequence variants that contribute to the population diversity in serum B(12) or folate levels do not modify the risk of developing these conditions. Yet, the study demonstrates the value of combining whole genome and exome sequencing approaches to ascertain the genetic and molecular architectures underlying quantitative trait associations.


Assuntos
Deficiência de Ácido Fólico/genética , Ácido Fólico/sangue , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas , Vitamina B 12/sangue , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Dinamarca , Exoma , Ácido Fólico/metabolismo , Deficiência de Ácido Fólico/metabolismo , Genoma Humano , Humanos , Islândia , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Vitamina B 12/metabolismo
18.
PLoS One ; 6(6): e20640, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21674055

RESUMO

BACKGROUND: Two meta-analyses of genome-wide association studies (GWAS) have suggested that four variants: rs2605100 in lysophospholipase-like 1 (LYPLAL1), rs10146997 in neuroxin 3 (NRXN3), rs545854 in methionine sulfoxide reductase A (MSRA), and rs987237 in transcription factor activating enhancer-binding protein 2 beta (TFAP2B) associate with measures of central obesity. To elucidate potential underlying phenotypes we aimed to investigate whether these variants associated with: 1) quantitative metabolic traits, 2) anthropometric measures (waist circumference (WC), waist-hip ratio, and BMI), or 3) type 2 diabetes, and central and general overweight and obesity. METHODOLOGY/PRINCIPAL FINDINGS: The four variants were genotyped in Danish individuals using KASPar®. Quantitative metabolic traits were examined in a population-based sample (n = 6,038) and WC and BMI were furthermore analyzed in a combined study sample (n = 13,507). Case-control studies of diabetes and adiposity included 15,326 individuals. The major G-allele of LYPLAL1 rs2605100 associated with increased fasting serum triglyceride concentrations (per allele effect (ß) = 3%(1;5(95%CI)), p(additive) = 2.7×10(-3)), an association driven by the male gender (p(interaction) = 0.02). The same allele associated with increased fasting serum insulin concentrations (ß = 3%(1;5), p(additive) = 2.5×10(-3)) and increased insulin resistance (HOMA-IR) (ß = 4%(1;6), p(additive) = 1.5×10(-3)). The minor G-allele of rs10146997 in NRXN3 associated with increased WC among women (ß = 0.55cm (0.20;0.89), p(additive) = 1.7×10(-3), p(interaction) = 1.0×10(-3)), but showed no associations with obesity related metabolic traits. The MSRA rs545854 and TFAP2B rs987237 showed nominal associations with central obesity; however, no underlying metabolic phenotypes became obvious, when investigating quantitative metabolic traits. None of the variants influenced the prevalence of type 2 diabetes. CONCLUSION/SIGNIFICANCE: We demonstrate that several of the central obesity-associated variants in LYPLAL1, NRXN3, MSRA, and TFAP2B associate with metabolic and anthropometric traits in Danish adults. However, analyses were made without adjusting for multiple testing, and further studies are needed to confirm the putative role of LYPLAL1, NRXN3, MSRA, and TFAP2B in the pathophysiology of obesity.


Assuntos
Variação Genética , Lisofosfolipase/genética , Metionina Sulfóxido Redutases/genética , Proteínas do Tecido Nervoso/genética , Obesidade/genética , Obesidade/metabolismo , Fator de Transcrição AP-2/genética , População Branca/genética , Adiposidade/genética , Adulto , Estudos de Casos e Controles , Dinamarca , Diabetes Mellitus Tipo 2/complicações , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/fisiopatologia , Caracteres Sexuais , Circunferência da Cintura/genética , Relação Cintura-Quadril
19.
PLoS One ; 6(1): e16542, 2011 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-21339799

