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Effect of Genetic Variants Related to Lipid Metabolism as Risk Factors for Cholelithiasis After Bariatric Surgery in Brazilian Population

Pinheiro-Junior, Sidney; Pinhel, Marcela A. S.; Nakazone, Marcelo A.; Pinheiro, Anielli; Amorim, Gisele F. S.; Florim, Greiciane M. S.; Mazeti, Camila M.; Gregorio, Michele L.; Moschetta, Marina G.; Brito, Gilberto B.; Brienze, Sergio L. A.; Nonino, Carla
Fonte: SPRINGER; NEW YORK Publicador: SPRINGER; NEW YORK
Tipo: Artigo de Revista Científica
ENG
Relevância na Pesquisa
55.98%
The manifestation of cholelithiasis after bariatric surgery may depend on genetic factors related to lipid metabolism, including apolipoprotein E (APOE) and cholesteryl ester transfer protein (CETP) gene polymorphisms. We investigated the association between APOE HhaI and CETP TaqIB polymorphisms [PCR-RFLP] and occurrence of cholelithiasis over up to 8 months of follow-up after gastroplasty to Roux-en-Y gastric bypass in 220 patients distributed in Group 1 (G1) 114 with cholelithiasis postoperatively and Group 2 (G2) 106 without cholelithiasis, including biochemical and anthropometric profiles analyses. In our series, the allelic and genotypic distributions of CETP TaqIB and APOE HhaI polymorphisms were similar in both groups (P > 0.05). The subgroup analysis evidenced that 54% of the patients from G1, APOE*4 allele carriers compared with APOE*3/3 carriers, presented altered low-density lipoprotein cholesterol (LDL cholesterol) serum levels (P = 0.022) before bariatric surgery. The B1 allele for CETP was associated to more quickly elevation of HDL cholesterol levels just in individuals without cholelitiasis (P < 0.0001). The multivariate logistic regression analysis demonstrates correlation between APOE*4 allele, higher total cholesterol (TC) serum levels and prediposition to cholelitiasis in preoperative period. However...

Diferenças etnicas na distribuição de variantes geneticos da sintase endotelial do oxido nitrico; Ethinic differences in the distribution of nitric oxide endothelial synthase genetic variants

Aline Saldanha Marroni
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 18/01/2006 PT
Relevância na Pesquisa
56.18%
O óxido nítrico (NO) é um gás solúvel com importantes papéis fisiológicos. Alterações na biodisponibilidade de NO contribuem para o desenvolvimento de vários estados fisiopatológicos, tais como hipertensão arterial, aterosclerose, doença coronariana e hipertensão pulmonar. A importância do NO no controle cardiovascular levou a estudos visando avaliar se polimorfismos do gene da eNOS estão associados com doenças cardiovasculares. Três polimorfismos de interesse clínico do gene da eNOS têm sido estudados: T ?786C na região promotora, 4a/4b no íntron 4 e Glu298Asp no éxon 7. Diversos estudos têm apresentado resultados contraditórios sobre a associação desses polimorfismos com doenças cardiovasculares. Demonstrou-se que numa população dos EUA, estes variantes genéticos apresentam acentuada diferença étnica em sua distribuição. Não se sabe se na população brasileira ocorrem essas mesmas diferenças étnicas na distribuição de variantes da eNOS observadas na população americana. O objetivo desse trabalho foi avaliar a freqüência desses polimorfismos em voluntários diferentes etnicamente (136 negros e 154 brancos) na população brasileira. Também foi estimada a frequência haplotípica e a associação entre os variantes genéticos. A amplificação do DNA genômico foi feita por Reação de Polimerase em Cadeia (PCR) e os genótipos foram determinados por eletroforese em gel de poliacrilamida. O variante Asp298 foi mais comum em brancos (32.8%) que em negros (15.1%)(P<0.004). De modo similar...

