scholarly journals MOLECULAR EPIDEMIOLOGY OF RENAL CANCER

2018 ◽  
Vol 14 (3) ◽  
pp. 107-119 ◽  
Author(s):  
D. G. Zaridze ◽  
A. F. Mukeriya ◽  
O. V. Shan’gina ◽  
V. B. Matveev
Keyword(s):  
Risk Factors ◽  
Molecular Epidemiology ◽  
Genetic Susceptibility ◽  
Association Studies ◽  
Cell Cancer ◽  
Transitional Cell ◽  
Occupational Exposures ◽  
Candidate Gene Approach ◽  
Genome Wide Association Studies ◽  
Very High

Kidney cancer consists of renal cell cancer (RCC) accounting for over 90 % of all kidney carcinomas and the transitional cell cancer. Clear cell cancer is a predominant type (80–85 %) of RCC. Smoking, overweight, obesity, hypertension, occupational exposures to pesticides, specifically to trichloroethylene are considered causal risk factors for sporadic i.e. non-hereditary RCC. The majority of sporadic RCC have polygenic etiology. They develop as a result of combined effect of large number of low penetrance genetic susceptibility genes (genetic polymorphism). The interplay of exposures to environmental risk factors and genetic susceptibility of exposed individuals is believed to influence the risk of developing sporadic RCC. Inheritance of high penetrance genes is associated with very high risk of the RCC. To these genes belongs, for example, VHL (von Hippel–Lindau). Germline mutations in VHL are causing VHL syndrome and hereditary type of RCC. Risk of RCC in individuals with germ-line mutations is very high however the proportion RCC associated with these events is very low (>5–7 %). Environmental factors virtually do not influence the risk of these cancers.The studies in molecular epidemiology based on candidate gene approach have shown that certain types (variants) of polymorphisms of GST, MTHFR, TYMS, VHL genes are associated with RCC. The genome wide association studies identified over twenty locus with single nucleotide polymorphism affecting the risk of RCC. The risk loci so far identified for RCC account for only about 10 % of the familial risk of RCC. Thus more studies with larger sample size are needed. As more RCC susceptibility alleles are discovered, deciphering the biological basis of risk variants should provide new insights into the biology of RCC that may lead to new approaches to prevention, early detection and therapeutic intervention.

scholarly journals RISK FACTORS FOR RENAL CELL CARCINOMA

2018 ◽  
Vol 17 (5) ◽  
pp. 77-86
Author(s):  
D. G. Zaridze ◽  
A. F. Mukeria ◽  
O. V. Shangina
Keyword(s):  
Risk Factors ◽  
Genetic Susceptibility ◽  
Renal Cell ◽  
Association Studies ◽  
Cell Cancer ◽  
Decisive Role ◽  
Occupational Exposures ◽  
Candidate Gene Approach ◽  
Genome Wide Association Studies ◽  
Continue Smoking

Smoking, overweight, obesity, hypertension, occupational exposures to pesticides, specifically to trichloroethylene are considered causal risk factors for sporadic i.e. non-hereditary renal cell cancer (RCC). Some of these factors not only increase the risk of RCC but also affect the survival of patients. For example, in patients with RCC who continue smoking, the risk of dying from other causes is twice as high as in patient who quit smoking. The risk of second cancer is 5 times higher in patients who continue smoking 20 or more cigarettes per day than in non-smokers. The low penetrance polymorphism is an important factor in etiology of sporadic RCC, which contrary to high penetrance mutations is a common event. However, the risk associated with this type of inheritance is quite low. The majority of sporadic RCC have polygenic etiology. They develop as a result of combined effect of large number of low penetrance genetic susceptibility genes (genetic polymorphism). Environmental factors play a decisive role in causation of sporadic RCC. The interplay of exposures to environmental risk factors and genetic susceptibility of exposed individuals is believed to influence the risk of developing sporadic RCC. The studies in molecular epidemiology based on candidate gene approach have shown that polymorphisms of certain genes, for example glutathione-S-transferase family genes, are associated with RCC. The genome wide association studies identified about twenty loci with single nucleotide polymorphism (SNPs) affecting the risk of RCC. However the risk loci so far identified for RCC account for only about 10 % of the familial risk of RCC. The power of largest studies which include many thousands of observations allow to detect 80 % of the major common loci (with minor allele frequency – MAF>0.2) conferring risk ≥1.2. However, for detecting alleles with smaller effects and/or MAF<0.1, more studies with larger sample size are needed. By implication, variants with such profiles probably represent a much larger class of susceptibility loci for RCC and hence a large number of variants remain to be discovered. Future investigation of the genes targeted by the risk SNPs is likely to yield increased insight into biology of RCC and will lead to new approaches for prevention, early detection and treatment.

