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1.
J Med Genet ; 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33811135

RESUMO

BACKGROUND: Rare protein-truncating variants (PTVs) in partner and localiser of BRCA2 (PALB2) confer increased risk to breast cancer, but relatively few studies have reported the prevalence in South-East Asian populations. Here, we describe the prevalence of rare variants in PALB2 in a population-based study of 7840 breast cancer cases and 7928 healthy Chinese, Malay and Indian women from Malaysia and Singapore, and describe the functional impact of germline missense variants identified in this population. METHODS: Mutation testing was performed on germline DNA (n=15 768) using targeted sequencing panels. The functional impact of missense variants was tested in mouse embryonic stem cell based functional assays. RESULTS: PTVs in PALB2 were found in 0.73% of breast cancer patients and 0.14% of healthy individuals (OR=5.44; 95% CI 2.85 to 10.39, p<0.0001). In contrast, rare missense variants in PALB2 were not associated with increased risk of breast cancer. Whereas PTVs were associated with later stage of presentation and higher-grade tumours, no significant association was observed with missense variants in PALB2. However, two novel rare missense variants (p.L1027R and p.G1043V) produced unstable proteins and resulted in a decrease in homologous recombination-mediated repair of DNA double-strand breaks. CONCLUSION: Despite genetic and lifestyle differences between Asian and other populations, the population prevalence of PALB2 PTVs and associated relative risk of breast cancer, are similar to those reported in European populations.

2.
Nat Commun ; 11(1): 3833, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737321

RESUMO

Polygenic risk scores (PRS) have been shown to predict breast cancer risk in European women, but their utility in Asian women is unclear. Here we evaluate the best performing PRSs for European-ancestry women using data from 17,262 breast cancer cases and 17,695 controls of Asian ancestry from 13 case-control studies, and 10,255 Chinese women from a prospective cohort (413 incident breast cancers). Compared to women in the middle quintile of the risk distribution, women in the highest 1% of PRS distribution have a ~2.7-fold risk and women in the lowest 1% of PRS distribution has ~0.4-fold risk of developing breast cancer. There is no evidence of heterogeneity in PRS performance in Chinese, Malay and Indian women. A PRS developed for European-ancestry women is also predictive of breast cancer risk in Asian women and can help in developing risk-stratified screening programmes in Asia.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Ásia/epidemiologia , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etnologia , Estudos de Casos e Controles , Europa (Continente)/epidemiologia , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , Razão de Chances , Prognóstico , Risco
3.
Sci Rep ; 10(1): 503, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31949192

RESUMO

Incidence of breast cancer is rising rapidly in Asia. Some breast cancer risk factors are modifiable. We examined the impact of known breast cancer risk factors, including body mass index (BMI), reproductive and hormonal risk factors, and breast density on the incidence of breast cancer, in Singapore. The study population was a population-based prospective trial of screening mammography - Singapore Breast Cancer Screening Project. Population attributable risk and absolute risks of breast cancer due to various risk factors were calculated. Among 28,130 women, 474 women (1.7%) developed breast cancer. The population attributable risk was highest for ethnicity (49.4%) and lowest for family history of breast cancer (3.8%). The proportion of breast cancers that is attributable to modifiable risk factor BMI was 16.2%. The proportion of breast cancers that is attributable to reproductive risk factors were low; 9.2% for age at menarche and 4.2% for number of live births. Up to 45.9% of all breast cancers could be avoided if all women had breast density <12% and BMI <25 kg/m2. Notably, sixty percent of women with the lowest risk based on non-modifiable risk factors will never reach the risk level recommended for mammography screening. A combination of easily assessable breast cancer risk factors can help to identify women at high risk of developing breast cancer for targeted screening. A large number of high-risk women could benefit from risk-reduction and risk stratification strategies.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/epidemiologia , Medição de Risco/métodos , Índice de Massa Corporal , Densidade da Mama , Detecção Precoce de Câncer , Feminino , Humanos , Incidência , Mamografia , Pessoa de Meia-Idade , Estudos Prospectivos , Singapura/epidemiologia
4.
PLoS One ; 13(11): e0206554, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30383853