Novel coding genetic variants of the GBP1 gene in wild and domestic pigs (Sus scrofa)

Chen, Shanyuan; Gomes, Rui; Costa, Vânia; Rocha, Isabel; Zsolnai, Attila; Anton, István; Charneca, Rui; Santos, Pedro; Nunes, José Luis; Buzgó, József; Varga, Gyula; Zhang, Ya-ping; Beja-Pereira, Albano
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
ENG
Relevância na Pesquisa
56.03%
The interferon-induced guanylate-binding protein 1 gene (GBP1) plays an important role in host defense against viral, bacterial and protozoan infections. To explore novel genetic variants in this gene, we re-sequenced a 587-bp fragment spanning the exon 2 of the GBP1 gene in a sample panel consisting of 34 wild boars and 59 local domestic pigs from three geographic regions (China, Iberian Peninsula, and Central Europe) and 12 individuals of three commercial breeds (Pietrain, Landrace, and Large White). In a final 543-bp sequence fragment, there were 14 single nucleotide polymorphisms (SNPs), of which five were coding (three novel mutations). A total of 19 haplotypes were reconstructed and most haplotypes were shared by two or more sample groups. Those shared haplotypes revealed a clear signature of genetic introgression from Chinese domestic pigs into European domestic pigs. In addition, there were six haplotypes with frequencies below 1%, but none of them were present in the three commercial breeds (Pietrain, Landrace, and Large White). Although a limited number of individuals and breeds were analyzed, the absence of rare alleles (or haplotypes) in the commercial breeds is an indication that a significant proportion of genetic diversity in domestic species is not present in commercial breeds. This study demonstrated the potential to find sufficient genetic variation for population genetic analyses of demography versus selection...

Association of high-density lipoprotein and apolipoprotein E genetic variants with age-related macular degeneration

Cezario,Sabrina Mayara; Calastri,Maria Clara Jéssica; Oliveira,Camila Ive Ferreira; Carmo,Tayanne Silva; Pinhel,Marcela Augusta de Souza; Godoy,Moacir Fernandes de; Jorge,Rodrigo; Cotrim,Carina Costa; Souza,Dorotéia Rossi Silva; Siqueira,Rubens Camargo
Fonte: Conselho Brasileiro de Oftalmologia Publicador: Conselho Brasileiro de Oftalmologia
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/04/2015 EN
Relevância na Pesquisa
56.02%
Purpose: This study aimed to evaluate the association of age-related macular degeneration (AMD) with apolipoprotein E (APOE) variants and serum lipid profiles, including levels and fractions of total serum cholesterol (TC), low-density lipoprotein cholesterol (LDLc), and high-density lipoprotein cholesterol (HDLc), and triglycerides (TG). Methods: Genotyping of APOE-HhaI was performed in 134 patients (study group, SG) and 164 individuals without AMD (control group, CG), aged 50-89 years. Lipid profiles were analyzed in a subgroup of 30 subjects of both groups, matched according to age and sex. The significance level was set at P<0.05. Results: APOE E3/E3 was more prevalent (SG=74.6%; CG=77.4%), with no difference between both groups (P=0.667). The same result was observed for risk genotypes (APOE E -/2: SG=7.4%; CG=10.3%, P=0.624). Serum levels of TC, LDLc, and TG revealed similar median values between SG (193.5, 116, and 155 mg/dL, respectively) and CG (207.5, 120, and 123.5 mg/dL, respectively; P >0.05). For HDLc, a higher median value was observed in SG (53.3 mg/dL) versus CG (42.5 mg/dL; P=0.016). Logistic regression analysis showed the same value, and the HDLc/TC ratio was -11.423 (P=0.014), as also confirmed by an increase in HDLc in SG. The association between lipid profiles and apolipoprotein E genotypes was similar in both groups (P>0.05). Conclusion: APOE-HhaI is not associated with AMD. However...

Association between the g.296596G > A genetic variant of RELN gene and susceptibility to autism in a Chinese Han population

Fu,Xiaoyan; Mei,Zhu; Sun,Lixin
Fonte: Sociedade Brasileira de Genética Publicador: Sociedade Brasileira de Genética
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/01/2013 EN
Relevância na Pesquisa
56.16%
Autism is a childhood neuro-developmental disorder, and Reelin (RELN) is an important candidate gene for influencing autism. This study aimed at investigating the influence of genetic variants of the RELN gene on autism susceptibility. In this study, 205 autism patients and 210 healthy controls were recruited and the genetic variants of the RELN gene were genotyped by the created restriction site-polymerase chain reaction (CRS-PCR) method. The influence of genetic variants on autism susceptibility was analyzed by association analysis, and the g.296596G > A genetic variant in exon10 of the RELN gene was detected. The frequencies of allele/genotype in autistic patients were significantly different from those in healthy controls, and a statistically significant association was detected between this genetic variant and autism susceptibility. Our data lead to the inference that the g.296596G > A genetic variant in the RELN gene has a potential influence on autism susceptibility in the Chinese Han population.

