Cohort Differences in the Associations of Selected Candidate Genes With Risk of All-Cause Mortality at Advanced Ages

Abstract Considerable efforts have been made to identify the genetic basis of human longevity, with only limited progress. One important drawback of current genetic studies is the limited knowledge of gene-environment interaction. Using 2 cohorts of long-lived individuals born in 1905 and 1915 in Denmark, we performed survival analysis to estimate risk of mortality for major candidate genes of aging and longevity and their cohort effects. Through statistical modeling that combines individual genetic and survival information with cohort-specific survival data, we estimated the relative risks of mortality from ages 95 to 103 years associated with genetic variants in apolipoprotein E (APOE), forkhead box class O3a, clusterin, and phosphatidylinositol binding clathrin assembly protein. Our analysis estimated a decreased risk of carrying the APOE$\varepsilon $4 allele (change in risk = –0.403, 95% confidence interval (CI): −0.831, 0.021; P = 0.040) in men of the later cohort, although the allele itself was harmful to survival across sexes (relative risk = 1.161, 95% CI: 1.027, 1.345; P = 0.026). We also estimated a cohort effect of increased risk for the minor allele of rs3851179 in phosphatidylinositol binding clathrin assembly protein with borderline significance (change in risk = 0.165, 95% CI: −0.010, 0.331; P = 0.052) in women. Our estimated significant cohort effect on APOE$\varepsilon $4 is indicative of the interplay between the gene and the changing environment that modulates survival at extreme ages.

Download Full-text

Gene–environment interplay in the etiology of psychosis

Psychological Medicine ◽

10.1017/s003329171700383x ◽

2018 ◽

Vol 48 (12) ◽

pp. 1925-1936 ◽

Cited By ~ 26

Author(s):

Alyson Zwicker ◽

Eileen M. Denovan-Wright ◽

Rudolf Uher

Keyword(s):

Environmental Factors ◽

Genetic Risk ◽

Environmental Exposures ◽

Response To Treatment ◽

Human Potential ◽

Specific Gene ◽

Environment Interaction ◽

Gene Environment ◽

Increased Risk ◽

The Impact

AbstractSchizophrenia and other types of psychosis incur suffering, high health care costs and loss of human potential, due to the combination of early onset and poor response to treatment. Our ability to prevent or cure psychosis depends on knowledge of causal mechanisms. Molecular genetic studies show that thousands of common and rare variants contribute to the genetic risk for psychosis. Epidemiological studies have identified many environmental factors associated with increased risk of psychosis. However, no single genetic or environmental factor is sufficient to cause psychosis on its own. The risk of developing psychosis increases with the accumulation of many genetic risk variants and exposures to multiple adverse environmental factors. Additionally, the impact of environmental exposures likely depends on genetic factors, through gene–environment interactions. Only a few specific gene–environment combinations that lead to increased risk of psychosis have been identified to date. An example of replicable gene–environment interaction is a common polymorphism in theAKT1gene that makes its carriers sensitive to developing psychosis with regular cannabis use. A synthesis of results from twin studies, molecular genetics, and epidemiological research outlines the many genetic and environmental factors contributing to psychosis. The interplay between these factors needs to be considered to draw a complete picture of etiology. To reach a more complete explanation of psychosis that can inform preventive strategies, future research should focus on longitudinal assessments of multiple environmental exposures within large, genotyped cohorts beginning early in life.

Download Full-text

Interaction between ELMO1 gene polymorphisms and environment factors on susceptibility to diabetic nephropathy in Chinese Han population

Diabetology & Metabolic Syndrome ◽

10.1186/s13098-019-0492-0 ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 1

Author(s):