scholarly journals Tobacco, Genetic Susceptibility and Lung cancer

2010 ◽  
Vol 3 ◽  
pp. TUI.S2819
Author(s):  
Ravindran Ankathil
Keyword(s):  
Risk Factors ◽  
Lung Cancer ◽  
Genetic Susceptibility ◽  
Candidate Genes ◽  
Genetic Polymorphisms ◽  
High Frequency ◽  
Association Studies ◽  
Susceptibility Gene ◽  
Susceptibility Genes ◽  
Genome Wide Association Studies

Exposure to tobacco smoke is an established risk factor for lung cancer, although a possible role for genetic susceptibility in the development of lung cancer has been inferred from familial clustering of the disease and segregation analysis. Findings of familial aggregation and statistical evidence for a major susceptibility gene have led to the search for high penetrant, rare, single genes and low penetrant, high frequency susceptibility genes for lung cancer. The relatively small number of linkage studies conducted to date, have identified potential lung cancer susceptibility loci on chromosomes 6q, 12p, and 19q. A variety of studies have examined single nucleotide polymorphisms of several low penetrant, high frequency genes encoding for enzymes involved in the metabolism of carcinogens and DNA damage repair, as likely candidate susceptibility genes. These studies have produced somewhat conflicting findings and, when significant, only modest associations have been reported. Relatively few studies have looked for potential gene-environment interactions, explored associations between two or more genetic polymorphisms or evaluated interactions between genetic polymorphisms and endogenous risk factors. Few large scale genome wide association studies conducted recently have provided evidence that common variation on chromosome 15q25.1, 5p15.33 and 6p21.33 influences lung cancer risk and cancer types with strong environmental risk factors. It is hoped that newer research strategies, selecting candidate genes within pathways and genotype at multiple markers within a gene, employing new technologies, may allow complete coverage of the variation within candidate genes in multiple pathways and to unravel the genetic susceptibility to lung cancer. This knowledge could, in turn, be used to identify persons at risk, to individualize treatments such as chemoprevention, to personalize harms of smoking and to motivate cessation.

scholarly journals Chemotherapy-Related Cardiac Dysfunction

2018 ◽  
Vol 11 (1) ◽  
Author(s):  
Marijke Linschoten ◽  
Arco J. Teske ◽  
Maarten J. Cramer ◽  
Elsken van der Wall ◽  
Folkert W. Asselbergs
Keyword(s):  
Risk Factors ◽  
Risk Stratification ◽  
Genetic Variants ◽  
Cardiac Dysfunction ◽  
Genetic Risk ◽  
Drug Transport ◽  
Association Studies ◽  
Genetic Risk Factors ◽  
Candidate Gene Approach ◽  
Genome Wide Association Studies

Chemotherapy-related cardiac dysfunction is a significant side effect of anticancer treatment. Risk stratification is based on clinical- and treatment-related risk factors that do not adequately explain individual susceptibility. The addition of genetic variants may improve risk assessment. We conducted a systematic literature search in PubMed and Embase, to identify studies investigating genetic risk factors for chemotherapy-related cardiac dysfunction. Included were articles describing genetic variants in humans altering susceptibility to chemotherapy-related cardiac dysfunction. The validity of identified studies was assessed by 10 criteria, including assessment of population stratification, statistical methodology, and replication of findings. We identified 40 studies: 34 exploring genetic risk factors for anthracycline-induced cardiotoxicity (n=9678) and 6 studies related to trastuzumab-associated cardiotoxicity (n=642). The majority (35/40) of studies had a candidate gene approach, whereas 5 genome-wide association studies have been performed. We identified 25 genetic variants in 20 genes and 2 intergenic variants reported significant at least once. The overall validity of studies was limited, with small cohorts, failure to assess population ancestry and lack of replication. SNPs with the most robust evidence up to this point are CELF4 rs1786814 (sarcomere structure and function), RARG rs2229774 (topoisomerase-2β expression), SLC28A3 rs7853758 (drug transport), UGT1A6 rs17863783 (drug metabolism), and 1 intergenic variant (rs28714259). Existing evidence supports the hypothesis that genetic variation contributes to chemotherapy-related cardiac dysfunction. Although many variants identified by this systematic review show potential to improve risk stratification, future studies are necessary for validation and assessment of their value in a diagnostic and prognostic setting.

