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1.
Am J Clin Nutr ; 109(2): 276-287, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30721968

RESUMO

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass. Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci. Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms). Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection. Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.


Assuntos
Tecido Adiposo/metabolismo , Composição Corporal/genética , Compartimentos de Líquidos Corporais/metabolismo , Músculo Esquelético/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único , Proteínas ADAMTS/genética , Absorciometria de Fóton , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Impedância Elétrica , Grupo com Ancestrais do Continente Europeu/genética , Proteínas da Matriz Extracelular/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Ligação a RNA/genética , Receptor Tipo 4 de Melanocortina/genética , Versicanas/genética , Adulto Jovem
2.
J Am Soc Nephrol ; 29(10): 2583-2592, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30217807

RESUMO

BACKGROUND: Fibroblast growth factor 23 (FGF23), a bone-derived hormone that regulates phosphorus and vitamin D metabolism, contributes to the pathogenesis of mineral and bone disorders in CKD and is an emerging cardiovascular risk factor. Central elements of FGF23 regulation remain incompletely understood; genetic variation may help explain interindividual differences. METHODS: We performed a meta-analysis of genome-wide association studies of circulating FGF23 concentrations among 16,624 participants of European ancestry from seven cohort studies, excluding participants with eGFR<30 ml/min per 1.73 m2 to focus on FGF23 under normal conditions. We evaluated the association of single-nucleotide polymorphisms (SNPs) with natural log-transformed FGF23 concentration, adjusted for age, sex, study site, and principal components of ancestry. A second model additionally adjusted for BMI and eGFR. RESULTS: We discovered 154 SNPs from five independent regions associated with FGF23 concentration. The SNP with the strongest association, rs17216707 (P=3.0×10-24), lies upstream of CYP24A1, which encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D. Each additional copy of the T allele at this locus is associated with 5% higher FGF23 concentration. Another locus strongly associated with variations in FGF23 concentration is rs11741640, within RGS14 and upstream of SLC34A1 (a gene involved in renal phosphate transport). Additional adjustment for BMI and eGFR did not materially alter the magnitude of these associations. Another top locus (within ABO, the ABO blood group transferase gene) was no longer statistically significant at the genome-wide level. CONCLUSIONS: Common genetic variants located near genes involved in vitamin D metabolism and renal phosphate transport are associated with differences in circulating FGF23 concentrations.

3.
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
4.
PLoS One ; 12(4): e0176277, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28448539

RESUMO

CONTEXT: Obesity in men is associated with low serum testosterone and both are associated with several diseases and increased mortality. OBJECTIVES: Examine the direction and causality of the relationship between body mass index (BMI) and serum testosterone. DESIGN: Bi-directional Mendelian randomization (MR) analysis on prospective cohorts. SETTING: Five cohorts from Denmark, Germany and Sweden (Inter99, SHIP, SHIP Trend, GOOD and MrOS Sweden). PARTICIPANTS: 7446 Caucasian men, genotyped for 97 BMI-associated SNPs and three testosterone-associated SNPs. MAIN OUTCOME MEASURES: BMI and serum testosterone adjusted for age, smoking, time of blood sampling and site. RESULTS: 1 SD genetically instrumented increase in BMI was associated with a 0.25 SD decrease in serum testosterone (IV ratio: -0.25, 95% CI: -0.42--0.09, p = 2.8*10-3). For a body weight reduction altering the BMI from 30 to 25 kg/m2, the effect would equal a 13% increase in serum testosterone. No association was seen for genetically instrumented testosterone with BMI, a finding that was confirmed using large-scale data from the GIANT consortium (n = 104349). CONCLUSIONS: Our results suggest that there is a causal effect of BMI on serum testosterone in men. Population level interventions to reduce BMI are expected to increase serum testosterone in men.


Assuntos
Análise da Randomização Mendeliana , Obesidade/sangue , Obesidade/genética , Testosterona/sangue , Adolescente , Adulto , Idoso , Índice de Massa Corporal , Predisposição Genética para Doença , Humanos , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Adulto Jovem
5.
J Am Soc Nephrol ; 28(5): 1553-1565, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27927781

RESUMO

Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies (n=22,653 and n=6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry. We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 (P=4.2 × 10-53), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of the minor allele at this SNP associated with 7% higher serum PTH concentration. The other SNPs associated with serum PTH concentration included rs4074995 within RGS14 (P=6.6 × 10-17), rs219779 adjacent to CLDN14 (P=3.5 × 10-16), rs4443100 near RTDR1 (P=8.7 × 10-9), and rs73186030 near CASR (P=4.8 × 10-8). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.