Yi Hou ◽

Yong Gao ◽

Yan Zhang ◽

Si-Tong Lin ◽

Yue Yu ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Alcohol Drinking ◽

Control Group ◽

Environment Interaction ◽

Nucleotide Polymorphisms ◽

Chinese Han ◽

Gene Environment Interaction ◽

Gene Environment ◽

Increased Risk ◽

Significant Gene

Abstract Background The association of diabetic nephropathy (DN) risk with single nucleotide polymorphisms (SNPs) within Engulfment and Cell Motility 1 (ELMO1) gene and gene–environment synergistic effect have not been extensively examined in, therefore, the purpose of this study is to explore the association between multiple SNPs in ELMO1 gene, and the relationship between gene–environment synergy effect and the risk of DN. Methods Genotyping for 4 SNPs was performed with polymerase chain reaction (PCR) and following restriction fragment length polymorphism (RFLP) methods. Hardy–Weinberg balance of the control group was tested by SNPstats (online software: http://bioinfo.iconologia.net/snpstats). The best combination of four SNPs of ELMO1 gene and environmental factors was screened by GMDR model. Logistic regression was used to calculating the OR values between different genotypes of ELMO1 gene and DN. Results The rs741301-G allele and the rs10255208-GG genotype were associated with an increased risk of DN risk, adjusted ORs (95% CI) were 1.75 (1.19–2.28) and 1.41 (1.06–1.92), respectively, both p-values were < 0.001. We also found that the others SNPs-rs1345365 and rs7782979 were not significantly associated with susceptibility to DN. GMDR model found a significant gene–alcohol drinking interaction combination (p = 0.0107), but no significant gene–hypertension interaction combinations. Alcohol drinkers with rs741301-AG/GG genotype also have the highest DN risk, compared to never drinkers with rs741301-AA genotype, OR (95% CI) 3.52 (1.93–4.98). Conclusions The rs741301-G allele and the rs10255208-GG genotype, gene–environment interaction between rs741301 and alcohol drinking were all associated with increased DN risk.

Download Full-text

Extremely low birth weight babies grown up: Gene–environment interaction predicts internalizing problems in the third and fourth decades of life

Development and Psychopathology ◽

10.1017/s0954579416000511 ◽

2016 ◽

Vol 29 (3) ◽

pp. 837-843 ◽

Cited By ~ 7

Author(s):

Ayelet Lahat ◽

Ryan J. van Lieshout ◽

Karen J. Mathewson ◽

James Mackillop ◽

Saroj Saigal ◽

...

Keyword(s):

Birth Weight ◽

Low Birth Weight ◽

Internalizing Problems ◽

Self Report ◽

Extremely Low Birth Weight ◽

Environment Interaction ◽

Region Gene ◽

The Third ◽

Gene Environment ◽

Increased Risk

AbstractExtremely low birth weight (ELBW; <1000 g) infants have been exposed to stressful intrauterine and early postnatal environments. Even greater early adversity has been experienced by ELBW survivors who were also born small for gestational age (SGA; <10th percentile for GA) compared to those born appropriate for GA (AGA). ELBW survivors, particularly those born SGA, face increased risk for internalizing problems compared to normal BW (NBW; ≥2500 g) controls. Internalizing problems are related to allelic variations in the promoter region of the serotonin transporter linked polymorphic region gene (5-HTTLPR). We followed the oldest longitudinal cohort of ELBW survivors to adulthood. Participants provided buccal cells and reported on internalizing problems, using the Young Adult Self-Report when they were in their mid-20s (ELBW/SGA, N = 28; ELBW/AGA, N = 60; NBW, N = 81) and mid-30s (ELBW/SGA, N = 27; ELBW/AGA, N = 58; NBW, N = 76). The findings indicate that ELBW/SGAs carrying the 5-HTTLPR short allele reported increased internalizing problems, particularly depression, during the third and fourth decades of life. This is the first known report on gene–environment interactions predicting psychopathology among ELBW survivors. Our findings elucidate putative neurobiological pathways that underlie risk for psychopathology.

Download Full-text

Gene-Environment Interaction between the IL1RN Variants and Childhood Environmental Tobacco Smoke Exposure in Asthma Risk

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17062036 ◽

2020 ◽

Vol 17 (6) ◽

pp. 2036

Author(s):

Yongzhao Shao ◽

Yian Zhang ◽

Mengling Liu ◽

Maria-Elena Fernandez-Beros ◽

Meng Qian ◽

...

Keyword(s):