RESUMO

BACKGROUND AND PURPOSE: Polymorphisms in coagulation genes have been associated with early-onset ischemic stroke. Here we pursue an a priori hypothesis that genetic variation in the endothelial-based receptors of the thrombomodulin-protein C system (THBD and PROCR) may similarly be associated with early-onset ischemic stroke. We explored this hypothesis utilizing a multi-stage design of discovery and replication. METHODS: Discovery was performed in the Genetics-of-Early-Onset Stroke (GEOS) Study, a biracial population-based case-control study of ischemic stroke among men and women aged 15-49 including 829 cases of first ischemic stroke (42.2% African-American) and 850 age-comparable stroke-free controls (38.1% African-American). Twenty-four single-nucleotide-polymorphisms (SNPs) in THBD and 22 SNPs in PROCR were evaluated. Following LD pruning (r2≥0.8), we advanced uncorrelated SNPs forward for association analyses. Associated SNPs were evaluated for replication in an early-onset ischemic stroke population (onset-age<60 years) consisting of 3676 cases and 21118 non-stroke controls from 6 case-control studies. Lastly, we determined if the replicated SNPs also associated with older-onset ischemic stroke in the METASTROKE data-base. RESULTS: Among GEOS Caucasians, PROCR rs9574, which was in strong LD with 8 other SNPs, and one additional independent SNP rs2069951, were significantly associated with ischemic stroke (rs9574, OR = 1.33, p = 0.003; rs2069951, OR = 1.80, p = 0.006) using an additive-model adjusting for age, gender and population-structure. Adjusting for risk factors did not change the associations; however, associations were strengthened among those without risk factors. PROCR rs9574 also associated with early-onset ischemic stroke in the replication sample (OR = 1.08, p = 0.015), but not older-onset stroke. There were no PROCR associations in African-Americans, nor were there any THBD associations in either ethnicity. CONCLUSION: PROCR polymorphisms are associated with early-onset ischemic stroke in Caucasians.


Assuntos
Isquemia Encefálica/genética , Receptor de Proteína C Endotelial/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/genética , Trombomodulina/genética , Adolescente , Adulto , Afro-Americanos/genética , Idade de Início , Isquemia Encefálica/epidemiologia , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/epidemiologia , Adulto Jovem
5.
PLoS One ; 13(9): e0203469, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30216346

RESUMO

BACKGROUND: Breast cancer risk factors have been examined extensively in Western setting and more developed Asian cities/countries. However, there are limited data on developing Asian countries. The purpose of this study was to examine breast cancer risk factors and the change of selected risk factors across birth cohorts in Malaysian women. METHODS: An unmatched hospital based case-control study was conducted from October 2002 to December 2016 in Selangor, Malaysia. A total of 3,683 cases and 3,980 controls were included in this study. Unconditional logistic regressions, adjusted for potential confounding factors, were conducted. The breast cancer risk factors were compared across four birth cohorts by ethnicity. RESULTS: Ever breastfed, longer breastfeeding duration, a higher soymilk and soy product intake, and a higher level of physical activity were associated with lower risk of breast cancer. Chinese had the lowest breastfeeding rate, shortest breastfeeding duration, lowest parity and highest age of first full term pregnancy. CONCLUSIONS: Our study shows that breastfeeding, soy intake and physical activity are modifiable risk factors for breast cancer. With the increasing incidence of breast cancer there is an urgent need to educate the women about lifestyle intervention they can take to reduce their breast cancer risk.


Assuntos
Neoplasias da Mama/epidemiologia , Adulto , Idoso , Aleitamento Materno , Estudos de Casos e Controles , Feminino , Humanos , Malásia/epidemiologia , Pessoa de Meia-Idade , Fatores de Risco , Proteínas de Soja/efeitos adversos
6.
Cancer Causes Control ; 29(9): 883-894, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30062608