Myostatin: genetic variants, therapy and gene doping

Yamada,André Katayama; Verlengia,Rozangela; Bueno Junior,Carlos Roberto
Fonte: Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Publicador: Universidade de São Paulo, Faculdade de Ciências Farmacêuticas
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/09/2012 EN
Relevância na Pesquisa
66.07%
Since its discovery, myostatin (MSTN) has been at the forefront of muscle therapy research because intrinsic mutations or inhibition of this protein, by either pharmacological or genetic means, result in muscle hypertrophy and hyperplasia. In addition to muscle growth, MSTN inhibition potentially disturbs connective tissue, leads to strength modulation, facilitates myoblast transplantation, promotes tissue regeneration, induces adipose tissue thermogenesis and increases muscle oxidative phenotype. It is also known that current advances in gene therapy have an impact on sports because of the illicit use of such methods. However, the adverse effects of these methods, their impact on athletic performance in humans and the means of detecting gene doping are as yet unknown. The aim of the present review is to discuss biosynthesis, genetic variants, pharmacological/genetic manipulation, doping and athletic performance in relation to the MSTN pathway. As will be concluded from the manuscript, MSTN emerges as a promising molecule for combating muscle wasting diseases and for triggering wide-ranging discussion in view of its possible use in gene doping.

Genetic Variants at the PDZ-Interacting Domain of the Scavenger Receptor Class B Type I Interact with Diet to Influence the Risk of Metabolic Syndrome in Obese Men and Women1–3

Junyent, Mireia; Arnett, Donna K.; Tsai, Michael Y.; Kabagambe, Edmond K.; Straka, Robert J.; Province, Michael; An, Ping; Lai, Chao-Qiang; Parnell, Laurence D.; Shen, Jian; Lee, Yu-Chi; Borecki, Ingrid; Ordovás, Jose M.
Fonte: American Society for Nutrition Publicador: American Society for Nutrition
Tipo: Artigo de Revista Científica
Publicado em /05/2009 EN
Relevância na Pesquisa
56.07%
The scaffolding protein PDZ domain containing 1 (PDZK1) regulates the HDL receptor scavenger receptor class B type I. However, the effect of PDZK1 genetic variants on lipids and metabolic syndrome (MetS) traits remains unknown. This study evaluated the association of 3 PDZK1 single nucleotide polymorphisms (SNP) (i33968C > T, i15371G > A, and i19738C > T) with lipids and risk of MetS and their potential interactions with diet. PDZK1 SNP were genotyped in 1000 participants (481 men, 519 women) included in the Genetics of Lipid Lowering Drugs and Diet Network study. Lipoprotein subfractions were measured by proton NMR spectroscopy and dietary intake was estimated using a validated questionnaire. The PDZK1_i33968C > T polymorphism was associated with MetS (P = 0.034), mainly driven by the association of the minor T allele with higher plasma triglycerides (P = 0.004) and VLDL (P = 0.021), and lower adiponectin concentrations (P = 0.022) than in participants homozygous for the major allele (C). We found a significant gene × BMI × diet interaction, in which the deleterious association of the i33968T allele with MetS was observed in obese participants with high PUFA and carbohydrate (P-values ranging from 0.004 to 0.020) intakes. Conversely...

Human Papillomavirus Type 16 Genetic Variants: Phylogeny and Classification Based on E6 and LCR

Cornet, Iris; Gheit, Tarik; Franceschi, Silvia; Vignat, Jerome; Burk, Robert D.; Sylla, Bakary S.; Tommasino, Massimo; Clifford, Gary M.;
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /06/2012 EN
Relevância na Pesquisa
56.02%
Naturally occurring genetic variants of human papillomavirus type 16 (HPV16) are common and have previously been classified into 4 major lineages; European-Asian (EAS), including the sublineages European (EUR) and Asian (As), African 1 (AFR1), African 2 (AFR2), and North-American/Asian-American (NA/AA). We aimed to improve the classification of HPV16 variant lineages by using a large resource of HPV16-positive cervical samples collected from geographically diverse populations in studies on HPV and/or cervical cancer undertaken by the International Agency for Research on Cancer. In total, we sequenced the entire E6 genes and long control regions (LCRs) of 953 HPV16 isolates from 27 different countries worldwide. Phylogenetic analyses confirmed previously described variant lineages and subclassifications. We characterized two new sublineages within each of the lineages AFR1 and AFR2 that are robustly classified using E6 and/or the LCR. We could differentiate previously identified AA1, AA2, and NA sublineages, although they could not be distinguished by E6 alone, requiring the LCR for correct phylogenetic classification. We thus provide a classification system for HPV16 genomes based on 13 and 32 phylogenetically distinguishing positions in E6 and the LCR...