Environmental Tobacco Smoke ◽

Tobacco Smoke ◽

Early Onset ◽

Adult Population ◽

Interleukin 1 ◽

Tobacco Smoke Exposure ◽

Environment Interaction ◽

Gene Environment Interaction ◽

Gene Environment ◽

Increased Risk

(1) Background: Variants of the interleukin-1 receptor antagonist (IL1RN) gene, encoding an anti-inflammatory cytokine, are associated with asthma. Asthma is a chronic inflammatory disease of the airway influenced by interactions between genetic variants and environmental factors. We discovered a gene–environment interaction (GEI) of IL1RN polymorphisms with childhood environmental tobacco smoke (ETS) exposure on asthma susceptibility in an urban adult population. (2) Methods: DNA samples from the NYU/Bellevue Asthma Registry were genotyped for tag SNPs in IL1RN in asthma cases and unrelated healthy controls. Logistic regressions were used to study the GEI between IL1RN variants and childhood ETS exposures on asthma and early onset asthma, respectively, adjusting for population admixture and other covariates. (3) Results: Whereas the rare genotypes of IL1RN SNPs (e.g., GG in SNP rs2234678) were associated with decreased risk for asthma among those without ETS exposure (odds ratio OR = 0.215, p = 0.021), they are associated with increased risk for early onset asthma among those with childhood ETS (OR = 4.467, p = 0.021). (4) Conclusions: We identified a GEI between polymorphisms of IL1RN and childhood ETS exposure in asthma. Analysis of GEI indicated that childhood ETS exposure disrupted the protective effect of some haplotypes/genotypes of IL1RN for asthma and turned them into high-risk polymorphisms for early onset asthma.

Download Full-text

Environment and Lifestyle: Their Influence on the Risk of RA

Journal of Clinical Medicine ◽

10.3390/jcm9103109 ◽

2020 ◽

Vol 9 (10) ◽

pp. 3109

Author(s):

Carine Salliot ◽

Yann Nguyen ◽

Marie-Christine Boutron-Ruault ◽

Raphaèle Seror

Keyword(s):

Large Scale ◽

Complex Disease ◽

Dietary Factors ◽

Environment Interaction ◽

Food Groups ◽

Gene Environment Interaction ◽

Gene Environment ◽

Increased Risk ◽

Environmental Agents ◽

Hormonal Exposures

Background: Rheumatoid arthritis (RA) is a complex disease in which environmental agents are thought to interact with genetic factors that lead to triggering of autoimmunity. Methods: We reviewed environmental, hormonal, and dietary factors that have been suggested to be associated with the risk of RA. Results: Smoking is the most robust factor associated with the risk of RA, with a clear gene–environment interaction. Among other inhalants, silica may increase the risk of RA in men. There is less evidence for pesticides, pollution, and other occupational inhalants. Regarding female hormonal exposures, there is some epidemiological evidence, although not consistent in the literature, to suggest a link between hormonal factors and the risk of RA. Regarding dietary factors, available evidence is conflicting. A high consumption of coffee seems to be associated with an increased risk of RA, whereas a moderate consumption of alcohol is inversely associated with the risk of RA, and there is less evidence regarding other food groups. Dietary pattern analyses (Mediterranean diet, the inflammatory potential of the diet, or diet quality) suggested a potential benefit of dietary modifications for individuals at high risk of RA. Conclusion: To date, smoking and silica exposure have been reproducibly demonstrated to trigger the emergence of RA. However, many other environmental factors have been studied, mostly with a case-control design. Results were conflicting and studies rarely considered potential gene–environment interactions. There is a need for large scale prospective studies and studies in predisposed individuals to better understand and prevent the disease and its course.

Download Full-text

Interactions between genetic polymorphisms of glucose metabolizing genes and smoking and alcohol consumption in the risk of type 2 diabetes mellitus

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2017-0232 ◽

2017 ◽

Vol 42 (12) ◽

pp. 1316-1321 ◽

Cited By ~ 4

Author(s):

Kaiping Gao ◽

Yongcheng Ren ◽

Jinjin Wang ◽

Zichen Liu ◽

Jianna Li ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Lifestyle Factors ◽

Environment Interaction ◽

Nucleotide Polymorphisms ◽

Gene Environment ◽

Increased Risk ◽

The Impact

The impact of gene-environment interaction on diabetes remains largely unknown. We aimed to investigate if interaction between glucose metabolizing genes and lifestyle factors is associated with type 2 diabetes mellitus (T2DM). Interactions between genotypes of 4 glucose metabolizing genes (MTNR1B, KCNQ1, KLF14, and GCKR) and lifestyle factors were estimated in 722 T2DM patients and 759 controls, using multiple logistic regression. No significant associations with T2DM were detected for the single nucleotide polymorphisms of MTNR1B, KLF14 and GCKR. However, rs151290 (KCNQ1) polymorphisms were found to be associated with risk of T2DM. Compared with AA, the odds ratios (ORs) of AC or CC genotypes for developing T2DM were 1.545 (P = 0.0489) and 1.603 (P = 0.0383), respectively. In stratified analyses, the associations were stronger in smokers with CC than smokers with AA (OR = 3.668, P = 0.013); drinkers with AC (OR = 5.518, P = 0.036), CC (OR = 8.691, P = 0.0095), and AC+CC (OR = 6.764, P = 0.016) than drinkers with AA. Compared with nondrinkers with AA, drinkers who carry AC and CC had 12.072-fold (P = 0.0007) and 8.147-fold (P = 0.0052) higher risk of developing T2DM. In conclusions, rs151290 (KCNQ1) polymorphisms are associated with increased risk of T2DM, alone and especially in interaction with smoking and alcohol.

