A New Look at Genetic and Environmental Architecture on Lipids Using Non-Normal Structural Equation Modeling in Male Twins: The NHLBI Twin Study.

This study examined genetic and environmental influences on the lipid concentrations of 1028 male twins using the novel univariate non-normal structural equation modeling (nnSEM) ADCE and ACE models. In the best fitting nnSEM ADCE model that was also better than the nnSEM ACE model, additive genetic factors (A) explained 4%, dominant genetic factors (D) explained 17%, and common (C) and unique (E) environmental factors explained 47% and 33% of the total variance of high-density lipoprotein cholesterol (HDL-C). The percentage of variation explained for other lipids was 0% (A), 30% (D), 34% (C) and 37% (E) for low-density lipoprotein cholesterol (LDL-C); 30, 0, 31 and 39% for total cholesterol; and 0, 31, 12 and 57% for triglycerides. It was concluded that additive and dominant genetic factors simultaneously affected HDL-C concentrations but not other lipids. Common and unique environmental factors influenced concentrations of all lipids.

Circulating MicroRNAs and Life Expectancy Among Identical Twins.

Human life expectancy is influenced not only by longevity assurance mechanisms and disease susceptibility loci but also by the environment, gene-environment interactions, and chance. MicroRNAs (miRNAs) are a class of small noncoding RNAs closely related to genes. Circulating miRNAs have been shown as promising noninvasive biomarkers in the development of many pathophysiological conditions. However, the concentration of miRNA in the circulation may also be affected by environmental factors. We used a next-generation sequencing platform to assess the association of circulating miRNA with life expectancy, for which deaths are due to all causes independent of genes. In addition, we showed that miRNAs are present in 41-year archived plasma samples, which may be useful for both life expectancy and all-cause mortality risk assessment. Plasma miRNAs from nine identical male twins were profiled using next-generation sequencing. The average absolute difference in the minimum life expectancy was 9.68 years. Intraclass correlation coefficients were above 0.4 for 50% of miRNAs. Comparing deceased twins with their alive co-twin brothers, the concentrations were increased for 34 but decreased for 30 miRNAs. Identical twins discordant in life expectancy were dissimilar in the majority of miRNAs, suggesting that environmental factors are pivotal in miRNAs related to life expectancy.

Midlife moderation-quantified healthy diet and 40-year mortality risk from CHD: the prospective National Heart, Lung, and Blood Institute Twin Study.

It is unknown whether influences of midlife whole diet on the long-term CHD mortality risk are independent of genetic and common environmental factors or familial predisposition. We addressed this question prospectively using data from the National Heart, Lung, and Blood Institute Twin Study. We included 910 male twins who were middle-aged and had usual diet assessed with nutritionist-administered, cross-checked dietary history interview at baseline (1969-1973). Moderation-quantified healthy diet (MQHD), a dietary pattern, was created to evaluate a whole diet. Primary outcome was time-to-CHD death. Hazard ratios (HR) were estimated using frailty survival model. Known CHD risk factors were controlled. During the follow-up of 40 years through 31 December 2009, 113 CHD deaths, 198 total cardiovascular deaths and 610 all-cause deaths occurred. In the entire cohort, the multivariable-adjusted HR for the overall association (equivalent to a general population association) was 0·76 (95 % CI 0·66, 0·88) per 10-unit increment in the MQHD score for CHD, and the multivariable-adjusted HR for a twin with a MQHD score ten units higher than his co-twin brother was 0·79 (95 % CI 0·64, 0·96, P=0·02) for CHD independent of familial predisposition. Similar results were found for a slightly more food-specified alternative moderation-quantified healthy diet (aMQHD). The between-pair association (reflecting familial influence) was significant for CHD for both MQHD and aMQHD. It is concluded that associations of MQHD and aMQHD with a lower long-term CHD mortality risk are both nutritionally and familially affected, supporting their use for dietary planning to prevent CHD mortality.