Estimating the contribution of genetic variants to difference in incidence of disease between population groups

Moonesinghe, Ramal; Ioannidis, John PA; Flanders, W Dana; Yang, Quanhe; Truman, Benedict I; Khoury, Muin J
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
46.28%
Genome-wide association studies have identified multiple genetic susceptibility variants to several complex human diseases. However, risk-genotype frequency at loci showing robust associations might differ substantially among different populations. In this paper, we present methods to assess the contribution of genetic variants to the difference in the incidence of disease between different population groups for different scenarios. We derive expressions for the contribution of a single genetic variant, multiple genetic variants, and the contribution of the joint effect of a genetic variant and an environmental factor to the difference in the incidence of disease. The contribution of genetic variants to the difference in incidence increases with increasing difference in risk-genotype frequency, but declines with increasing difference in incidence between the two populations. The contribution of genetic variants also increases with increasing relative risk and the contribution of joint effect of genetic and environmental factors increases with increasing relative risk of the gene–environmental interaction. The contribution of genetic variants to the difference in incidence between two populations can be expressed as a function of the population attributable risks of the genetic variants in the two populations. The contribution of a group of genetic variants to the disparity in incidence of disease could change considerably by adding one more genetic variant to the group. Any estimate of genetic contribution to the disparity in incidence of disease between two populations at this stage seems to be an elusive goal.

Cumulative association between age-related macular degeneration and less studied genetic variants in PLEKHA1/ARMS2/HTRA1: a meta and gene-cluster analysis

Yu, Weihong; Dong, Shuqian; Zhao, Chuntao; Wang, Haina; Dai, Fei; Yang, Jingyun
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
46.27%
The objective of this study is to examine the cumulative effect of the less studied genetic variants in PLEKHA1/ARMS2/HTRA1 on age-related macular degeneration (AMD). We performed an extensive literature search for studies on the association between AMD and the less studied genetic variants in PLEKHA1/ARMS2/HTRA1. Multiple meta-analyses were performed to evaluate the association between individual genetic variants and AMD. A gene-cluster analysis was used to investigate the cumulative effect of these less studied genetic variants on AMD. A total of 23 studies from 20 published papers met the eligibility criteria and were included in our analyses. Several genetic variants in the gene cluster are significantly associated with AMD in our meta-analyses or in individual studies. Gene-cluster analysis reveals a strong cumulative association between these genetic variants in this gene cluster and AMD (p<10−5). However, two previously suspected SNPs in ARMS2, including rs2736911, the SNP having the largest number of studies in our meta-analyses; and rs3793917, the SNP with the largest sample size, were not significantly associated with AMD (both p’s>0.12). Sensitivity analyses reveal significant association of AMD with rs2736911 in Chinese but not in Caucasian...

Comparison of multilevel modeling and the family-based association test for identifying genetic variants associated with systolic and diastolic blood pressure using Genetic Analysis Workshop 18 simulated data

Wang, Jian; Yu, Robert; Shete, Sanjay
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Publicado em 17/06/2014 EN
Relevância na Pesquisa
46.23%
Identifying genetic variants associated with complex diseases is an important task in genetic research. Although association studies based on unrelated individuals (ie, case-control genome-wide association studies) have successfully identified common single-nucleotide polymorphisms for many complex diseases, these studies are not so likely to identify rare genetic variants. In contrast, family-based association studies are particularly useful for identifying rare-variant associations. Recently, there has been some interest in employing multilevel models in family-based genetic association studies. However, the performance of such models in these studies, especially for longitudinal family-based sequence data, has not been fully investigated. Therefore, in this study, we investigated the performance of the multilevel model in the family-based genetic association analysis and compared it with the conventional family-based association test, by examining the powers and type I error rates of the 2 approaches using 3 data sets from the Genetic Analysis Workshop 18 simulated data: genome-wide association single-nucleotide polymorphism data, sequence data, and rare-variants-only data. Compared with the univariate family-based association test...