Assuntos
Variação Genética , Hormônio Paratireóideo/sangue , Hormônio Paratireóideo/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Europa (Continente) , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade
6.
Nat Genet ; 48(12): 1462-1472, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27798627

RESUMO

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.


Assuntos
Ordem de Nascimento , Estudo de Associação Genômica Ampla , Paridade/genética , Locos de Características Quantitativas , Reprodução/genética , Comportamento Reprodutivo/fisiologia , Feminino , Fertilidade/genética , Humanos , Idade Materna , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Gravidez
7.
Nat Commun ; 7: 13357, 2016 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-27876822

RESUMO

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.


Assuntos
Antropometria , Tamanho Corporal , Modelos Genéticos , Análise de Componente Principal , Estudo de Associação Genômica Ampla , Genótipo , Humanos
8.
J Am Geriatr Soc ; 64(11): 2242-2250, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27689675

RESUMO

OBJECTIVES: To investigate the role of a fall risk assessment, using the Downton Fall Risk Index (DFRI), in predicting fall-related injury, fall-related head injury and hip fracture, and death, in a large cohort of older women and men residing in Sweden. DESIGN: Cross sectional observational study. SETTING: Sweden. PARTICIPANTS: Older adults (mean age 82.4 ± 7.8) who had a fall risk assessment using the DFRI at baseline (N = 128,596). MEASUREMENTS: Information on all fall-related injuries, all fall-related head injuries and hip fractures, and all-cause mortality was collected from the Swedish Patient Register and Cause of Death Register. The predictive role of DFRI was calculated using Poisson regression models with age, sex, height, weight, and comorbidities as covariates, taking time to outcome or end of study into account. RESULTS: During a median follow-up of 253 days (interquartile range 90-402 days) (>80,000 patient-years), 15,299 participants had a fall-related injury, 2,864 a head injury, and 2,557 a hip fracture, and 23,307 died. High fall risk (DFRI ≥3) independently predicted fall-related injury (hazard ratio (HR) = 1.43, 95% confidence interval (CI) = 1.39-1.49), hip fracture (HR = 1.51, 95% CI =1.38-1.66), head injury (HR = 1.12, 95% CI = 1.03-1.22), and all-cause mortality (HR = 1.39, 95% CI = 1.35-1.43). DFRI more strongly predicted head injury (HR = 1.29, 95% CI = 1.21-1.36 vs HR = 1.08, 95% CI = 1.04-1.11) and hip fracture (HR = 1.41, 95% CI = 1.30-1.53 vs HR = 1.08, 95% CI = 1.05-1.11) in 70-year old men than in 90-year old women (P < .001). CONCLUSION: Fall risk assessment using DFRI independently predicts fall-related injury, fall-related head injury and hip fracture, and all-cause mortality in older men and women, indicating its clinical usefulness to identify individuals who would benefit from interventions.


Assuntos
Acidentes por Quedas/estatística & dados numéricos , Causas de Morte , Traumatismos Craniocerebrais/etiologia , Fraturas do Quadril/etiologia , Medição de Risco , Ferimentos e Lesões/etiologia , Acidentes por Quedas/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Antropometria , Traumatismos Craniocerebrais/epidemiologia , Traumatismos Craniocerebrais/mortalidade , Estudos Transversais , Feminino , Avaliação Geriátrica , Fraturas do Quadril/epidemiologia , Fraturas do Quadril/mortalidade , Humanos , Masculino , Sistema de Registros , Fatores de Risco , Fatores Sexuais , Suécia/epidemiologia , Ferimentos e Lesões/epidemiologia , Ferimentos e Lesões/mortalidade
10.
Aging Cell ; 15(5): 811-24, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27329260

RESUMO

The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype-phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci.