Download Full-text

Three phases of Gene × Environment interaction research: Theoretical assumptions underlying gene selection

Development and Psychopathology ◽

10.1017/s0954579420000966 ◽

2020 ◽

pp. 1-12

Author(s):

Xiaoya Zhang ◽

Jay Belsky

Keyword(s):

Candidate Genes ◽

Gene Selection ◽

Differential Susceptibility ◽

Environment Interaction ◽

Gene Environment Interaction ◽

Gene Environment ◽

Polygenic Scores ◽

Theoretical Assumptions ◽

Selection Of ◽

Three Phases

Abstract Some Gene × Environment interaction (G×E) research has focused upon single candidate genes, whereas other related work has targeted multiple genes (e.g., polygenic scores). Each approach has informed efforts to identify individuals who are either especially vulnerable to the negative effects of contextual adversity (diathesis stress) or especially susceptible to both positive and negative contextual conditions (differential susceptibility). A critical step in all such molecular G×E research is the selection of genetic variants thought to moderate environmental influences, a subject that has not received a great deal of attention in critiques of G×E research (beyond the observation of small effects of individual genes). Here we conceptually distinguish three phases of G×E work based on the selection of genes presumed to moderate environmental effects and the theoretical basis of such decisions: (a) single candidate genes, (b) composited (multiple) candidate genes, and (c) GWAS-derived polygenic scores. This illustrative, not exhaustive, review makes it clear that implicit or explicit theoretical assumptions inform gene selection in ways that have not been clearly articulated or fully appreciated.

Download Full-text

Association of Sex, Age, and Comorbidities with Mortality in COVID-19 Patients: A Systematic Review and Meta-Analysis

Intervirology ◽

10.1159/000512592 ◽

2020 ◽

pp. 1-12

Author(s):

Mohitosh Biswas ◽

Shawonur Rahaman ◽

Tapash Kumar Biswas ◽

Zahirul Haque ◽

Baharudin Ibrahim

Keyword(s):

Systematic Review ◽

Cardiovascular Disease ◽

Meta Analysis ◽

Statistical Significance ◽

Considerable Proportion ◽

Relative Risks ◽

Risk Of Mortality ◽

Increased Risk ◽

Male Patients ◽

Reduce Risk

Introduction: Although severe acute respiratory syndrome coronavirus-2 infection is causing mortality in considerable proportion of coronavirus disease-2019 (COVID-19) patients, however, evidence for the association of sex, age, and comorbidities on the risk of mortality is not well-aggregated yet. It was aimed to assess the association of sex, age, and comorbidities with mortality in COVID-2019 patients. Methods: Literatures were searched using different keywords in various databases. Relative risks (RRs) were calculated by RevMan software where statistical significance was set as p < 0.05. Results: COVID-19 male patients were associated with significantly increased risk of mortality compared to females (RR 1.86: 95% confidence interval [CI] 1.67–2.07; p < 0.00001). Patients with age ≥50 years were associated with 15.4-folds significantly increased risk of mortality compared to patients with age <50 years (RR 15.44: 95% CI 13.02–18.31; p < 0.00001). Comorbidities were also associated with significantly increased risk of mortality; kidney disease (RR 4.90: 95% CI 3.04–7.88; p < 0.00001), cereborovascular disease (RR 4.78; 95% CI 3.39–6.76; p < 0.00001), cardiovascular disease (RR 3.05: 95% CI 2.20–4.25; p < 0.00001), respiratory disease (RR 2.74: 95% CI 2.04–3.67; p < 0.00001), diabetes (RR 1.97: 95% CI 1.48–2.64; p < 0.00001), hypertension (RR 1.95: 95% CI 1.58–2.40; p < 0.00001), and cancer (RR 1.89; 95% CI 1.25–2.84; p = 0.002) but not liver disease (RR 1.64: 95% CI 0.82–3.28; p= 0.16). Conclusion: Implementation of adequate protection and interventions for COVID-19 patients in general and in particular male patients with age ≥50 years having comorbidities may significantly reduce risk of mortality associated with COVID-19.

Download Full-text

Competing causes of death in patients with neuroendocrine tumor.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e23009 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e23009-e23009

Author(s):

Soon Khai Low ◽

Bao Long Hoang Trong ◽

Nourelhoda Sami Bahaie ◽

Dimitrios Giannis ◽

Gehad Mohamed Tawfik ◽

...