Pharmacogenetics of Statin-Induced Myopathy: A Focused Review of the Clinical Translation of Pharmacokinetic Genetic Variants

Talameh, Jasmine A; Kitzmiller, Joseph P
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 23/04/2014 EN
Relevância na Pesquisa
46.24%
Statins are the most commonly prescribed drugs in the United States and are extremely effective in reducing major cardiovascular events in the millions of Americans with hyperlipidemia. However, many patients (up to 25%) cannot tolerate or discontinue statin therapy due to statin-induced myopathy (SIM). Patients will continue to experience SIM at unacceptably high rates or experience unnecessary cardiovascular events (as a result of discontinuing or decreasing their statin therapy) until strategies for predicting or mitigating SIM are identified. A promising strategy for predicting or mitigating SIM is pharmacogenetic testing, particularly of pharmacokinetic genetic variants as SIM is related to statin exposure. Data is emerging on the association between pharmacokinetic genetic variants and SIM. A current, critical evaluation of the literature on pharmacokinetic genetic variants and SIM for potential translation to clinical practice is lacking. This review focuses specifically on pharmacokinetic genetic variants and their association with SIM clinical outcomes. We also discuss future directions, specific to the research on pharmacokinetic genetic variants, which could speed the translation into clinical practice. For simvastatin, we did not find sufficient evidence to support the clinical translation of pharmacokinetic genetic variants other than SLCO1B1. However...

Effects of Genetic Variants Previously Associated with Fasting Glucose and Insulin in the Diabetes Prevention Program

Jablonski, Kathleen A.; McAteer, Jarred B.; Franks, Paul W.; Mason, Clinton C.; Mather, Kieren; Goldberg, Ronald; Dabelea, Dana; Kahn, Steven E.; Arakaki, Richard F.; Shuldiner, Alan R.; Knowler, William C.; Florez, Jose Carlos; Horton, Edward S.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
EN_US
Relevância na Pesquisa
56.13%
Common genetic variants have been recently associated with fasting glucose and insulin levels in white populations. Whether these associations replicate in pre-diabetes is not known. We extended these findings to the Diabetes Prevention Program, a clinical trial in which participants at high risk for diabetes were randomized to placebo, lifestyle modification or metformin for diabetes prevention. We genotyped previously reported polymorphisms (or their proxies) in/near G6PC2, MTNR1B, GCK, DGKB, GCKR, ADCY5, MADD, CRY2, ADRA2A, FADS1, PROX1, SLC2A2, GLIS3, C2CD4B, IGF1, and IRS1 in 3,548 Diabetes Prevention Program participants. We analyzed variants for association with baseline glycemic traits, incident diabetes and their interaction with response to metformin or lifestyle intervention. We replicated associations with fasting glucose at MTNR1B (P<0.001), G6PC2 (P = 0.002) and GCKR (P = 0.001). We noted impaired β-cell function in carriers of glucose-raising alleles at MTNR1B (P<0.001), and an increase in the insulinogenic index for the glucose-raising allele at G6PC2 (P<0.001). The association of MTNR1B with fasting glucose and impaired β-cell function persisted at 1 year despite adjustment for the baseline trait, indicating a sustained deleterious effect at this locus. We also replicated the association of MADD with fasting proinsulin levels (P<0.001). We detected no significant impact of these variants on diabetes incidence or interaction with preventive interventions. The association of several polymorphisms with quantitative glycemic traits is replicated in a cohort of high-risk persons. These variants do not have a detectable impact on diabetes incidence or response to metformin or lifestyle modification in the Diabetes Prevention Program.

Association of genetic variants in the TMCO1 gene with clinical parameters related to glaucoma and characterization of the protein in the eye