Assuntos
Envelhecimento/genética , Estudo de Associação Genômica Ampla , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Fator de Crescimento Insulin-Like I/genética , Característica Quantitativa Herdável , Adulto , Envelhecimento/sangue , Feminino , Regulação da Expressão Gênica , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Masculino , Metaboloma/genética , Locos de Características Quantitativas/genética , Sequências Reguladoras de Ácido Nucleico/genética
11.
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
12.
PLoS Genet ; 11(10): e1005378, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26426971

RESUMO

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.


Assuntos
Índice de Massa Corporal , Tamanho Corporal/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Adulto , Fatores Etários , Idoso , Mapeamento Cromossômico , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Caracteres Sexuais , Relação Cintura-Quadril
13.
Nature ; 526(7571): 112-7, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26367794

RESUMO

The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.


Assuntos
Densidade Óssea/genética , Fraturas Ósseas/genética , Genoma Humano/genética , Proteínas de Homeodomínio/genética , Animais , Osso e Ossos/metabolismo , Modelos Animais de Doenças , Europa (Continente)/etnologia , Grupo com Ancestrais do Continente Europeu/genética , Exoma/genética , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Genômica , Genótipo , Humanos , Camundongos , Análise de Sequência de DNA , Proteínas Wnt/genética
14.
Mol Psychiatry ; 20(5): 647-656, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25288136

RESUMO

Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee.


Assuntos
Coffea/metabolismo , Comportamento Alimentar , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Citocromo P-450 CYP1A2/genética , Humanos , Fenótipo
15.
J Bone Miner Res ; 30(1): 184-94, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25043339

RESUMO

It is important to identify the patients at highest risk of fractures. A recent large-scale meta-analysis identified 63 autosomal single-nucleotide polymorphisms (SNPs) associated with bone mineral density (BMD), of which 16 were also associated with fracture risk. Based on these findings, two genetic risk scores (GRS63 and GRS16) were developed. Our aim was to determine the clinical usefulness of these GRSs for the prediction of BMD, BMD change, and fracture risk in elderly subjects. We studied two male (Osteoporotic Fractures in Men Study [MrOS] US, MrOS Sweden) and one female (Study of Osteoporotic Fractures [SOF]) large prospective cohorts of older subjects, looking at BMD, BMD change, and radiographically and/or medically confirmed incident fractures (8067 subjects, 2185 incident nonvertebral or vertebral fractures). GRS63 was associated with BMD (≅3% of the variation explained) but not with BMD change. Both GRS63 and GRS16 were associated with fractures. After BMD adjustment, the effect sizes for these associations were substantially reduced. Similar results were found using an unweighted GRS63 and an unweighted GRS16 compared with those found using the corresponding weighted risk scores. Only minor improvements in C-statistics (AUC) for fractures were found when the GRSs were added to a base model (age, weight, and height), and no significant improvements in C-statistics were found when they were added to a model further adjusted for BMD. Net reclassification improvements with the addition of the GRSs to a base model were modest and substantially attenuated in BMD-adjusted models. GRS63 is associated with BMD, but not BMD change, suggesting that the genetic determinants of BMD differ from those of BMD change. When BMD is known, the clinical utility of the two GRSs for fracture prediction is limited in elderly subjects.


Assuntos
Densidade Óssea/genética , Fraturas Ósseas/genética , Modelos Genéticos , Osteoporose/genética , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Feminino , Fraturas Ósseas/epidemiologia , Humanos , Masculino , Osteoporose/epidemiologia , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Risco
16.
Hum Mol Genet ; 23(24): 6684-93, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25080503

RESUMO

Osteoprotegerin (OPG) is involved in bone homeostasis and tumor cell survival. Circulating OPG levels are also important biomarkers of various clinical traits, such as cancers and atherosclerosis. OPG levels were measured in serum or in plasma. In a meta-analysis of genome-wide association studies in up to 10 336 individuals from European and Asian origin, we discovered that variants >100 kb upstream of the TNFRSF11B gene encoding OPG and another new locus on chromosome 17q11.2 were significantly associated with OPG variation. We also identified a suggestive locus on chromosome 14q21.2 associated with the trait. Moreover, we estimated that over half of the heritability of OPG levels could be explained by all variants examined in our study. Our findings provide further insight into the genetic regulation of circulating OPG levels.


