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1.
Am J Gastroenterol ; 2020 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-32868629

RESUMO

INTRODUCTION: Sustained high alcohol intake is necessary but not sufficient to produce alcohol-related cirrhosis. Identification of risk factors, apart from lifetime alcohol exposure, would assist in discovery of mechanisms and prediction of risk. METHODS: We conducted a multicenter case-control study (GenomALC) comparing 1,293 cases (with alcohol-related cirrhosis, 75.6% male) and 754 controls (with equivalent alcohol exposure but no evidence of liver disease, 73.6% male). Information confirming or excluding cirrhosis, and on alcohol intake and other potential risk factors, was obtained from clinical records and by interview. Case-control differences in risk factors discovered in the GenomALC participants were validated using similar data from 407 cases and 6,573 controls from UK Biobank. RESULTS: The GenomALC case and control groups reported similar lifetime alcohol intake (1,374 vs 1,412 kg). Cases had a higher prevalence of diabetes (20.5% (262/1,288) vs 6.5% (48/734), P = 2.27 × 10) and higher premorbid body mass index (26.37 ± 0.16 kg/m) than controls (24.44 ± 0.18 kg/m, P = 5.77 × 10). Controls were significantly more likely to have been wine drinkers, coffee drinkers, smokers, and cannabis users than cases. Cases reported a higher proportion of parents who died of liver disease than controls (odds ratio 2.25 95% confidence interval 1.55-3.26). Data from UK Biobank confirmed these findings for diabetes, body mass index, proportion of alcohol as wine, and coffee consumption. DISCUSSION: If these relationships are causal, measures such as weight loss, intensive treatment of diabetes or prediabetic states, and coffee consumption should reduce the risk of alcohol-related cirrhosis.

2.
Hepatology ; 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32853455

RESUMO

Only a minority of heavy drinkers progress to alcohol-related cirrhosis (ALC). The aim of this study was to identify common genetic variants that underlie risk for ALC. We analyzed data from 1,128 subjects of European ancestry with ALC and 614 heavy drinking subjects without known liver disease from Australia, the United States, the United Kingdom and three countries in Europe. Genome-wide association study (GWAS) was performed, adjusting for principal components and clinical covariates (alcohol use, age, sex, BMI, diabetes). We validated our GWAS findings using UK Biobank. We then performed a meta-analysis combining data from our study, the UK Biobank, and a previously published GWAS. Our GWAS found genome-wide significant risk association of rs738409 in PNPLA3 (Odds Ratio (OR)=2.19 (G allele), p-value=4.93x10-17 ) and rs4607179 near HSD17B13 (OR=0.57 (C allele), p-value=1.09x10-10 ) with ALC. Conditional analysis accounting for the PNPLA3 and HSD17B13 loci identified a new protective association at rs374702773 in Fas Associated Factor family member 2 (FAF2) (OR=0.61 (del(T) allele), p-value=2.56x10-8 ) for ALC. This association was replicated in the UK Biobank using conditional analysis (OR=0.79, p-value=0.001). Meta-analysis (without conditioning) confirmed genome-wide significance for the newly identified FAF2 locus as well as PNPLA3 and HSD17B13. Two other previously known loci (SERPINA1, SUGP1/TM6SF2) were also genome-wide significant in the meta-analysis. GeneOntology pathway analysis identified lipid droplets as the target for several identified genes. In conclusion, our GWAS identified a new locus at FAF2 associated with reduced risk of ALC among heavy drinkers. Like the PNPLA3 and HSD17B13 gene products, the FAF2 product has been localized to fat droplets in hepatocytes. Our genetic findings implicate lipid droplets in the biological pathway(s) underlying ALC.