scholarly journals Type 2 diabetes genes – Present status and data from Norwegian studies

2013 ◽  
Vol 23 (1) ◽  
Author(s):  
Jens K. Hertel Hertel ◽  
Stefan Johansson ◽  
Kristian Midthjell ◽  
Ottar Nygård ◽  
Pål R. Njølstad ◽  
...  
Keyword(s):  
Risk Factors ◽  
Type 2 Diabetes ◽  
Genetic Risk ◽  
Association Studies ◽  
Pancreatic Beta Cell ◽  
Genetic Risk Factors ◽  
Candidate Gene Approach ◽  
Genome Wide Association Studies ◽  
Complex Disorders

The worldwide rise in prevalence of type 2 diabetes has led to an intense search for the genetic risk factors of this disease. In type 2 diabetes and other complex disorders, multiple genetic and environmental factors, as well as the interaction between these factors, determine the phenotype. In this review, we summarize present knowledge, generated by more than two decades of efforts to dissect the genetic architecture of type 2 diabetes. Initial studies were either based on a candidate gene approach or attempted to fine-map signals generated from linkage analysis. Despite the detection of multiple genomic regions proposed to be linked to type 2 diabetes, subsequent positional fine-mapping of candidates were mostly inconclusive. However, the introduction of genome-wide association studies (GWAS), applied on thousands of patients and controls, completely changed the field. To date, more than 50 susceptibility loci for type 2 diabetes have been detected through the establishment of large research consortia, the application of GWAS on intermediary diabetes phenotypes and the use of study samples of different ethnicities. Still, the common variants identified in the GWAS era only explain some of the heritability seen for type 2 diabetes. Thus, focus is now shifting towards searching also for rare variants using new high-throughput sequencing technologies. For genes involved in the genetic predisposition to type 2 diabetes the emerging picture is that there are hundreds of different gene variants working in a complex interplay influencing pancreatic beta cell function/mass and, only to a lesser extent, insulin action. Several Norwegian studies have contributed to the field, extending our understanding of genetic risk factors in type 2 diabetes and in diabetes-related phenotypes like obesity and cardiovascular disease.

scholarly journals Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett’s oesophagus and provides insights into clinical heterogeneity in reflux diagnosis

Gut ◽  
2021 ◽  
pp. gutjnl-2020-323906
Author(s):  
Jue-Sheng Ong ◽  
Jiyuan An ◽  
Xikun Han ◽  
Matthew H Law ◽  
Priyanka Nandakumar ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Testing ◽  
Association Studies ◽  
Barrett’S Oesophagus ◽  
Oesophageal Reflux ◽  
Oesophageal Adenocarcinoma ◽  
Specific Gene ◽  
Genome Wide Association Studies ◽  
Disease Heterogeneity ◽  
Barrett's Oesophagus

ObjectiveGastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett’s oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications.DesignWe applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA).ResultsWe identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA.ConclusionOur multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci.

scholarly journals Genetic Basis of Mastitis Resistance in Dairy Cattle – A Review / Podstawy Genetyczne Odporności Krów Mlecznych Na Zapalenie Wymienia – Artykuł Przeglądowy

2013 ◽  
Vol 13 (4) ◽  
pp. 663-673 ◽  
Author(s):  
Grażyna Sender ◽  
Agnieszka Korwin-Kossakowska ◽  
Adrianna Pawlik ◽  
Karima Galal Abdel Hameed ◽  
Jolanta Oprządek
Keyword(s):  
Dairy Cattle ◽  
Association Studies ◽  
Genetic Resistance ◽  
Clinical Mastitis ◽  
Future Research ◽  
Complex Nature ◽  
Candidate Gene Approach ◽  
Genome Wide Association Studies ◽  
Polygenic Control ◽  
Breeding Programmes

Abstract Mastitis is one of the most important mammary gland diseases impacting lactating animals. Resistance to this disease could be improved by breeding. There are several selection methods for mastitis resistance. To improve the natural genetic resistance of cows in succeeding generations, current breeding programmes use somatic cell count and clinical mastitis cases as resistance traits. However, these methods of selection have met with limited success. This is partly due to the complex nature of the disease. The limited progress in improving udder health by conventional selection procedures requires applying information on molecular markers of mastitis susceptibility in marker-assisted selection schemes. Mastitis is under polygenic control, so there are many genes that control this trait in many loci. This review briefly describes genome-wide association studies which have been carried out to identify quantitative trait loci associated with mastitis resistance in dairy cattle worldwide. It also characterizes the candidate gene approach focus on identifying genes that are strong candidates for the mastitis resistance trait. In the conclusion of the paper we focus our attention on future research which should be conducted in the field of the resistance to mastitis.