Assuntos
Cromossomos Humanos Par 14/química , Cromossomos Humanos Par 17/química , Loci Gênicos , Osteoprotegerina/genética , Polimorfismo Genético , Característica Quantitativa Herdável , Grupo com Ancestrais do Continente Asiático , Grupo com Ancestrais do Continente Europeu , Feminino , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Masculino , Osteoprotegerina/sangue
17.
PLoS Genet ; 10(7): e1004474, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25010111

RESUMO

Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30-60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that <1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding α1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independent signals were identified within the region, represented by common SNPs; detailed biochemical investigation in a nested sub-cohort showed all these SNPs were associated with variation in total cortisol binding activity in plasma, but some variants influenced total CBG concentrations while the top hit (rs12589136) influenced the immunoreactivity of the reactive centre loop of CBG. Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants. These findings reveal a novel common genetic source of variation in binding of cortisol by CBG, and reinforce the key role of CBG in determining plasma cortisol levels. In turn this genetic variation may contribute to cortisol-associated degenerative diseases.


Assuntos
Estudo de Associação Genômica Ampla , Hidrocortisona/sangue , Transcortina/genética , alfa 1-Antitripsina/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Exoma/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único/genética , Ligação Proteica , Transcortina/metabolismo , alfa 1-Antitripsina/metabolismo
18.
Lancet Diabetes Endocrinol ; 2(9): 719-29, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24974252

RESUMO

BACKGROUND: Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with blood pressure and hypertension risk. METHODS: In this mendelian randomisation study, we generated an allele score (25[OH]D synthesis score) based on variants of genes that affect 25(OH)D synthesis or substrate availability (CYP2R1 and DHCR7), which we used as a proxy for 25(OH)D concentration. We meta-analysed data for up to 108 173 individuals from 35 studies in the D-CarDia collaboration to investigate associations between the allele score and blood pressure measurements. We complemented these analyses with previously published summary statistics from the International Consortium on Blood Pressure (ICBP), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and the Global Blood Pressure Genetics (Global BPGen) consortium. FINDINGS: In phenotypic analyses (up to n=49 363), increased 25(OH)D concentration was associated with decreased systolic blood pressure (ß per 10% increase, -0·12 mm Hg, 95% CI -0·20 to -0·04; p=0·003) and reduced odds of hypertension (odds ratio [OR] 0·98, 95% CI 0·97-0·99; p=0·0003), but not with decreased diastolic blood pressure (ß per 10% increase, -0·02 mm Hg, -0·08 to 0·03; p=0·37). In meta-analyses in which we combined data from D-CarDia and the ICBP (n=146 581, after exclusion of overlapping studies), each 25(OH)D-increasing allele of the synthesis score was associated with a change of -0·10 mm Hg in systolic blood pressure (-0·21 to -0·0001; p=0·0498) and a change of -0·08 mm Hg in diastolic blood pressure (-0·15 to -0·02; p=0·01). When D-CarDia and consortia data for hypertension were meta-analysed together (n=142 255), the synthesis score was associated with a reduced odds of hypertension (OR per allele, 0·98, 0·96-0·99; p=0·001). In instrumental variable analysis, each 10% increase in genetically instrumented 25(OH)D concentration was associated with a change of -0·29 mm Hg in diastolic blood pressure (-0·52 to -0·07; p=0·01), a change of -0·37 mm Hg in systolic blood pressure (-0·73 to 0·003; p=0·052), and an 8·1% decreased odds of hypertension (OR 0·92, 0·87-0·97; p=0·002). INTERPRETATION: Increased plasma concentrations of 25(OH)D might reduce the risk of hypertension. This finding warrants further investigation in an independent, similarly powered study. FUNDING: British Heart Foundation, UK Medical Research Council, and Academy of Finland.


