Smoking and reverse cholesterol transport: evidence for gene-environment interaction

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66077/1/j.1399-0004.1989.tb03201.x.pd

Alcohol intake, drinking patterns, and prostate cancer risk and mortality : a 30-year prospective cohort study of Finnish twins

Purpose Alcohol intake may be associated with cancer risk, but epidemiologic evidence for prostate cancer is inconsistent. We aimed to prospectively investigate the association between midlife alcohol intake and drinking patterns with future prostate cancer risk and mortality in a population-based cohort of Finnish twins. Methods Data were drawn from the Older Finnish Twin Cohort and included 11,372 twins followed from 1981 to 2012. Alcohol consumption was assessed by questionnaires administered at two time points over follow-up. Over the study period, 601 incident cases of prostate cancer and 110 deaths from prostate cancer occurred. Cox regression was used to evaluate associations between weekly alcohol intake and binge drinking patterns with prostate cancer risk and prostate cancer-specific mortality. Within-pair co-twin analyses were performed to control for potential confounding by shared genetic and early environmental factors. Results Compared to light drinkers ( Conclusion Heavy regular alcohol consumption and binge drinking patterns may be associated with increased prostate cancer risk, while abstinence may be associated with increased risk of prostate cancer-specific mortality compared to light alcohol consumption.Peer reviewe

The heritability of BMI varies across the range of BMI-a heritability curve analysis in a twin cohort

Background The heritability of traits such as body mass index (BMI), a measure of obesity, is generally estimated using family and twin studies, and increasingly by molecular genetic approaches. These studies generally assume that genetic effects are uniform across all trait values, yet there is emerging evidence that this may not always be the case. Method/Subjects This paper analyzes twin data using a recently developed measure of heritability called the heritability curve. Under the assumption that trait values in twin pairs are governed by a flexible Gaussian mixture distribution, heritability curves may vary across trait values. The data consist of repeated measures of BMI on 1506 monozygotic (MZ) and 2843 like-sexed dizygotic (DZ) adult twin pairs, gathered from multiple surveys in older Finnish Twin Cohorts. Results The heritability curve and BMI value-specific MZ and DZ pairwise correlations were estimated, and these varied across the range of BMI. MZ correlations were highest at BMI values from 21 to 24, with a stronger decrease for women than for men at higher values. Models with additive and dominance effects fit best at low and high BMI values, while models with additive genetic and common environmental effects fit best in the normal range of BMI. Conclusions We demonstrate that twin and molecular genetic studies need to consider how genetic effects vary across trait values. Such variation may reconcile findings of traits with high heritability and major differences in mean values between countries or over time.Peer reviewe

Sleep disruption, chronotype, shift work, and prostate cancer risk and mortality : a 30-year prospective cohort study of Finnish twins

Sleep disruption and shift work have been associated with cancer risk, but epidemiologic evidence for prostate cancer remains limited. We aimed to prospectively investigate the association between midlife sleep- and circadian-related parameters and later prostate cancer risk and mortality in a population-based cohort of Finnish twins. Data were drawn from the Older Finnish Twin Cohort and included 11,370 twins followed from 1981 to 2012. Over the study period, 602 incident cases of prostate cancer and 110 deaths from prostate cancer occurred. Cox regression was used to evaluate associations between midlife sleep duration, sleep quality, chronotype, and shift work with prostate cancer risk and prostate cancer-specific mortality. Within-pair co-twin analyses were employed to account for potential familial confounding. Compared to "definite morning" types, "somewhat evening" types had a significantly increased risk of prostate cancer (HR 1.3; 95 % CI 1.1, 1.6). Chronotype significantly modified the relationship between shift work and prostate cancer risk (p-interaction <0.001). We found no significant association between sleep duration, sleep quality, or shift work and prostate cancer risk in the overall analyses and no significant association between any sleep- or circadian-related parameter and risk in co-twin analyses. Neither sleep- nor circadian-related parameters were significantly associated with prostate cancer-specific mortality. The association between sleep disruption, chronotype, and shift work with prostate cancer risk and mortality has never before been studied in a prospective study of male twins. Our findings suggest that chronotype may be associated with prostate cancer risk and modify the association between shift work and prostate cancer risk. Future studies of circadian disruption and prostate cancer should account for this individual-level characteristic.Peer reviewe

