RESUMEN
Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ~2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1 × 10E-09), previously identified in association with waist-hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9 × 10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6 × 10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 [women], p = 0.49 [men]). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist-hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not previously uncovered in large-scale GWAS of anthropometric traits.
Asunto(s)
Citocinas/genética , Grasa Intraabdominal , Proteínas/genética , Caracteres Sexuales , Grasa Subcutánea Abdominal , Adulto , Anciano , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Índice de Masa Corporal , Femenino , Estudio de Asociación del Genoma Completo , Proyecto Mapa de Haplotipos , Humanos , Lisofosfolipasa/genética , Masculino , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple , Población BlancaRESUMEN
BACKGROUND AND PURPOSE: Cerebral infarcts increase the risk for cognitive impairment. The relevance of location and number of infarcts with respect to cognitive function is less clear. METHODS: We studied the cross-sectional association between number and location of infarcts and cognitive performance in 4030 nondemented participants of the Age Gene/Environment Susceptibility-Reykjavik Study. Composite scores for memory, processing speed, and executive function were created from a neuropsychological battery. Subcortical, cortical, and cerebellar infarcts were identified on brain MRI. We performed linear regression analyses adjusted for demographic and vascular risk factors, depression, white matter lesions, and atrophy. RESULTS: Compared to participants with no infarcts, those with infarcts in multiple locations (n=287, 7%) had slower processing speed (beta=-0.19; P<0.001) and poorer memory (beta=-0.16; P<0.001) and executive function (beta=-0.12; P=0.003). Compared to no infarcts, the presence of either subcortical infarcts only (n=275; beta=-0.12; P=0.016) or cortical infarcts only (n=215; beta=-0.17; P=0.001) was associated with poorer memory performance. Compared to no infarcts, a combination of cortical and subcortical infarcts (n=45) was associated with slower processing speed (beta=-0.38; P<0.001) and poorer executive function (beta=-0.22; P=0.02), whereas a combination of cerebellar and subcortical infarcts (n=89) was associated with slower processing speed (beta=-0.15; P=0.04). Infarcts in all 3 locations was associated with slower processing speed (beta=-0.33; P=0.002). CONCLUSIONS: Having infarcts in >1 location is associated with poor performance in memory, processing speed, and executive function, independent of cardiovascular comorbidities, white matter lesions, and brain atrophy, suggesting that both the number and the distribution of infarcts jointly contribute to cognitive impairment.
Asunto(s)
Infarto Cerebral/patología , Infarto Cerebral/psicología , Trastornos del Conocimiento/patología , Trastornos del Conocimiento/psicología , Anciano , Enfermedades Cardiovasculares/epidemiología , Infarto Cerebral/genética , Trastornos del Conocimiento/genética , Demencia/diagnóstico , Demencia/psicología , Femenino , Humanos , Islandia/epidemiología , Imagen por Resonancia Magnética , Masculino , Pruebas Neuropsicológicas , Factores de RiesgoRESUMEN
Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size-weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men of European, African, Hispanic and Chinese ancestry, with and without sex stratification, for six traits associated with ectopic fat (hereinafter referred to as ectopic-fat traits). In total, we identified seven new loci associated with ectopic-fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; P < 5 × 10-8; false discovery rate < 1%). Functional analysis of these genes showed that loss of function of either Atxn1 or Ube2e2 in primary mouse adipose progenitor cells impaired adipocyte differentiation, suggesting physiological roles for ATXN1 and UBE2E2 in adipogenesis. Future studies are necessary to further explore the mechanisms by which these genes affect adipocyte biology and how their perturbations contribute to systemic metabolic disease.
