RESUMO
Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10-17), arthritis (GDF5 p = 4 × 10-13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.
Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Debilidade Muscular/genética , Sarcopenia/genética , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Estudos de Coortes , Europa (Continente) , Feminino , Fator 5 de Diferenciação de Crescimento/genética , Cadeias alfa de HLA-DQ/genética , Humanos , Masculino , Pessoa de Meia-Idade , Força Muscular/genética , Força Muscular/fisiologia , Debilidade Muscular/fisiopatologia , Polimorfismo de Nucleotídeo Único , Sarcopenia/fisiopatologiaRESUMO
BACKGROUND: Alcohol and tobacco use are heritable phenotypes. However, only a small number of common genetic variants have been identified, and common variants account for a modest proportion of the heritability. Therefore, this study aims to investigate the role of low-frequency and rare variants in alcohol and tobacco use. METHODS: We meta-analyzed ExomeChip association results from eight discovery cohorts and included 12,466 subjects and 7432 smokers in the analysis of alcohol consumption and tobacco use, respectively. The ExomeChip interrogates low-frequency and rare exonic variants, and in addition a small pool of common variants. We investigated top variants in an independent sample in which ICD-9 diagnoses of "alcoholism" (Nâ¯=â¯25,508) and "tobacco use disorder" (Nâ¯=â¯27,068) had been assessed. In addition to the single variant analysis, we performed gene-based, polygenic risk score (PRS), and pathway analyses. RESULTS: The meta-analysis did not yield exome-wide significant results. When we jointly analyzed our top results with the independent sample, no low-frequency or rare variants reached significance for alcohol consumption or tobacco use. However, two common variants that were present on the ExomeChip, rs16969968 (pâ¯=â¯2.39â¯×â¯10-7) and rs8034191 (pâ¯=â¯6.31â¯×â¯10-7) located in CHRNA5 and AGPHD1 at 15q25.1, showed evidence for association with tobacco use. DISCUSSION: Low-frequency and rare exonic variants with large effects do not play a major role in alcohol and tobacco use, nor does the aggregate effect of ExomeChip variants. However, our results confirmed the role of the CHRNA5-CHRNA3-CHRNB4 cluster of nicotinic acetylcholine receptor subunit genes in tobacco use.
Assuntos
Consumo de Bebidas Alcoólicas/genética , Éxons/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Uso de Tabaco/genética , Consumo de Bebidas Alcoólicas/epidemiologia , Alcoolismo/diagnóstico , Alcoolismo/epidemiologia , Alcoolismo/genética , Estudos de Coortes , Feminino , Predisposição Genética para Doença/epidemiologia , Humanos , Masculino , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores Nicotínicos/genética , Fatores de Risco , Uso de Tabaco/epidemiologia , Tabagismo/diagnóstico , Tabagismo/genéticaRESUMO
BACKGROUND: The role of dietary antioxidants and plasma oxidant-antioxidant status in low-grade chronic inflammation and adipocytokine levels is not established yet. OBJECTIVES: We aimed to evaluate whether total dietary antioxidant capacity (assessed by dietary ferric reducing antioxidant potential (FRAP)), serum uric acid (UA) and gamma glutamyltransferase (GGT) were associated with low-grade chronic inflammation and circulating adipocytokines. METHODS: Data of 4506 participants aged ≥55years from the Rotterdam Study were analyzed. Baseline (1990-1993) FRAP score was assessed by a food frequency questionnaire. Baseline UA and GGT levels were assessed in non-fasting serum samples. Serum high sensitivity C-reactive protein (hs-CRP) was measured at baseline and 10years later. Plasma leptin, adiponectin, plasminogen activator inhibitor-1 (PAI-1) and resistin levels were assessed 10years later. RESULTS: A high FRAP score was associated with lower levels of UA and GGT. Overall, no association was found between FRAP and hs-CRP levels. FRAP score was associated with lower levels of leptin and PAI-1, higher levels of adiponectin, and no difference in resistin levels. Increased levels of UA were associated with higher levels of hs-CRP, PAI-1 and leptin; lower levels of adiponectin and no difference in resistin levels. Similarly, GGT was associated with higher levels of hs-CRP whereas no association was observed between GGT and adipocytokines. CONCLUSION: These findings suggest that overall antioxidant capacity of diet and low levels of UA are associated with circulating adipocytokines whereas no consistent association was found with hs-CRP.