RESUMO

BACKGROUND: Physical activity is a modifiable lifestyle factor associated with reduced breast cancer risk. Mammographic density is a strong, independent risk factor for breast cancer, and some breast cancer risk factors have been shown to modify mammographic density. However, the effect of physical activity on mammographic density, studied predominantly among Caucasians, has yielded conflicting results. In this study, we examined, in an Asian population, the association between physical activity and mammographic density. METHODS: We conducted a cross-sectional study of 2,377 Malaysian women aged 40-74 years. Physical activity information was obtained at screening mammogram and mammographic density was measured from mammograms by the area-based STRATUS method (n = 1,522) and the volumetric Volpara™ (n = 1,200) method. Linear regression analyses were performed to evaluate the association between physical activity and mammographic density, adjusting for potential confounders. RESULTS: We observed that recent physical activity was associated with area-based mammographic density measures among postmenopausal women, but not premenopausal women. In the fully adjusted model, postmenopausal women with the highest level of recent physical activity had 8.0 cm2 [95% confidence interval: 1.3, 14.3 cm2] lower non-dense area and 3.1% [0.1, 6.3%] higher area-based percent density, compared to women with the lowest level of recent physical activity. Physical activity was not associated to volumetric mammographic density. CONCLUSIONS: Our findings suggest that the beneficial effects of physical activity on breast cancer risk may not be measurable through mammographic density. Future research is needed to identify appropriate biomarkers to assess the effect of physical activity on breast cancer risk.


Assuntos
Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Densidade da Mama , Exercício Físico , Mamografia , Adulto , Mama , Neoplasias da Mama/prevenção & controle , Estudos de Coortes , Estudos Transversais , Grupos Étnicos , Feminino , Humanos , Pessoa de Meia-Idade , Pré-Menopausa , Fatores de Risco
7.
J Med Genet ; 55(2): 97-103, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28993434

RESUMO

BACKGROUND: Genetic testing for BRCA1 and BRCA2 is offered typically to selected women based on age of onset and family history of cancer. However, current internationally accepted genetic testing referral guidelines are built mostly on data from cancer genetics clinics in women of European descent. To evaluate the appropriateness of such guidelines in Asians, we have determined the prevalence of germ line variants in an unselected cohort of Asian patients with breast cancer and healthy controls. METHODS: Germ line DNA from a hospital-based study of 2575 unselected patients with breast cancer and 2809 healthy controls were subjected to amplicon-based targeted sequencing of exonic and proximal splice site junction regions of BRCA1 and BRCA2 using the Fluidigm Access Array system, with sequencing conducted on a Illumina HiSeq2500 platform. Variant calling was performed with GATK UnifiedGenotyper and were validated by Sanger sequencing. RESULTS: Fifty-five (2.1%) BRCA1 and 66 (2.6%) BRCA2 deleterious mutations were identified among patients with breast cancer and five (0.18%) BRCA1 and six (0.21%) BRCA2 mutations among controls. One thousand one hundred and eighty-six (46%) patients and 97 (80%) carriers fulfilled the National Comprehensive Cancer Network guidelines for genetic testing. CONCLUSION: Five per cent of unselected Asian patients with breast cancer carry deleterious variants in BRCA1 or BRCA2. While current referral guidelines identified the majority of carriers, one in two patients would be referred for genetic services. Given that such services are largely unavailable in majority of low-resource settings in Asia, our study highlights the need for more efficient guidelines to identify at-risk individuals in Asia.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Mutação , Adulto , Neoplasias da Mama/etnologia , Neoplasias da Mama/etiologia , Estudos de Casos e Controles , Feminino , Mutação em Linhagem Germinativa , Humanos , Malásia , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto
8.
Nat Genet ; 49(7): 1113-1119, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28530674

RESUMO

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10-8, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.


Assuntos
Artérias/patologia , Doença da Artéria Coronariana/genética , Estudo de Associação Genômica Ampla , Aterosclerose/genética , Adesão Celular/genética , Quimiotaxia de Leucócito/genética , Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/fisiopatologia , Metabolismo Energético/genética , Feminino , Predisposição Genética para Doença , Genótipo , Código das Histonas , Humanos , Masculino , Músculo Liso Vascular/patologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Fatores de Risco
9.
BMC Cancer ; 17(1): 149, 2017 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-28222693