Asunto(s)
Adipocitos/citología , Distribución de la Grasa Corporal , Diferenciación Celular , Sitios Genéticos/genética , Marcadores Genéticos/genética , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple/genética , Adipocitos/metabolismo , Animales , Estudios de Cohortes , Etnicidad/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/genética , FenotipoRESUMEN
BACKGROUND: The metabolic effects of omega-6 polyunsaturated fatty acids (PUFAs) remain contentious, and little evidence is available regarding their potential role in primary prevention of type 2 diabetes. We aimed to assess the associations of linoleic acid and arachidonic acid biomarkers with incident type 2 diabetes. METHODS: We did a pooled analysis of new, harmonised, individual-level analyses for the biomarkers linoleic acid and its metabolite arachidonic acid and incident type 2 diabetes. We analysed data from 20 prospective cohort studies from ten countries (Iceland, the Netherlands, the USA, Taiwan, the UK, Germany, Finland, Australia, Sweden, and France), with biomarkers sampled between 1970 and 2010. Participants included in the analyses were aged 18 years or older and had data available for linoleic acid and arachidonic acid biomarkers at baseline. We excluded participants with type 2 diabetes at baseline. The main outcome was the association between omega-6 PUFA biomarkers and incident type 2 diabetes. We assessed the relative risk of type 2 diabetes prospectively for each cohort and lipid compartment separately using a prespecified analytic plan for exposures, covariates, effect modifiers, and analysis, and the findings were then pooled using inverse-variance weighted meta-analysis. FINDINGS: Participants were 39â740 adults, aged (range of cohort means) 49-76 years with a BMI (range of cohort means) of 23·3-28·4 kg/m2, who did not have type 2 diabetes at baseline. During a follow-up of 366â073 person-years, we identified 4347 cases of incident type 2 diabetes. In multivariable-adjusted pooled analyses, higher proportions of linoleic acid biomarkers as percentages of total fatty acid were associated with a lower risk of type 2 diabetes overall (risk ratio [RR] per interquintile range 0·65, 95% CI 0·60-0·72, p<0·0001; I2=53·9%, pheterogeneity=0·002). The associations between linoleic acid biomarkers and type 2 diabetes were generally similar in different lipid compartments, including phospholipids, plasma, cholesterol esters, and adipose tissue. Levels of arachidonic acid biomarker were not significantly associated with type 2 diabetes risk overall (RR per interquintile range 0·96, 95% CI 0·88-1·05; p=0·38; I2=63·0%, pheterogeneity<0·0001). The associations between linoleic acid and arachidonic acid biomarkers and the risk of type 2 diabetes were not significantly modified by any prespecified potential sources of heterogeneity (ie, age, BMI, sex, race, aspirin use, omega-3 PUFA levels, or variants of the FADS gene; all pheterogeneity≥0·13). INTERPRETATION: Findings suggest that linoleic acid has long-term benefits for the prevention of type 2 diabetes and that arachidonic acid is not harmful. FUNDING: Funders are shown in the appendix.
Asunto(s)
Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Ácidos Grasos Omega-6/sangre , Adulto , Ácido Araquidónico/sangre , Biomarcadores/sangre , Estudios de Cohortes , Diabetes Mellitus Tipo 2/diagnóstico , Humanos , Incidencia , Ácido Linoleico/sangre , Estudios Prospectivos , Factores de Riesgo , Estadística como Asunto/métodosRESUMEN
OBJECTIVES: To compare the relative predictive power of handgrip and leg extension strength in predicting slow walking. DESIGN: Report of correlative analysis from two epidemiological cohort studies. SETTING: Foundation of the National Institutes of Health Sarcopenia Project. PARTICIPANTS: Men and women aged 67 to 93 (N=6,766). MEASUREMENTS: Leg strength, handgrip strength, and gait speed were measured. Strength cutpoints associated with slow gait speed were developed using classification and regression tree analyses and compared using ordinary least squares regression models. RESULTS: The cutpoints of lower extremity strength associated with slow gait speed were 154.6 N-m in men and 89.9 N-m in women for isometric leg extension strength and 94.5 N-m in men and 62.3 N-m in women for isokinetic leg extension strength. Weakness defined according to handgrip strength (odds ratios (OR)=1.99 to 4.33, c-statistics=0.53 to 0.67) or leg strength (ORs=2.52 to 5.77; c-statistics=0.61 to 0.66) was strongly related to odds of slow gait speed. Lower extremity strength contributed 1% to 16% of the variance and handgrip strength contributed 3% to 17% of the variance in the prediction of gait speed depending on sex and mode of strength assessment. CONCLUSION: Muscle weakness of the leg extensors and forearm flexors is related to slow gait speed. Leg extension strength is only a slightly better predictor of slow gait speed. Thus, handgrip and leg extension strength appear to be suitable for screening for muscle weakness in older adults.