Assuntos
Colestanotriol 26-Mono-Oxigenase/genética , Hipertensão/prevenção & controle , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Polimorfismo de Nucleotídeo Único , Deficiência de Vitamina D/prevenção & controle , Vitamina D/análogos & derivados , Adulto , Índice de Massa Corporal , Família 2 do Citocromo P450 , Feminino , Predisposição Genética para Doença , Humanos , Hipertensão/sangue , Hipertensão/genética , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Fenótipo , Ensaios Clínicos Controlados Aleatórios como Assunto , Vitamina D/administração & dosagem , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/genética
19.
J Bone Miner Res ; 29(4): 1015-24, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24014423

RESUMO

We hypothesized that bone resorption acts to increase bone strength through stimulation of periosteal expansion. Hence, we examined whether bone resorption, as reflected by serum ß-C-telopeptides of type I collagen (CTX), is positively associated with periosteal circumference (PC), in contrast to inverse associations with parameters related to bone remodeling such as cortical bone mineral density (BMDC ). CTX and mid-tibial peripheral quantitative computed tomography (pQCT) scans were available in 1130 adolescents (mean age 15.5 years) from the Avon Longitudinal Study of Parents and Children (ALSPAC). Analyses were adjusted for age, gender, time of sampling, tanner stage, lean mass, fat mass, and height. CTX was positively related to PC (ß=0.19 [0.13, 0.24]) (coefficient=SD change per SD increase in CTX, 95% confidence interval)] but inversely associated with BMDC (ß=-0.46 [-0.52,-0.40]) and cortical thickness [ß=-0.11 (-0.18, -0.03)]. CTX was positively related to bone strength as reflected by the strength-strain index (SSI) (ß=0.09 [0.03, 0.14]). To examine the causal nature of this relationship, we then analyzed whether single-nucleotide polymorphisms (SNPs) within key osteoclast regulatory genes, known to reduce areal/cortical BMD, conversely increase PC. Fifteen such genetic variants within or proximal to genes encoding receptor activator of NF-κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) were identified by literature search. Six of the 15 alleles that were inversely related to BMD were positively related to CTX (p<0.05 cut-off) (n=2379). Subsequently, we performed a meta-analysis of associations between these SNPs and PC in ALSPAC (n=3382), Gothenburg Osteoporosis and Obesity Determinants (GOOD) (n=938), and the Young Finns Study (YFS) (n=1558). Five of the 15 alleles that were inversely related to BMD were positively related to PC (p<0.05 cut-off). We conclude that despite having lower BMD, individuals with a genetic predisposition to higher bone resorption have greater bone size, suggesting that higher bone resorption is permissive for greater periosteal expansion.


Assuntos
Reabsorção Óssea , Colágeno Tipo I/genética , Marcadores Genéticos , Periósteo/anatomia & histologia , Ligante RANK/metabolismo , Tomografia Computadorizada por Raios X/métodos , Adolescente , Colágeno Tipo I/química , Estudos Transversais , Feminino , Humanos , Masculino
20.
J Med Genet ; 50(7): 473-8, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23572186

RESUMO

BACKGROUND: Forearm fractures affect 1.7 million individuals worldwide each year and most occur earlier in life than hip fractures. While the heritability of forearm bone mineral density (BMD) and fracture is high, their genetic determinants are largely unknown. AIM: To identify genetic variants associated with forearm BMD and forearm fractures. METHODS: BMD at distal radius, measured by dual-energy x-ray absorptiometry, was tested for association with common genetic variants. We conducted a meta-analysis of genome-wide association studies for BMD in 5866 subjects of European descent and then selected the variants for replication in 715 Mexican American samples. Gene-based association was carried out to supplement the single-nucleotide polymorphism (SNP) association test. We then tested the BMD-associated SNPs for association with forearm fracture in 2023 cases and 3740 controls. RESULTS: We found that five SNPs in the introns of MEF2C were associated with forearm BMD at a genome-wide significance level (p<5×10(-8)) in meta-analysis (lead SNP, rs11951031[T] -0.20 SDs per allele, p=9.01×10(-9)). The gene-based association test suggested an association between MEF2C and forearm BMD (p=0.003). The association between MEF2C variants and risk of fracture did not achieve statistical significance (SNP rs12521522[A]: OR=1.14 (95% CI 0.92 to 1.35), p=0.14). Meta-analysis also revealed two genome-wide suggestive loci at CTNNA2 and 6q23.2. CONCLUSIONS: These findings demonstrate that variants at MEF2C were associated with forearm BMD, implicating this gene in the determination of BMD at forearm.


Assuntos
Densidade Óssea/genética , Antebraço/fisiopatologia , Polimorfismo de Nucleotídeo Único , Absorciometria de Fóton , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu , Feminino , Estudo de Associação Genômica Ampla , Humanos , Fatores de Transcrição MEF2/genética , Masculino
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