Keyword(s):

Causes Of Death ◽

Heart Diseases ◽

Unknown Primary ◽

Relative Risks ◽

Time Period ◽

Risk Of Mortality ◽

Increased Risk ◽

Standardized Mortality Ratios ◽

Competing Causes ◽

Using Data

e23009 Background: Increasing survival of patients with neuroendocrine tumors (NETs) may be associated with higher risk of mortality due to causes other than the primary NET, namely the competing causes of death (CCD). Therefore, our study focused on comprehensively investigating the magnitude of the CCD on the overall NET mortality and the associated demographic, clinicopathologic and treatment factors using data from the Surveillance, Epidemiology, and End Results (SEER) database. Methods: Patients with histologically confirmed primary NET diagnosed from 1973 through 2015 were identified using the SEER-9 registries for subsequent data collection and analysis. CCD were stratified and analyzed using standardized mortality ratios (SMRs) as measures of the relative risks of mortality for NET patients in comparison to the general population in the US adjusted by age, sex and race over the same time period. Competing risk regression analysis was performed using Fine and Gray multivariate regression model. Results: A total of 29,981 NET patients were included, 5481 (42.5%) of which deceased due to CCD. Overall SMR attributed to CCD was 2.50 [95% Confidence interval (CI): 2.43–2.56]. The SMR of non-cancer CCD was 2.65 (95% CI:2.58–2.73) and that of SPN was 1.91 (95% CI:1.79–2.04). Heart diseases and other cardiovascular diseases accounted for approximately half of all non-cancer CCD. SPN mortality accounted for 16.1% of CCD, with lung and bronchus cancer being the most prevalent. Stratification by the year of diagnosis revealed a drastic rise in CCD was observed in the last decade between 2005 and 2015, during which the SMR peaked. Advanced age, black race, small intestinal and gastric NETs, and cancer-directed surgery were significantly associated with an increased risk of CCD (p<0.001). Interestingly, female sex, pancreatic NETs, recto-anal NETs, NETs of unknown primary site, race other than white and black, distant and regional spread, chemotherapy and radiotherapy were significantly associated with a decrease in the incidence of CCD. Conclusions: CCD play an increasingly significant role in NET mortality in recent years, especially for those with higher risk of CCD. Further prospective studies are needed to evaluate the association of NETs with these CCD.

Download Full-text

Oral Clefts, Maternal Smoking, and TGFA: A Meta-Analysis of Gene-Environment Interaction

The Cleft Palate-Craniofacial Journal ◽

10.1597/02-128.1 ◽

2005 ◽

Vol 42 (1) ◽

pp. 58-63 ◽

Cited By ~ 65

Author(s):

Joanna S. Zeiger ◽

Terri H. Beaty ◽

Kung-Yee Liang

Keyword(s):

Logistic Regression ◽

Maternal Smoking ◽

Meta Analysis ◽

Case Control ◽

Environment Interaction ◽

Oral Clefts ◽

Gene Environment Interaction ◽

Gene Environment ◽

Increased Risk ◽

Polytomous Logistic Regression

Objective A meta-analysis was performed to examine the association among maternal cigarette smoking, infant genotype at the Taq1 site in the transforming growth factor α (TGFA) locus, and risk of nonsyndromic oral clefts, both cleft palate (CP) and cleft lip with or without cleft palate (CL/P). Design Five published case-control studies were included in the meta-analyis. Pooled Mantel-Haenszel odds ratios (OR) and 95% confidence intervals (CIs) were computed. Gene-environment interaction was also assessed by using the pooled data in a case-only analysis and polytomous logistic regression. Results Among nonsmoking mothers, there was no evidence of any increased risk for CP if the infant carried the TGFA Taq1 C2 allele. If the mother reported smoking, however, there was an overall increased risk for CP if the infant carried the C2 allele (ORsmokers = 1.95; 95% CI = 1.22 to 3.10). TGFA genotype did not increase risk to CL/P, regardless of maternal smoking status. Polytomous logistic regression revealed a significant overall smoking effect for CL/P (OR = 1.64, 95% CI = 1.33 to 2.02) and CP (OR = 1.42, 95% CI = 1.06 to 1.90). Conclusions While maternal smoking was a consistent risk factor for both CL/P and CP across all studies, the suggestive evidence for gene-environment interaction between the infant's genotype at the Taq1 marker in TGFA and maternal smoking was limited to CP. Furthermore, evidence for such gene-environment interaction was strongest in a case-control study drawn from a birth defect registry where infants with non-cleft defects served as controls.

Download Full-text