3.
Sci Rep ; 10(1): 12609, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32724068

RESUMO

Scores on an optimistic-pessimistic personality scale have been associated with mortality, but optimism and pessimism scores are separable traits and it is unclear which has effects on health or longevity. The Life Orientation Test (LOT), containing items for optimism and pessimism, was included in a twin study on health of Australians aged over 50 in 1993-1995. After a mean of 20 years, participants were matched against death information from the Australian National Death Index. 1,068 out of 2,978 participants with useable LOT scores had died. Survival analysis tested for associations between separate optimism and pessimism scores and mortality from any cause, and from cancers, cardiovascular diseases or other known causes. Age-adjusted scores on the pessimism scale were associated with all-cause and cardiovascular mortality (Hazard Ratios per 1 standard deviation unit, 95% confidence intervals and p-values 1.134, 1.065-1.207, 8.85 × 10-5 and 1.196, 1.045-1.368, 0.0093, respectively) but not with cancer deaths. Optimism scores, which were only weakly correlated with pessimism scores (age-adjusted rank correlation = - 0.176), did not show significant associations with overall or cause-specific mortality. Reverse causation (disease causing pessimism) is unlikely because in that case both cardiovascular diseases and cancers would be expected to lead to pessimism.

5.
Am J Med Genet B Neuropsychiatr Genet ; 183(6): 309-330, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32681593

RESUMO

It is imperative to understand the specific and shared etiologies of major depression and cardio-metabolic disease, as both traits are frequently comorbid and each represents a major burden to society. This study examined whether there is a genetic association between major depression and cardio-metabolic traits and if this association is stratified by age at onset for major depression. Polygenic risk scores analysis and linkage disequilibrium score regression was performed to examine whether differences in shared genetic etiology exist between depression case control status (N cases = 40,940, N controls = 67,532), earlier (N = 15,844), and later onset depression (N = 15,800) with body mass index, coronary artery disease, stroke, and type 2 diabetes in 11 data sets from the Psychiatric Genomics Consortium, Generation Scotland, and UK Biobank. All cardio-metabolic polygenic risk scores were associated with depression status. Significant genetic correlations were found between depression and body mass index, coronary artery disease, and type 2 diabetes. Higher polygenic risk for body mass index, coronary artery disease, and type 2 diabetes was associated with both early and later onset depression, while higher polygenic risk for stroke was associated with later onset depression only. Significant genetic correlations were found between body mass index and later onset depression, and between coronary artery disease and both early and late onset depression. The phenotypic associations between major depression and cardio-metabolic traits may partly reflect their overlapping genetic etiology irrespective of the age depression first presents.

6.
Twin Res Hum Genet ; 23(2): 77-79, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32482194

RESUMO

Biomarkers diagnose, predict or assess the risk of disease, and studies of the effects of genetic variation on biomarker phenotypes in the general population complement studies on patients diagnosed with disease. This paper traces the evolution of studies on biomarker genetics over the past 40 years through examples drawn from the work of Professor Martin and his colleagues.

7.
Twin Res Hum Genet ; 23(6): 307-315, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33509326

RESUMO

Mortality risk is known to be associated with many physiological or biochemical risk factors, and polygenic risk scores (PRSs) may offer an additional or alternative approach to risk stratification. We have compared the predictive value of common biochemical tests, PRSs and information on parental survival in a cohort of twins and their families. Common biochemical test results were available for up to 13,365 apparently healthy men and women, aged 17-93 years (mean 49.0, standard deviation [SD] 13.7) at blood collection. PRSs for longevity were available for 14,169 study participants and reported parental survival for 25,784 participants. A search for information on date and cause of death was conducted through the Australian National Death Index, with median follow-up of 11.3 years. Cox regression was used to evaluate associations with mortality from all causes, cancers, cardiovascular diseases and other causes. Linear relationships with all-cause mortality were strongest for C-reactive protein, gamma-glutamyl transferase, glucose and alkaline phosphatase, with hazard ratios (HRs) of 1.16 (95% CI [1.07, 1.24]), 1.15 (95% CI 1.04-1.21), 1.13 (95% CI [1.08, 1.19]) and 1.11 (95% CI [1.05, 1.88]) per SD difference, respectively. Significant nonlinear effects were found for urea, uric acid and butyrylcholinesterase. Lipid risk factors were not statistically significant for mortality in our cohort. Family history and PRS showed weaker but significant associations with survival, with HR in the range 1.05 to 1.09 per SD difference. In conclusion, biochemical tests currently predict long-term mortality more strongly than genetic scores based on genotyping or on reported parental survival.