scholarly journals Evaluating the effects of alcohol and tobacco use on cardiovascular disease using multivariable Mendelian randomization

2019 ◽  
Author(s):  
Daniel B. Rosoff ◽  
George Davey Smith ◽  
Nehal Mehta ◽  
Toni-Kim Clarke ◽  
Falk W. Lohoff
Keyword(s):  
Risk Factors ◽  
Cardiovascular Disease ◽  
Alcohol Use ◽  
Tobacco Use ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Density Lipoprotein ◽  
Genome Wide Association Studies ◽  
Cvd Risk ◽  
Increased Risk

ABSTRACTAlcohol and tobacco use, two major modifiable risk factors for cardiovascular disease (CVD), are often consumed together. Using large publicly available genome-wide association studies (results from > 940,000 participants), we conducted two-sample multivariable Mendelian randomization (MR) to simultaneously assess the independent effects of alcohol and tobacco use on CVD risk factors and events. We found genetic instruments associated with increased alcohol use, controlling for tobacco use, associated with increased high-density-lipoprotein-cholesterol (HDL-C), decreased triglycerides, but not with coronary heart disease (CHD), myocardial infarction (MI), nor stroke; and instruments for increased tobacco use, controlling for alcohol use, associated with decreased HDL-C, increased triglycerides, and increased risk of CHD and MI. Exploratory analysis found associations with HDL-C, LDL-C, and intermediate-density-lipoprotein metabolites. Consistency of results across complementary methods accommodating different MR assumptions strengthened causal inference, providing strong genetic evidence for the causal effects of modifiable lifestyle risk factors on CVD risk.

scholarly journals Chromatin architecture in addiction circuitry elucidates biological mechanisms underlying cigarette smoking and alcohol use traits.

2021 ◽  
Author(s):  
Nancy Y.A Sey ◽  
Benxia Hu ◽  
Marina Iskhakova ◽  
Huaigu Sun ◽  
Neda Shokrian ◽  
...  
Keyword(s):  
Risk Factors ◽  
Alcohol Use ◽  
Cigarette Smoking ◽  
Genetic Risk ◽  
Target Genes ◽  
Association Studies ◽  
Critical Role ◽  
Genetic Risk Factors ◽  
Genome Wide Association Studies ◽  
Risk Genes

Cigarette smoking and alcohol use are among the most prevalent substances used worldwide and account for a substantial proportion of preventable morbidity and mortality, underscoring the public health significance of understanding their etiology. Genome-wide association studies (GWAS) have successfully identified genetic variants associated with cigarette smoking and alcohol use traits. However, the vast majority of risk variants reside in non-coding regions of the genome, and their target genes and neurobiological mechanisms are unknown. Chromosomal conformation mappings can address this knowledge gap by charting the interaction profiles of risk-associated regulatory variants with target genes. To investigate the functional impact of common variants associated with cigarette smoking and alcohol use traits, we applied Hi-C coupled MAGMA (H-MAGMA) built upon cortical and midbrain dopaminergic neuronal Hi-C datasets to GWAS summary statistics of nicotine dependence, cigarettes per day, problematic alcohol use, and drinks per week. The identified risk genes mapped to key pathways associated with cigarette smoking and alcohol use traits, including drug metabolic processes and neuronal apoptosis. Risk genes were highly expressed in cortical glutamatergic, midbrain dopaminergic, GABAergic, and serotonergic neurons, suggesting them as relevant cell types in understanding the mechanisms by which genetic risk factors influence cigarette smoking and alcohol use. Lastly, we identified pleiotropic genes between cigarette smoking and alcohol use traits under the assumption that they may reveal substance-agnostic, shared neurobiological mechanisms of addiction. The number of pleiotropic genes was ~26-fold higher in dopaminergic neurons than in cortical neurons, emphasizing the critical role of ascending dopaminergic pathways in mediating general addiction phenotypes. Collectively, brain region- and neuronal subtype-specific 3D genome architecture refines neurobiological hypotheses for smoking, alcohol, and general addiction phenotypes by linking genetic risk factors to their target genes.

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