Sharma, S.; Burdon, K.; Chidlow, G.; Klebe, S.; Crawford, A.; Dimasi, D.; Dave, A.; Martin, S.; Javadiyan, S.; Wood, J.; Casson, R.; Danoy, P.; Griggs, K.; Hewitt, A.; Landers, J.; Mitchell, P.; Mackey, D.; Craig, J.
Fonte: Assoc Research Vision Ophthalmology Inc Publicador: Assoc Research Vision Ophthalmology Inc
Tipo: Artigo de Revista Científica
Publicado em //2012 EN
Relevância na Pesquisa
55.98%
Purpose. Glaucoma is the leading cause of irreversible blindness worldwide. Primary open angle glaucoma (POAG) is the most common subtype. We recently reported association of genetic variants at chromosomal loci, 1q24 and 9p21, with POAG. In this study, we determined association of the most significantly associated single nucleotide polymorphism (SNP) rs4656461, at 1q24 near the TMCO1 gene, with the clinical parameters related to glaucoma risk and diagnosis, and determined ocular expression and subcellular localization of the human TMCO1 protein to understand the mechanism of its involvement in POAG. Methods. Association of SNP rs4656461 with five clinical parameters was assessed in 1420 POAG cases using linear regression. The TMCO1 gene was screened for mutations in 95 cases with a strong family history and advanced disease. Ocular expression and subcellular localization of the TMCO1 protein were determined by immunolabeling and as GFP-fusion. Results. The data suggest that individuals homozygous for the rs4656461 risk allele (GG) are 4 to 5 years younger at diagnosis than noncarriers of this allele. Our data demonstrate expression of the TMCO1 protein in most tissues in the human eye, including the trabecular meshwork and retina. However...

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Allen, H.L.; Estrada, K.; Lettre, G.; Berndt, S.I.; Weedon, M.N.; Rivadeneira, F.; Willer, C.J.; Jackson, A.U.; Vedantam, S.; Raychaudhuri, S.; Ferreira, T.; Wood, A.R.; Weyant, R.J.; Segre, A.V.; Speliotes, E.K.; Wheeler, E.; Soranzo, N.; Park, J.H.; Yan
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Publicado em //2010 EN
Relevância na Pesquisa
46.24%
Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits1, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth...

Genetic variants associated with increased risk of malignant pleural mesothelioma: a genome-wide association study

Matullo, G.; Guarrera, S.; Betti, M.; Fiorito, G.; Ferrante, D.; Voglino, F.; Cadby, G.; Di Gaetano, C.; Rosa, F.; Russo, A.; Hirvonen, A.; Casalone, E.; Tunesi, S.; Padoan, M.; Giordano, M.; Aspesi, A.; Casadio, C.; Ardissone, F.; Ruffini, E.; Betta, P.G
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em //2013 EN
Relevância na Pesquisa
56.04%
Asbestos exposure is the main risk factor for malignant pleural mesothelioma (MPM), a rare aggressive tumor. Nevertheless, only 5–17% of those exposed to asbestos develop MPM, suggesting the involvement of other environmental and genetic risk factors. To identify the genetic risk factors that may contribute to the development of MPM, we conducted a genome-wide association study (GWAS; 370,000 genotyped SNPs, 5 million imputed SNPs) in Italy, among 407 MPM cases and 389 controls with a complete history of asbestos exposure. A replication study was also undertaken and included 428 MPM cases and 1269 controls from Australia. Although no single marker reached the genome-wide significance threshold, several associations were supported by haplotype-, chromosomal region-, gene- and gene-ontology process-based analyses. Most of these SNPs were located in regions reported to harbor aberrant alterations in mesothelioma (SLC7A14, THRB, CEBP350, ADAMTS2, ETV1, PVT1 and MMP14 genes), causing at most a 2–3-fold increase in MPM risk. The Australian replication study showed significant associations in five of these chromosomal regions (3q26.2, 4q32.1, 7p22.2, 14q11.2, 15q14). Multivariate analysis suggested an independent contribution of 10 genetic variants...

Beyond Mendelian randomization: in which the authors discussed how to interpret evidence of shared genetic predictors

Burgess, Stephen; Butterworth, Adam S.; Thompson, John R.
Fonte: Elsevier Publicador: Elsevier
Tipo: Article; accepted version
EN
Relevância na Pesquisa
56.18%
This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.jclinepi.2015.08.001; Objective: Mendelian randomization is a popular technique for assessing and estimating the causal effects of risk factors. If genetic variants which are instrumental variables for a risk factor are shown to be additionally associated with a disease outcome, then the risk factor is a cause of the disease. However, in many cases, the instrumental variable assumptions are not plausible, or are in doubt. In this paper, we provide a theoretical classification of scenarios in which a causal conclusion is justified or not justified, and discuss the interpretation of causal effect estimates. Results: A list of guidelines based on the ?Bradford Hill criteria? for judging the plausibility of a causal finding from an applied Mendelian randomization study is provided. We also give a framework for performing and interpreting investigations performed in the style of Mendelian randomization, but where the choice of genetic variants is statistically, rather than biologically motivated. Such analyses should not be assigned the same evidential weight as a Mendelian randomization investigation. Conclusion: We discuss the role of such investigations (in the style of Mendelian randomization)...