8.
Drug Alcohol Depend ; 205: 107704, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31731259

RESUMO

BACKGROUND: Substance use, substance use disorders (SUDs), and psychiatric disorders commonly co-occur. Genetic risk common to these complex traits is an important explanation; however, little is known about how polygenic risk for tobacco or alcohol use overlaps the genetic risk for the comorbid SUDs and psychiatric disorders. METHODS: We constructed polygenic risk scores (PRSs) using GWAS meta-analysis summary statistics from a large discovery sample, GWAS & Sequencing Consortium of Alcohol and Nicotine use (GSCAN), for smoking initiation (SI; N = 631,564), age of initiating regular smoking (AI; N = 258,251), cigarettes per day (CPD; N = 258,999), smoking cessation (SC; N = 312,273), and drinks per week (DPW; N = 527,402). We then estimated the fixed effect of these PRSs on the liability to 15 phenotypes related to tobacco and alcohol use, substance use disorders, and psychiatric disorders in an independent target sample of Australian adults. RESULTS: After adjusting for multiple testing, 10 of 75 combinations of discovery and target phenotypes remained significant. PRS-SI (R2 range: 1.98%-5.09 %) was positively associated with SI, DPW, and with DSM-IV and FTND nicotine dependence, and conduct disorder. PRS-AI (R2: 3.91 %) negatively associated with DPW. PRS-CPD (R2: 1.56 %-1.77 %) positively associated with DSM-IV nicotine dependence and conduct disorder. PRS-DPW (R2: 3.39 %-6.26 %) positively associated with only DPW. The variation of DPW was significantly influenced by sex*PRS-SI, sex*PRS-AI and sex*PRS-DPW. Such interaction effect was not detected in the other 14 phenotypes. CONCLUSIONS: Polygenic risks associated with tobacco use are also associated with liability to alcohol consumption, nicotine dependence, and conduct disorder.


Assuntos
Alcoolismo/epidemiologia , Alcoolismo/genética , Transtornos Mentais/epidemiologia , Transtornos Mentais/genética , Herança Multifatorial/genética , Tabagismo/epidemiologia , Tabagismo/genética , Adolescente , Adulto , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/genética , Austrália/epidemiologia , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Uso de Tabaco/epidemiologia , Uso de Tabaco/genética , Adulto Jovem
9.
Sci Rep ; 9(1): 11623, 2019 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-31406173

RESUMO

Telomere shortening has been associated with multiple age-related diseases such as cardiovascular disease, diabetes, and dementia. However, the biological mechanisms responsible for these associations remain largely unknown. In order to gain insight into the metabolic processes driving the association of leukocyte telomere length (LTL) with age-related diseases, we investigated the association between LTL and serum metabolite levels in 7,853 individuals from seven independent cohorts. LTL was determined by quantitative polymerase chain reaction and the levels of 131 serum metabolites were measured with mass spectrometry in biological samples from the same blood draw. With partial correlation analysis, we identified six metabolites that were significantly associated with LTL after adjustment for multiple testing: lysophosphatidylcholine acyl C17:0 (lysoPC a C17:0, p-value = 7.1 × 10-6), methionine (p-value = 9.2 × 10-5), tyrosine (p-value = 2.1 × 10-4), phosphatidylcholine diacyl C32:1 (PC aa C32:1, p-value = 2.4 × 10-4), hydroxypropionylcarnitine (C3-OH, p-value = 2.6 × 10-4), and phosphatidylcholine acyl-alkyl C38:4 (PC ae C38:4, p-value = 9.0 × 10-4). Pathway analysis showed that the three phosphatidylcholines and methionine are involved in homocysteine metabolism and we found supporting evidence for an association of lipid metabolism with LTL. In conclusion, we found longer LTL associated with higher levels of lysoPC a C17:0 and PC ae C38:4, and with lower levels of methionine, tyrosine, PC aa C32:1, and C3-OH. These metabolites have been implicated in inflammation, oxidative stress, homocysteine metabolism, and in cardiovascular disease and diabetes, two major drivers of morbidity and mortality.