RESUMO

BACKGROUND: Genetic testing for BRCA1 and BRCA2 has led to the accurate identification of individuals at higher risk of cancer and the development of new therapies. Approximately 10-20% of the genetic testing for BRCA1 and BRCA2 leads to the identification of variants of uncertain significance (VUS), with higher proportions in Asians. We investigated the functional significance of 7 BRCA1 and 25 BRCA2 variants in a multi-ethnic Asian cohort using a case-control approach. METHODS: The MassARRAY genotyping was conducted in 1,394 Chinese, 406 Malay and 310 Indian breast cancer cases and 1,071 Chinese, 167 Malay and 255 Indian healthy controls. The association of individual variant with breast cancer risk was analyzed using logistic regression model adjusted for ethnicity, age and family history. RESULTS: Our study confirmed BRCA2 p.Ile3412Val is presented in >2% of unaffected women and is likely benign, and BRCA2 p.Ala1996Thr which is predicted to be likely pathogenic by in-silico models is presented in 2% of healthy Indian women suggesting that it may not be associated with breast cancer risk. Single-variant analysis suggests that BRCA1 p.Arg762Ser may be associated with breast cancer risk (OR = 7.4; 95% CI, 0.9-62.3; p = 0.06). CONCLUSIONS: Our study shows that BRCA2 p.Ile3412Val and p.Ala1996Thr are likely benign and highlights the need for population-specific studies to determine the likely functional significance of population-specific variants. Our study also suggests that BRCA1 p.Arg762Ser may be associated with increased risk of breast cancer but other methods or larger studies are required to determine a more precise estimate of breast cancer risk.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Grupos Étnicos/genética , Substituição de Aminoácidos , Neoplasias da Mama/etnologia , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Malásia/etnologia , Masculino , Análise de Sequência com Séries de Oligonucleotídeos
10.
Breast Cancer Res Treat ; 161(2): 353-362, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27864652

RESUMO

PURPOSE: Mammographic density is a measurable and modifiable biomarker that is strongly and independently associated with breast cancer risk. Paradoxically, although Asian women have lower risk of breast cancer, studies of minority Asian women in predominantly Caucasian populations have found that Asian women have higher percent density. In this cross-sectional study, we compared the distribution of mammographic density for a matched cohort of Asian women from Malaysia and Caucasian women from Sweden, and determined if variations in mammographic density could be attributed to population differences in breast cancer risk factors. METHODS: Volumetric mammographic density was compared for 1501 Malaysian and 4501 Swedish healthy women, matched on age and body mass index. We used multivariable log-linear regression to determine the risk factors associated with mammographic density and mediation analysis to identify factors that account for differences in mammographic density between the two cohorts. RESULTS: Compared to Caucasian women, percent density was 2.0% higher among Asian women (p < 0.001), and dense volume was 5.7 cm3 higher among pre-menopausal Asian women (p < 0.001). Dense volume was 3.0 cm3 lower among post-menopausal Asian women (p = 0.009) compared to post-menopausal Caucasian women, and this difference was attributed to population differences in height, weight, and parity (p < 0.001). CONCLUSIONS: Our analysis suggests that among post-menopausal women, population differences in mammographic density and risk to breast cancer may be accounted for by height, weight, and parity. Given that pre-menopausal Asian and Caucasian women have similar population risk to breast cancer but different dense volume, development of more appropriate biomarkers of risk in pre-menopausal women is required.


Assuntos
Grupo com Ancestrais do Continente Asiático , Densidade da Mama , Neoplasias da Mama/epidemiologia , Grupo com Ancestrais do Continente Europeu , Neoplasias da Mama/etiologia , Estudos Transversais , Feminino , Humanos , Malásia/epidemiologia , Mamografia , Pessoa de Meia-Idade , Vigilância da População , Fatores de Risco , Suécia/epidemiologia
11.
Stroke ; 47(2): 307-16, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26732560

RESUMO

BACKGROUND AND PURPOSE: Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset <60 years. METHODS: The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10(-6) and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls. RESULTS: One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10(-9)). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2. CONCLUSIONS: HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.