A comprehensive meta-analysis of common genetic variants in Autism Spectrum Conditions

Warrier, Varun; Chee, Vivienne; Smith, Paula; Chakrabarti, Bhismadev; Baron-Cohen, Simon
Fonte: Universidade de Cambridge Publicador: Universidade de Cambridge
Tipo: Article; accepted version
EN
Relevância na Pesquisa
66.21%
This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s13229-015-0041-0; Background: Autism Spectrum Conditions (ASC) are a group of neurodevelopmental conditions characterized by difficulties in social interaction and communication alongside repetitive and stereotyped behaviours. ASC are heritable, and common genetic variants contribute substantial phenotypic variability. More than 600 genes have been implicated in ASC to date. However, a comprehensive investigation of candidate gene association studies in ASC is lacking. Methods: In this study, we systematically reviewed the literature for association studies for 552 genes associated with ASC. We identified 58 common genetic variants in 27 genes that have been investigated in three or more independent cohorts and conducted a meta-analysis for 55 of these variants. We investigated publication bias and sensitivity, and performed stratified analyses for a subset of these variants. Results: We identified 15 variants nominally significant for the mean effect size, eight of which had P values below a threshold of significance of 0.01. 11 of these 15 variants were re-investigated for effect sizes and significance in the larger Psychiatric Genomics Consortium dataset...

Apoptotic variants as predictors of risk of oropharyngeal cancer recurrence after definitive radiotherapy.

Zhang, F; Sturgis, EM; Sun, Y; Zhang, Y; Wei, Q; Zhang, C; Zheng, H; Li, G
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Artigo de Revista Científica Formato: 2454 - 2461
Publicado em 15/11/2015 ENG
Relevância na Pesquisa
56.01%
Single nucleotide polymorphisms (SNPs) in the promoter region of FAS and FASLG may alter their transcriptional activity. Thus, we determined the associations between four FAS and FASLG promoter variants (FAS1377G>A, rs2234767; 670A>G, rs1800682; FASLG844T>C, rs763110 and 124A>G, rs5030772) and the risk of recurrence of squamous cell carcinoma of the oropharynx (SCCOP). We evaluated the associations between FAS and FASLG genetic variants and the risk of recurrence in a cohort of 1,008 patients. The log-rank test and multivariate Cox models were used to evaluate the associations. Compared with patients with common homozygous genotypes of FAS670 and FASLG844 polymorphisms, patients with variant genotypes had lower disease-free survival rates (log-rank p < 0.0001 and p < 0.0001, respectively) and an approximately threefold higher risk of SCCOP recurrence (HR, 3.2;95% CI, 2.2-4.6; and HR, 3.1; 95% CI, 2.2-4.4, respectively) after multivariate adjustment. Furthermore, among patients with HPV16-positive tumors, those with variant genotypes of these two polymorphisms had lower disease-free survival rates (log-rank, p < 0.0001 and p < 0.0001, respectively) and a higher recurrence risk than did patients with common homozygous genotypes (HR...

Genetic and Environmental Contributions to Baseline Cognitive Ability and Cognitive Response to Topiramate

Cirulli, Elizabeth Trilby
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação
Publicado em //2010
Relevância na Pesquisa
46.31%

Although much research has focused on cognitive ability and the genetic and environmental factors that might influence it, this aspect of human nature is still far from being well understood. It has been well-established that certain factors such as age and education have significant impacts on performance on most cognitive tests, but the effects of variables such as cognitive pastimes and strategies used during testing have generally not been assessed. Additionally, no genetic variant has yet been unequivocally shown to influence the normal variation in cognitive ability of healthy individuals. Candidate gene studies of cognition have produced conflicting results that have not been replicable, and genome-wide association studies have not found common variants with large influences on this trait.

Here, we have recruited a large cohort of healthy volunteers (n=1,887) and administered a brief cognitive battery utilizing diverse, common, and well-known tests. In addition to providing standard demographic information, the subjects also filled out a questionnaire that was designed to assess novel factors such as whether they had seen the test before, in what cognitive pastimes they participated, and what strategies they had used during testing. Linear regression models were built to assess the effects of these variables on the test scores. I found that the addition of novel covariates to standard ones increased the percent of the variation in test score that was explained for all tests; for some tests...