Assuntos
Homocisteína/metabolismo , Leucócitos/ultraestrutura , Metabolismo dos Lipídeos , Metabolômica/métodos , Telômero , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Encurtamento do Telômero
10.
Nat Hum Behav ; 3(9): 950-961, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31358974

RESUMO

Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d-1) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus consortia, collecting data from 480,842 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 new common loci and investigated their potential functional importance using magnetic resonance imaging data and gene expression studies. We identify genetic pathways associated with alcohol consumption and suggest genetic mechanisms that are shared with neuropsychiatric disorders such as schizophrenia.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Genes/genética , Predisposição Genética para Doença/genética , Transtornos Mentais/genética , Adulto , Idoso , Alcoolismo/genética , Encéfalo/fisiopatologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Genes/fisiologia , Estudo de Associação Genômica Ampla , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Esquizofrenia/genética
11.
Alcohol Clin Exp Res ; 43(3): 473-482, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30589442

RESUMO

BACKGROUND: Alcohol dependence and long-term excessive alcohol use may cause liver damage, but only some patients develop cirrhosis. Similarly, high alcohol intake without evident liver disease often but not always produces abnormal enzymatic liver function tests (LFTs), particularly gamma-glutamyl transferase (GGT). We postulate that the factors predisposing to cirrhosis in alcoholics and to liver enzyme abnormality in drinkers are similar, and that biochemical LFTs could therefore be useful as markers of risk of alcoholic liver disease in excessive drinkers. METHODS: Data from participants in twin and twin-family studies on alcohol use and dependence were used to identify 1,003 people who had reported excessive alcohol intake (28 drinks or more per week). A total of 962 of these provided blood for biochemical tests at the same time. Body mass index (BMI) and biomarkers of metabolic syndrome, inflammation, and iron stores were used in logistic regression with abnormality in serum GGT, alanine aminotransferase (ALT), or aspartate aminotransferase (AST) as outcomes. We conducted genome-wide association analyses for GGT, ALT, and AST separately in the group reporting excessive alcohol intake (N = 951) and a low-intake group reporting 14 drinks or fewer per week (N = 8,716), and compared results. RESULTS: Abnormal GGT and ALT among excessive drinkers were associated with higher BMI, triglycerides, insulin, uric acid, C-reactive protein, ferritin, and transferrin saturation; and with lower high-density-lipoprotein cholesterol. Abnormal AST was associated with triglycerides, ferritin, and transferrin saturation. ALT was significantly associated with variants at reported genetic loci for alcoholic liver disease (PNPLA3, rs738409, p = 0.0076; TM6SF2, rs10401969, p = 0.0076; HSD17B13, rs10433879, p = 0.0024). CONCLUSIONS: Known risk factors for alcoholic cirrhosis including obesity and markers of metabolic syndrome, iron overload and inflammation are associated with liver enzyme abnormality in excessive drinkers.


Assuntos
Alanina Transaminase/sangue , Consumo de Bebidas Alcoólicas/sangue , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Testes de Função Hepática/estatística & dados numéricos , gama-Glutamiltransferase/sangue , 17-Hidroxiesteroide Desidrogenases/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas/genética , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lipase/genética , Hepatopatias Alcoólicas/genética , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
12.
JAMA Psychiatry ; 75(9): 901-910, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29936532