Genome-Wide Association of the Laboratory-Based Nicotine Metabolite Ratio in Three Ancestries.

INTRODUCTION: Metabolic enzyme variation and other patient and environmental characteristics influence smoking behaviors, treatment success, and risk of related disease. Population-specific variation in metabolic genes contributes to challenges in developing and optimizing pharmacogenetic interventions. We applied a custom genome-wide genotyping array for addiction research (Smokescreen), to three laboratory-based studies of nicotine metabolism with oral or venous administration of labeled nicotine and cotinine, to model nicotine metabolism in multiple populations. The trans-3'-hydroxycotinine/cotinine ratio, the nicotine metabolite ratio (NMR), was the nicotine metabolism measure analyzed. METHODS: Three hundred twelve individuals of self-identified European, African, and Asian American ancestry were genotyped and included in ancestry-specific genome-wide association scans (GWAS) and a meta-GWAS analysis of the NMR. We modeled natural-log transformed NMR with covariates: principal components of genetic ancestry, age, sex, body mass index, and smoking status. RESULTS: African and Asian American NMRs were statistically significantly (P values ≤ 5E-5) lower than European American NMRs. Meta-GWAS analysis identified 36 genome-wide significant variants over a 43 kilobase pair region at CYP2A6 with minimum P = 2.46E-18 at rs12459249, proximal to CYP2A6. Additional minima were located in intron 4 (rs56113850, P = 6.61E-18) and in the CYP2A6-CYP2A7 intergenic region (rs34226463, P = 1.45E-12). Most (34/36) genome-wide significant variants suggested reduced CYP2A6 activity; functional mechanisms were identified and tested in knowledge-bases. Conditional analysis resulted in intergenic variants of possible interest (P values < 5E-5). CONCLUSIONS: This meta-GWAS of the NMR identifies CYP2A6 variants, replicates the top-ranked single nucleotide polymorphism from a recent Finnish meta-GWAS of the NMR, identifies functional mechanisms, and provides pan-continental population biomarkers for nicotine metabolism. IMPLICATIONS: This multiple ancestry meta-GWAS of the laboratory study-based NMR provides novel evidence and replication for genome-wide association of CYP2A6 single nucleotide and insertion-deletion polymorphisms. We identify three regions of genome-wide significance: proximal, intronic, and distal to CYP2A6. We replicate the top-ranking single nucleotide polymorphism from a recent GWAS of the NMR in Finnish smokers, identify a functional mechanism for this intronic variant from in silico analyses of RNA-seq data that is consistent with CYP2A6 expression measured in postmortem lung and liver, and provide additional support for the intergenic region between CYP2A6 and CYP2A7.

Genetic and environmental influences on the prospective correlation between systemic inflammation and coronary heart disease death in male twins.

OBJECTIVE: Because of lack of evidence, we aimed to examine to what degree low-grade systemic inflammation and coronary heart disease (CHD) death shared common genetic and environmental substrates. APPROACH AND RESULTS: From the 41-year prospective National Heart, Lung, and Blood Institute Twin Study, we included 950 middle-aged male twins at baseline (1969-1973). Low-grade systemic inflammation was measured with plasma levels of interleukin-6 (IL-6) and C-reactive protein. Univariate and bivariate structural equation models were used, adjusted for a risk score for CHD death. The score-adjusted heritability was 19% for IL-6, 27% for C-reactive protein, and 22% for CHD death. The positive phenotypic correlation of IL-6 with CHD death (radjusted=0.27; 95% confidence interval [CI], 0.08-0.43) was driven by additive genetic factors (contribution [relative contribution], 0.30 [111%]) but attenuated by unique environment (-0.03 [-11%]). The genetic correlation between IL-6 and CHD death was 0.74 (95% CI, 0.21-1.00), whereas the unique environmental correlation was -0.05 (95% CI, -0.35 to 0.25). The proportion of genetic variance for CHD death shared with that for IL-6 was 74%. The phenotypic correlation of C-reactive protein with CHD death (radjusted=0.10; 95% CI, -0.02 to 0.22) was explained by additive genetic factors (0.20 [149%]) but was attenuated by the unique environment (-0.09 [-49%]). The genetic correlation of C-reactive protein with CHD death was 0.63 (95% CI, -0.07 to 1.00), whereas the unique environmental correlation was -0.07 (95% CI, -0.29 to 0.17). CONCLUSIONS: Low-grade systemic inflammation, measured by IL-6, and long-term CHD death share moderate genetic substrates that augment both traits.