Assuntos
Isquemia Encefálica/genética , Serina Endopeptidases/genética , Acidente Vascular Cerebral/genética , Adulto , Grupo com Ancestrais do Continente Africano/genética , Idade de Início , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Isquemia Encefálica/complicações , Cromossomos Humanos Par 10 , Simulação por Computador , DNA Intergênico/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Serina Endopeptidases/metabolismo , Acidente Vascular Cerebral/etiologia
12.
Cancer Epidemiol Biomarkers Prev ; 25(2): 327-33, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26677210

RESUMO

BACKGROUND: Mammographic density is an established risk factor for breast cancer and has a strong heritable component. Genome-wide association studies (GWAS) for mammographic density conducted in women of European descent have identified several genetic associations, but none of the studies have been tested in Asians. We sought to investigate whether these genetic loci, and loci associated with breast cancer risk and breast size, are associated with mammographic density in an Asian cohort. METHODS: We conducted genotyping by mass spectrometry in 1,189 women (865 Chinese, 187 Indian, and 137 Malay). Quantitative measurements of mammographic density were performed using ImageJ, a fully automated thresholding technique. The associations of SNPs to densities were analyzed using linear regression models. RESULTS: We successfully evaluated the associations of 36 SNPs with mammographic densities. After adjusting for age, body mass index, parity, and menopausal status, we found that in our cohort of 865 Malaysian Chinese, three SNPs in the 6q25.1 region near ESR1 (rs2046210, rs12173570, and rs10484919) that were associated with mammographic density, breast cancer risk, or breast size in previous GWAS were significantly associated with both percentage density and absolute dense area. We could not replicate the most significant association found previously in European women (rs10995190, ZNF365 gene) because the minor allele was absent for Asian women. CONCLUSION: We found that the directions of genetic associations were similar to those reported in Caucasian women. IMPACT: Our results show that even in Asian women with lower population risk to breast cancer, there is shared heritability between mammographic density and breast cancer risk.


Assuntos
Densidade da Mama/genética , Neoplasias da Mama/genética , Cromossomos Humanos Par 6/genética , Grupo com Ancestrais do Continente Europeu , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Risco
13.
BMC Public Health ; 15: 548, 2015 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-26065413

RESUMO

BACKGROUND: To date, because of limited budgets and lower incidence of breast cancer, the majority of Asian countries do not have population-based screening programmes, but instead offer opportunistic screening. However, there have been few studies which have assessed the motivators for women attending such programmes and the appropriateness of the programmes in terms of targeting women at risk. METHODS: We conducted a prospective cross-sectional study of 1,619 women aged 40 to 74 years attending a subsidized opportunistic screening mammogram from October 2011 to October 2013 at a private hospital in Malaysia. Breast cancer risk was estimated using the Gail Model and two-step cluster analysis was used to examine the motivators of attending screening. RESULTS: Although Malaysia comprises 54.5% Malay, 24.5% Chinese and 7.3% Indian, the majority of women in the MyMammo Study were Chinese (70.1%) and 99.2% had a <2% ten-year risk of breast cancer. The most commonly cited barriers were the perception of not being at risk and fear of painful mammography. We found that highly educated women, cited doctors, family and friends as their main motivators. Of those with only secondary school education, their main motivators were doctors. CONCLUSIONS: Taken together, our results suggest the women attending opportunistic mammography screening in Asia are at low risk of breast cancer and this poses challenges to cost-effective and equitable strategies for cancer control. We propose that to improve uptake of screening mammography, awareness programmes should target both doctors and members of the public.


Assuntos
Neoplasias da Mama/diagnóstico , Hospitais Privados , Mamografia , Motivação , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Adulto , Idoso , Análise Custo-Benefício , Estudos Transversais , Detecção Precoce de Câncer , Feminino , Humanos , Malásia , Programas de Rastreamento , Pessoa de Meia-Idade , Estudos Prospectivos , Risco
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.
Stat Methods Med Res ; 23(1): 60-73, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22523184

RESUMO

We discuss inference for longitudinal clinical trials subject to possibly informative dropout. A selection of available methods is reviewed for the simple case of trials with two timepoints. Using data from two such clinical trials, each with two treatments, we demonstrate that different analysis methods can at times lead to quite different conclusions from the same data. We investigate properties of complete-case estimators for the type of trials considered, with emphasis on interpretation and meaning of parameters. We contrast longitudinal and crossover designs and argue that for crossover studies there are often good reasons to prefer a complete case analysis. More generally, we suggest that there is merit in an approach in which no untestable assumptions are made. Such an approach would combine a dropout analysis, an analysis of complete-case data only, and a careful statement of justified conclusions.