RESUMO

Importance: Urban life has been proposed as an environmental risk factor accounting for the increased prevalence of schizophrenia in urban areas. An alternative hypothesis is that individuals with increased genetic risk tend to live in urban/dense areas. Objective: To assess whether adults with higher genetic risk for schizophrenia have an increased probability to live in more populated areas than those with lower risk. Design, Setting, and Participants: Four large, cross-sectional samples of genotyped individuals of European ancestry older than 18 years with known addresses in Australia, the United Kingdom, and the Netherlands were included in the analysis. Data were based on the postcode of residence at the time of last contact with the participants. Community-based samples who took part in studies conducted by the Queensland Institute for Medical Research Berghofer Medical Research Institute (QIMR), UK Biobank (UKB), Netherlands Twin Register (NTR), or QSkin Sun and Health Study (QSKIN) were included. Genome-wide association analysis and mendelian randomization (MR) were included. The study was conducted between 2016 and 2018. Exposures: Polygenic risk scores for schizophrenia derived from genetic data (genetic risk is independently measured from the occurrence of the disease). Socioeconomic status of the area was included as a moderator in some of the models. Main Outcomes and Measures: Population density of the place of residence of the participants determined from census data. Remoteness and socioeconomic status of the area were also tested. Results: The QIMR participants (15 544; 10 197 [65.6%] women; mean [SD] age, 54.4 [13.2] years) living in more densely populated areas (people per square kilometer) had a higher genetic loading for schizophrenia (r2 = 0.12%; P = 5.69 × 10-5), a result that was replicated across all 3 other cohorts (UKB: 345 246; 187 469 [54.3%] women; age, 65.7 [8.0] years; NTR: 11 212; 6727 [60.0%] women; age, 48.6 [17.5] years; and QSKIN: 15 726; 8602 [54.7%] women; age, 57.0 [7.9] years). This genetic association could account for 1.7% (95% CI, 0.8%-3.2%) of the schizophrenia risk. Estimates from MR analyses performed in the UKB sample were significant (b = 0.049; P = 3.7 × 10-7 using GSMR), suggesting that the genetic liability to schizophrenia may have a causal association with the tendency to live in urbanized locations. Conclusions and Relevance: The results of this study appear to support the hypothesis that individuals with increased genetic risk tend to live in urban/dense areas and suggest the need to refine the social stress model for schizophrenia by including genetics as well as possible gene-environment interactions.


Assuntos
Densidade Demográfica , Esquizofrenia , Adulto , Idoso , Austrália/epidemiologia , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Herança Multifatorial , Países Baixos/epidemiologia , Características de Residência , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Fatores de Risco , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Classe Social , Reino Unido/epidemiologia
13.
Addiction ; 113(1): 158-166, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28833688

RESUMO

BACKGROUND AND AIMS: Both high alcohol intake and alcohol dependence increase mortality, and both are associated with smoking. We aimed to compare the associations of quantity of alcohol, number of alcohol-related symptoms and smoking history with all-cause mortality, and to assess symptom count and smoking history as confounders or mediators of the effects of high alcohol intake. DESIGN: Survival was analysed by Cox regression with sex, body mass index, alcohol intake (overall and by beverage), maximum drinks on any day, alcohol symptom count and smoking status as potential predictors of age at death. SETTING: Australia. PARTICIPANTS: Participants were apparently healthy volunteers consisting of 33 593 Australian adult twins and their relatives who completed questionnaires or interviews between 1979 and 2005. MEASUREMENTS: Data on alcohol use, smoking and occurrence of symptoms related to alcohol use disorders and death records from the Australian National Death Index. FINDINGS: A total of 3764 participants were matched with deaths occurring within Australia up to July 2014. Individually, alcohol intake [hazard ratio (HR) = 1.0082, 95% confidence interval (CI) = 1.0063-1.0102, per drink per week], beer intake (HR = 1.0159, 95% CI = 1.0123-1.0195, per drink per week), life-time maximum number of drinks in 1 day (HR = 1.0176, 95% CI = 1.0130-1.0221, per drink), symptom count (HR = 1.0867, 95% CI = 1.0633-1.1106, per symptom) and smoking status (HR = 2.82, 95% CI = 2.52-3.16 for smokers of 10+ cigarettes/day versus never-smokers) were each significant predictors of all-cause mortality. After adjustment for the independently significant predictors alcohol symptom count and smoking status, alcohol intake was no longer significant (adjusted HR = 1.0012 per drink per week, 95% CI = 0.9979-1.0145). CONCLUSIONS: Number of symptoms related to high alcohol intake and tobacco smoking appear to account for the positive association between alcohol consumption and premature mortality.


Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Alcoolismo/epidemiologia , Fumar Cigarros/epidemiologia , Mortalidade Prematura , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Cerveja , Causas de Morte , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Fumar/epidemiologia , Análise de Sobrevida , Fumar Tabaco
14.
Alcohol ; 66: 1-7, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29277282

RESUMO

Laboratory tests can play an important role in assessment of alcoholic patients, including for evaluation of liver damage and as markers of alcohol intake. Evidence on test performance should lead to better selection of appropriate tests and improved interpretation of results. We compared laboratory test results from 1578 patients between cases (with alcoholic cirrhosis; 753 men, 243 women) and controls (with equivalent lifetime alcohol intake but no liver disease; 439 men, 143 women). Comparisons were also made between 631 cases who had reportedly been abstinent from alcohol for over 60 days and 364 who had not. ROC curve analysis was used to estimate and compare tests' ability to distinguish patients with and without cirrhosis, and abstinent and drinking cases. The best tests for presence of cirrhosis were INR and bilirubin, with areas under the ROC curve (AUCs) of 0.91 ± 0.01 and 0.88 ± 0.01, respectively. Confining analysis to patients with no current or previous ascites gave AUCs of 0.88 ± 0.01 for INR and 0.85 ± 0.01 for bilirubin. GGT and AST showed discrimination between abstinence and recent drinking in patients with cirrhosis, including those without ascites, when appropriate (and for GGT, sex-specific) limits were used. For AST, a cut-off limit of 85 units/L gave 90% specificity and 37% sensitivity. For GGT, cut-off limits of 288 units/L in men and 138 units/L in women gave 90% specificity for both and 40% sensitivity in men, 63% sensitivity in women. INR and bilirubin show the best separation between patients with alcoholic cirrhosis (with or without ascites) and control patients with similar lifetime alcohol exposure. Although AST and GGT are substantially increased by liver disease, they can give useful information on recent alcohol intake in patients with alcoholic cirrhosis when appropriate cut-off limits are used.


Assuntos
Abstinência de Álcool , Consumo de Bebidas Alcoólicas/sangue , Bilirrubina/sangue , Ensaios Enzimáticos Clínicos , Coeficiente Internacional Normatizado , Cirrose Hepática Alcoólica/sangue , Cirrose Hepática Alcoólica/diagnóstico , Testes de Função Hepática/métodos , Adulto , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/prevenção & controle , Área Sob a Curva , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Europa (Continente) , Feminino , Humanos , Cirrose Hepática Alcoólica/etiologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC , Reprodutibilidade dos Testes , Fatores de Risco , Fatores Sexuais , Estados Unidos , gama-Glutamiltransferase/sangue
16.
J Psychiatr Res ; 94: 148-155, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28715705

RESUMO

Lower levels of circulating iron have been associated with depression. Our objective was to investigate the phenotypic and genetic relationship between measures of circulating levels of iron (serum iron, transferrin, transferrin saturation, and ferritin) and depressive symptoms. Data were available from ongoing studies at QIMR Berghofer Medical Research Institute (QIMRB), including twin adolescents (mean age 15.1 years, standard deviation (SD) 3.2 years), and twin adults (mean age 23.2 years, SD 2.2 years). In the adolescent cohort, there were 3416 participants from 1688 families. In the adult cohort there were 9035 participants from 4533 families. We estimated heritabilities of, and phenotypic and genetic correlations between, traits. We conducted analyses that linked results from published large-scale genome-wide association studies (including iron and Major Depressive Disorder) with our study samples using single SNP and multi-SNP genetic risk score analyses, and LD score regression analyses. In both cohorts, measures of iron, transferrin, transferrin saturation, and log 10 of ferritin (L10Fer) were all highly heritable, while depressive measures were moderately heritable. In adolescents, depression measures were higher in those in the middle 10th versus top 10th percentile of transferrin saturation measures (p = 0.002). Genetic profile risk scores of the iron measures were not significantly associated with depression in study participants. LD score analyses showed no significant genetic relationship between iron and depression. Genetic factors strongly influence iron measures in adolescents and adults. Using several different strategies we find no evidence for a genetic contribution to the relationship between blood measures of iron and measures of depression.


Assuntos
Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/genética , Ferritinas/sangue , Predisposição Genética para Doença , Ferro/sangue , Sistema de Registros/estatística & dados numéricos , Transferrina/análise , Adolescente , Adulto , Austrália/epidemiologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Queensland/epidemiologia , Adulto Jovem
17.
J Alzheimers Dis ; 59(1): 85-99, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28582860

RESUMO

Iron deposition in the brain is a prominent feature of Alzheimer's disease (AD). Recently, peripheral iron measures have also been shown to be associated with AD status. However, it is not known whether these associations are causal: do elevated or depleted iron levels throughout life have an effect on AD risk? We evaluate the effects of peripheral iron on AD risk using a genetic profile score approach by testing whether variants affecting iron, transferrin, or ferritin levels selected from GWAS meta-analysis of approximately 24,000 individuals are also associated with AD risk in an independent case-control cohort (n∼10,000). Conversely, we test whether AD risk variants from a GWAS meta-analysis of approximately 54,000 account for any variance in iron measures (n∼9,000). We do not identify a genetic relationship, suggesting that peripheral iron is not causal in the initiation of AD pathology.