IMI - Myopia Genetics Report

The knowledge on the genetic background of refractive error and myopia has expanded dramatically in the past few years. This white paper aims to provide a concise summary of current genetic findings and defines the direction where development is needed. We performed an extensive literature search and conducted informal discussions with key stakeholders. Specific topics reviewed included common refractive error, any and high myopia, and myopia related to syndromes. To date, almost 200 genetic loci have been identified for refractive error and myopia, and risk variants mostly carry low risk but are highly prevalent in the general population. Several genes for secondary syndromic myopia overlap with those for common myopia. Polygenic risk scores show overrepresentation of high myopia in the higher deciles of risk. Annotated genes have a wide variety of functions, and all retinal layers appear to be sites of expression. The current genetic findings offer a world of new molecules involved in myopiagenesis. As the missing heritability is still large, further genetic advances are needed. This Committee recommends expanding large-scale, in-depth genetic studies using complementary big data analytics, consideration of gene-environment effects by thorough measurement of environmental exposures, and focus on subgroups with extreme phenotypes and high familial occurrence. Functional characterization of associated variants is simultaneously needed to bridge the knowledge gap between sequence variance and consequence for eye growth.Peer reviewe

An integrative machine learning approach to discovering multi-level molecular mechanisms of obesity using data from monozygotic twin pairs

We combined clinical, cytokine, genomic, methylation and dietary data from 43 young adult monozygotic twin pairs (aged 22-36 years, 53% female), where 25 of the twin pairs were substantially weight discordant (delta body mass index > 3 kg m(-2)). These measurements were originally taken as part of the TwinFat study, a substudy of The Finnish Twin Cohort study. These five large multivariate datasets (comprising 42, 71, 1587, 1605 and 63 variables, respectively) were jointly analysed using an integrative machine learning method called group factor analysis (GFA) to offer new hypotheses into the multi-molecular-level interactions associated with the development of obesity. New potential links between cytokines and weight gain are identified, as well as associations between dietary, inflammatory and epigenetic factors. This encouraging case study aims to enthuse the research community to boldly attempt new machine learning approaches which have the potential to yield novel and unintuitive hypotheses. The source code of the GFA method is publically available as the R package GFA.Peer reviewe

The Genetic Background of Metabolic Trait Clusters in Children and Adolescents

Background: It is well known that metabolic risk factors of cardiovascular diseases are correlated, but the background of this clustering in children is more poorly known than in adults. Thus, we studied the contribution of genetic and environmental factors to the clustering of metabolic traits in childhood and adolescence. Data and Methods: Nine metabolic traits were measured in 214 complete twin pairs aged 3-18 years in the Autonomous Region of Madeira, Portugal, in 2007 and 2008. The variation of and covariations between the traits were decomposed into genetic and environmental components by using classical genetic twin modeling. Results: A model, including additive genetic and environmental factors unique for each twin individual, explained the variation of metabolic factors well. Under this model, the heritability estimates varied from 0.47 (systolic blood pressure in children under 12 years of age) to 0.91 (high-density lipoprotein [HDL] cholesterol in adolescents 12 years of age or older). The most systematic correlations were found between adiposity (body mass index and waist circumference) and blood lipids (HDL cholesterol, low-density lipoprotein cholesterol, and triglycerides), as well as blood pressure. These correlations were mainly explained by common genetic factors. Conclusions: Our results suggest that obesity, in particular, is behind the clustering of metabolic factors in children and adolescents. Both general and abdominal obesity partly share the same genetic background as blood lipids and blood pressure. Obesity prevention early in childhood is important in reducing the risk of metabolic diseases in adulthood.Peer reviewe

Genome-wide association study in Finnish twins highlights the connection between nicotine addiction and neurotrophin signaling pathway

The heritability of nicotine dependence based on family studies is substantial. Nevertheless, knowledge of the underlying genetic architecture remains meager. Our aim was to identify novel genetic variants responsible for interindividual differences in smoking behavior. We performed a genome-wide association study on 1715 ever smokers ascertained from the population-based Finnish Twin Cohort enriched for heavy smoking. Data imputation used the 1000 Genomes Phase I reference panel together with a whole genome sequence-based Finnish reference panel. We analyzed three measures of nicotine addiction-smoking quantity, nicotine dependence and nicotine withdrawal. We annotated all genome-wide significant SNPs for their functional potential. First, we detected genome-wide significant association on 16p12 with smoking quantity (P = 8.5 x 10(-9)), near CLEC19A. The lead-SNP stands 22 kb from a binding site for NF-kappa B transcription factors, which play a role in the neurotrophin signaling pathway. However, the signal was not replicated in an independent Finnish population-based sample, FINRISK (n = 6763). Second, nicotine withdrawal showed association on 2q21 in an intron of TMEM163 (P = 2.1 x 10(-9)), and on 11p15 (P = 6.6 x 10(-8)) in an intron of AP2A2, and P = 4.2 x 10(-7) for a missense variant in MUC6, both involved in the neurotrophin signaling pathway). Third, association was detected on 3p22.3 for maximum number of cigarettes smoked per day (P = 3.1 x 10(-8)) near STAC. Associating CLEC19A and TMEM163 SNPs were annotated to influence gene expression or methylation. The neurotrophin signaling pathway has previously been associated with smoking behavior. Our findings further support the role in nicotine addiction.Peer reviewe