Assuntos
Ensaios Clínicos como Assunto , Modelos Estatísticos , Pacientes Desistentes do Tratamento , Estudos Cross-Over , Interpretação Estatística de Dados , Humanos , Estudos Longitudinais
16.
PLoS Genet ; 9(8): e1003657, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23950726

RESUMO

Genome-wide association studies (GWAS) yielded significant advances in defining the genetic architecture of complex traits and disease. Still, a major hurdle of GWAS is narrowing down multiple genetic associations to a few causal variants for functional studies. This becomes critical in multi-phenotype GWAS where detection and interpretability of complex SNP(s)-trait(s) associations are complicated by complex Linkage Disequilibrium patterns between SNPs and correlation between traits. Here we propose a computationally efficient algorithm (GUESS) to explore complex genetic-association models and maximize genetic variant detection. We integrated our algorithm with a new Bayesian strategy for multi-phenotype analysis to identify the specific contribution of each SNP to different trait combinations and study genetic regulation of lipid metabolism in the Gutenberg Health Study (GHS). Despite the relatively small size of GHS (n  =  3,175), when compared with the largest published meta-GWAS (n > 100,000), GUESS recovered most of the major associations and was better at refining multi-trait associations than alternative methods. Amongst the new findings provided by GUESS, we revealed a strong association of SORT1 with TG-APOB and LIPC with TG-HDL phenotypic groups, which were overlooked in the larger meta-GWAS and not revealed by competing approaches, associations that we replicated in two independent cohorts. Moreover, we demonstrated the increased power of GUESS over alternative multi-phenotype approaches, both Bayesian and non-Bayesian, in a simulation study that mimics real-case scenarios. We showed that our parallel implementation based on Graphics Processing Units outperforms alternative multi-phenotype methods. Beyond multivariate modelling of multi-phenotypes, our Bayesian model employs a flexible hierarchical prior structure for genetic effects that adapts to any correlation structure of the predictors and increases the power to identify associated variants. This provides a powerful tool for the analysis of diverse genomic features, for instance including gene expression and exome sequencing data, where complex dependencies are present in the predictor space.


Assuntos
Algoritmos , Evolução Biológica , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas/genética , Teorema de Bayes , Exoma/genética , Expressão Gênica , Humanos , Desequilíbrio de Ligação , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
17.
J Am Coll Cardiol ; 62(9): 789-98, 2013 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-23727086

RESUMO

OBJECTIVES: This study sought to identify loci for coronary artery calcification (CAC) in patients with chronic kidney disease (CKD). BACKGROUND: CKD is associated with increased CAC and subsequent coronary heart disease (CHD), but the mechanisms remain poorly defined. Genetic studies of CAC in CKD may provide a useful strategy for identifying novel pathways in CHD. METHODS: We performed a candidate gene study (∼2,100 genes; ∼50,000 single nucleotide polymorphisms [SNPs]) of CAC within the CRIC (Chronic Renal Insufficiency Cohort) study (N = 1,509; 57% European, 43% African ancestry). SNPs with preliminary evidence of association with CAC in CRIC were examined for association with CAC in the PennCAC (Penn Coronary Artery Calcification) (N = 2,560) and AFCS (Amish Family Calcification Study) (N = 784) samples. SNPs with suggestive replication were further analyzed for association with myocardial infarction (MI) in the PROMIS (Pakistan Risk of Myocardial Infarction Study) (N = 14,885). RESULTS: Of 268 SNPs reaching p < 5 × 10(-4) for CAC in CRIC, 28 SNPs in 23 loci had nominal support (p < 0.05 and in same direction) for CAC in PennCAC or AFCS. Besides chr9p21 and COL4A1, known loci for CHD, these included SNPs having reported genome-wide association study association with hypertension (e.g., ATP2B1). In PROMIS, 4 of the 23 suggestive CAC loci (chr9p21, COL4A1, ATP2B1, and ABCA4) had significant associations with MI, consistent with their direction of effect on CAC. CONCLUSIONS: We identified several loci associated with CAC in CKD that also relate to MI in a general population sample. CKD imparts a high risk of CHD and may provide a useful setting for discovery of novel CHD genes and pathways.