Assuntos
Doença de Alzheimer/sangue , Ferritinas/sangue , Ferro/sangue , Transferrina/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Estudos de Coortes , Planejamento em Saúde Comunitária , Feminino , Estudos de Associação Genética/estatística & dados numéricos , Humanos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética
18.
PLoS Genet ; 13(4): e1006528, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28448500

RESUMO

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


Assuntos
Adiposidade/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Exercício Físico , Obesidade/genética , Adiposidade/fisiologia , Índice de Massa Corporal , Epigenômica , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Obesidade/fisiopatologia , Circunferência da Cintura , Relação Cintura-Quadril
19.
Clin Chim Acta ; 467: 15-20, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28322729

RESUMO

Carbohydrate-deficient transferrin (CDT) is a glycoform profile of serum transferrin that increases in response to sustained high alcohol intake and over the last decades has become an important alcohol biomarker with clinical and forensic applications. However, the wide range of CDT measurement procedures has resulted in lack of uniform results and reference limits, and hampered comparison of results. In 2005, the IFCC therefore founded a special working group (WG) aiming for standardisation of CDT measurement. This review summarises the history of CDT and the actions taken by the WG-CDT. Initial steps included the definition of the measurand (serum disialotransferrin to total transferrin fraction expressed in %), and the determination of a well-defined anion-exchange HPLC procedure as the candidate reference measurement procedure (cRMP). Subsequent achievements were the establishment of a network of reference laboratories to perform the cRMP, setting a reference interval, and development of a reference material based on human serum for which the laboratory network assign values. Using a set of reference materials for calibration allowed for achieving equivalence of results of all present CDT measurement procedures. The final steps of the WG-CDT have been a full validation of the cRMP to make it an IFCC approved RMP, and providing guidance for international standardisation of all CDT measurement procedures.


Assuntos
Consumo de Bebidas Alcoólicas/sangue , Análise Química do Sangue/normas , Transferrina/análogos & derivados , Biomarcadores/sangue , Calibragem , Humanos , Padrões de Referência , Transferrina/análise
20.
Nephrol Dial Transplant ; 32(2): 273-278, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28186534

RESUMO

Background: Iron depletion is a known consequence of chronic kidney disease (CKD), but there is contradicting epidemiological evidence on whether iron itself affects kidney function and whether its effect is protective or detrimental in the general population. While epidemiological studies tend to be affected by confounding and reverse causation, Mendelian randomization (MR) can provide unconfounded estimates of causal effects by using genes as instruments. Methods: We performed an MR study of the effect of serum iron levels on estimated glomerular filtration rate (eGFR), using genetic variants known to be associated with iron. MR estimates of the effect of iron on eGFR were derived based on the association of each variant with iron and eGFR from two large genome-wide meta-analyses on 48 978 and 74 354 individuals. We performed a similar MR analysis for ferritin, which measures iron stored in the body, using variants associated with ferritin. Results: A combined MR estimate across all variants showed a 1.3% increase in eGFR per standard deviation increase in iron (95% confidence interval 0.4­2.1%; P = 0.004). The results for ferritin were consistent with those for iron. Secondary MR analyses of the effects of iron and ferritin on CKD did not show significant associations but had very low statistical power. Conclusions: Our study suggests a protective effect of iron on kidney function in the general population. Further research is required to confirm this causal association, investigate it in study populations at higher risk of CKD and explore its underlying mechanism of action.


Assuntos
Predisposição Genética para Doença , Ferro/sangue , Análise da Randomização Mendeliana , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/patologia , Taxa de Filtração Glomerular , Humanos , Insuficiência Renal Crônica/genética , Fatores de Risco
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