RESUMO

OBJECTIVE: Candidate genes for non-alcoholic fatty liver disease (NAFLD) identified by a bioinformatics approach were examined for variant associations to quantitative traits of NAFLD-related phenotypes. RESEARCH DESIGN AND METHODS: By integrating public database text mining, trans-organism protein-protein interaction transferal, and information on liver protein expression a protein-protein interaction network was constructed and from this a smaller isolated interactome was identified. Five genes from this interactome were selected for genetic analysis. Twenty-one tag single-nucleotide polymorphisms (SNPs) which captured all common variation in these genes were genotyped in 10,196 Danes, and analyzed for association with NAFLD-related quantitative traits, type 2 diabetes (T2D), central obesity, and WHO-defined metabolic syndrome (MetS). RESULTS: 273 genes were included in the protein-protein interaction analysis and EHHADH, ECHS1, HADHA, HADHB, and ACADL were selected for further examination. A total of 10 nominal statistical significant associations (P<0.05) to quantitative metabolic traits were identified. Also, the case-control study showed associations between variation in the five genes and T2D, central obesity, and MetS, respectively. Bonferroni adjustments for multiple testing negated all associations. CONCLUSIONS: Using a bioinformatics approach we identified five candidate genes for NAFLD. However, we failed to provide evidence of associations with major effects between SNPs in these five genes and NAFLD-related quantitative traits, T2D, central obesity, and MetS.


Assuntos
Biologia Computacional/métodos , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Mineração de Dados , Dinamarca , Diabetes Mellitus Tipo 2/genética , Fígado Gorduroso/genética , Humanos , Síndrome Metabólica/genética , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica , Obesidade/genética , Fenótipo , Ligação Proteica , Locos de Características Quantitativas
20.
BMC Med Genet ; 12: 4, 2011 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-21211036

RESUMO

BACKGROUND: A genome-wide association study (GWAS) using metabolite concentrations as proxies for enzymatic activity, suggested that two variants: rs2014355 in the gene encoding short-chain acyl-coenzyme A dehydrogenase (ACADS) and rs11161510 in the gene encoding medium-chain acyl-coenzyme A dehydrogenase (ACADM) impair fatty acid ß-oxidation. Chronic exposure to fatty acids due to an impaired ß-oxidation may down-regulate the glucose-stimulated insulin release and result in an increased risk of type 2 diabetes (T2D). We aimed to investigate whether the two variants associate with altered insulin release following an oral glucose load or with T2D. METHODS: The variants were genotyped using KASPar® PCR SNP genotyping system and investigated for associations with estimates of insulin release and insulin sensitivity following an oral glucose tolerance test (OGTT) in a random sample of middle-aged Danish individuals (nACADS = 4,324; nACADM = 4,337). The T2D-case-control study involved a total of ~8,300 Danish individuals (nACADS = 8,313; nACADM = 8,344). RESULTS: In glucose-tolerant individuals the minor C-allele of rs2014355 of ACADS associated with reduced measures of serum insulin at 30 min following an oral glucose load (per allele effect (ß) = -3.8% (-6.3%;-1.3%), P = 0.003), reduced incremental area under the insulin curve (ß = -3.6% (-6.3%;-0.9%), P = 0.009), reduced acute insulin response (ß = -2.2% (-4.2%;0.2%), P = 0.03), and with increased insulin sensitivity ISIMatsuda (ß = 2.9% (0.5%;5.2%), P = 0.02). The C-allele did not associate with two other measures of insulin sensitivity or with a derived disposition index. The C-allele was not associated with T2D in the case-control analysis (OR 1.07, 95% CI 0.96-1.18, P = 0.21). rs11161510 of ACADM did not associate with any indices of glucose-stimulated insulin release or with T2D. CONCLUSIONS: In glucose-tolerant individuals the minor C-allele of rs2014355 of ACADS was associated with reduced measures of glucose-stimulated insulin release during an OGTT, a finding which in part may be mediated through an impaired ß-oxidation of fatty acids.


Assuntos
Alelos , Glicemia/genética , Butiril-CoA Desidrogenase/genética , Insulina/sangue , Insulina/metabolismo , Adulto , Estudos de Casos e Controles , Ensaios Clínicos como Assunto , Estudos de Coortes , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Teste de Tolerância a Glucose , Humanos , Secreção de Insulina , Masculino , Pessoa de Meia-Idade , Prevalência
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