Assuntos
Vasos Coronários , Infarto do Miocárdio/genética , Polimorfismo de Nucleotídeo Único/genética , Insuficiência Renal Crônica/complicações , Calcificação Vascular/genética , Adulto , Grupo com Ancestrais do Continente Africano/genética , Idoso , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Estudos Prospectivos , Fatores de Risco , Calcificação Vascular/etiologia
18.
Diabetes ; 62(5): 1746-55, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23300278

RESUMO

We performed a genome-wide association study (GWAS) and a multistage meta-analysis of type 2 diabetes (T2D) in Punjabi Sikhs from India. Our discovery GWAS in 1,616 individuals (842 case subjects) was followed by in silico replication of the top 513 independent single nucleotide polymorphisms (SNPs) (P < 10⁻³) in Punjabi Sikhs (n = 2,819; 801 case subjects). We further replicated 66 SNPs (P < 10⁻4) through genotyping in a Punjabi Sikh sample (n = 2,894; 1,711 case subjects). On combined meta-analysis in Sikh populations (n = 7,329; 3,354 case subjects), we identified a novel locus in association with T2D at 13q12 represented by a directly genotyped intronic SNP (rs9552911, P = 1.82 × 10⁻8) in the SGCG gene. Next, we undertook in silico replication (stage 2b) of the top 513 signals (P < 10⁻³) in 29,157 non-Sikh South Asians (10,971 case subjects) and de novo genotyping of up to 31 top signals (P < 10⁻4) in 10,817 South Asians (5,157 case subjects) (stage 3b). In combined South Asian meta-analysis, we observed six suggestive associations (P < 10⁻5 to < 10⁻7), including SNPs at HMG1L1/CTCFL, PLXNA4, SCAP, and chr5p11. Further evaluation of 31 top SNPs in 33,707 East Asians (16,746 case subjects) (stage 3c) and 47,117 Europeans (8,130 case subjects) (stage 3d), and joint meta-analysis of 128,127 individuals (44,358 case subjects) from 27 multiethnic studies, did not reveal any additional loci nor was there any evidence of replication for the new variant. Our findings provide new evidence on the presence of a population-specific signal in relation to T2D, which may provide additional insights into T2D pathogenesis.


Assuntos
Diabetes Mellitus Tipo 2/genética , Polimorfismo de Nucleotídeo Único , Sarcoglicanas/genética , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Estudos de Coortes , Consanguinidade , Diabetes Mellitus Tipo 2/metabolismo , Europa (Continente) , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Índia , Masculino , Sarcoglicanas/metabolismo
19.
Lancet Neurol ; 11(11): 951-62, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23041239

RESUMO

BACKGROUND: Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes. METHODS: We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls. FINDINGS: We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10(-16)) and ZFHX3 (p=2·28×10(-8)), and for large-vessel stroke at a 9p21 locus (p=3·32×10(-5)) and HDAC9 (p=2·03×10(-12)). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5×10(-6). However, we were unable to replicate any of these novel associations in the replication cohort. INTERPRETATION: Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes. FUNDING: Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS).


Assuntos
Isquemia Encefálica/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Acidente Vascular Cerebral/genética , Isquemia Encefálica/diagnóstico , Bases de Dados Genéticas/tendências , Estudo de Associação Genômica Ampla/tendências , Humanos , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico
20.
Stat Med ; 31(16): 1675-87, 2012 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-22362410

RESUMO

Missing data arise in crossover trials, as they do in any form of clinical trial. Several papers have addressed the problems that missing data create, although almost all of these assume that the probability that a planned observation is missing does not depend on the value that would have been observed; that is, the data are missing at random (MAR). In many applications, this assumption is likely to be untenable; in which case, the data are missing not at random (MNAR). We investigate the effect on estimates of the treatment effect that assume data are MAR when data are actually MNAR. We also propose using the assumption of no carryover treatment effect, which is usually required for this design, to permit the estimation of a treatment effect when data are MNAR. The results are applied to a trial comparing two treatments for neuropathic pain and show that the estimate of treatment effect is sensitive to the assumption of MAR.


Assuntos
Estudos Cross-Over , Pacientes Desistentes do Tratamento , Ensaios Clínicos como Assunto/estatística & dados numéricos , Humanos , Modelos Estatísticos , Neuralgia/terapia , Resultado do Tratamento
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