Total Exposure Study Analysis consortium: a cross-sectional study of tobacco exposures.

BACKGROUND: The Total Exposure Study was a stratified, multi-center, cross-sectional study designed to estimate levels of biomarkers of tobacco-specific and non-specific exposure and of potential harm in U.S. adult current cigarette smokers (≥one manufactured cigarette per day over the last year) and tobacco product non-users (no smoking or use of any nicotine containing products over the last 5 years). The study was designed and sponsored by a tobacco company and implemented by contract research organizations in 2002-2003. Multiple analyses of smoking behavior, demographics, and biomarkers were performed. Study data and banked biospecimens were transferred from the sponsor to the Virginia Tobacco and Health Research Repository in 2010, and then to SRI International in 2012, for independent analysis and dissemination. METHODS: We analyzed biomarker distributions overall, and by biospecimen availability, for comparison with existing studies, and to evaluate generalizability to the entire sample. We calculated genome-wide statistical power for a priori hypotheses. We performed clinical chemistries, nucleic acid extractions and genotyping, and report correlation and quality control metrics. RESULTS: Vital signs, clinical chemistries, and laboratory measures of tobacco specific and non-specific toxicants are available from 3585 current cigarette smokers, and 1077 non-users. Peripheral blood mononuclear cells, red blood cells, plasma and 24-h urine biospecimens are available from 3073 participants (2355 smokers and 719 non-users). In multivariate analysis, participants with banked biospecimens were significantly more likely to self-identify as White, to be older, to have increased total nicotine equivalents per cigarette, decreased serum cotinine, and increased forced vital capacity, compared to participants without. Effect sizes were small (Cohen's d-values ≤ 0.11). Power for a priori hypotheses was 57 % in non-Hispanic Black (N = 340), and 96 % in non-Hispanic White (N = 1840), smokers. All DNA samples had genotype completion rates ≥97.5 %; 68 % of RNA samples yielded RIN scores ≥6.0. CONCLUSIONS: Total Exposure Study clinical and laboratory assessments and biospecimens comprise a unique resource for cigarette smoke health effects research. The Total Exposure Study Analysis Consortium seeks to perform molecular studies in multiple domains and will share data and analytic results in public repositories and the peer-reviewed literature. Data and banked biospecimens are available for independent or collaborative research.

Organic cation transporter variation and response to smoking cessation therapies.

INTRODUCTION: We evaluated chr6q25.3 organic cation transporter gene (SLC22A1, SLC22A2, SLC22A3) variation and response to smoking cessation therapies. The corresponding proteins are low-affinity transporters of choline, acetylcholine and monoamines, and smoking cessation pharmacotherapies expressed in multiple tissues. METHODS: We selected 7 common polymorphisms for mega-regression analysis. We assessed additive model association of polymorphisms with 7-day point prevalence abstinence overall and by assigned pharmacotherapy at end of treatment and at 6 months among European-ancestry participants of 7 randomized controlled trials adjusted for demographic, population genetic, and trial covariates. RESULTS: Initial results were obtained in 6 trials with 1,839 participants. Nominally statistically significant associations of 2 SLC22A2 polymorphisms were observed: (1) with rs316019 at 6 months, overall ([c.808T>G; p.Ser270Ala], OR = 1.306, 95% CI = 1.034-1.649, p = .025), and among those randomized to nicotine replacement therapy (NRT) (OR = 1.784, 95% CI = 1.072-2.970, p = .026); and (2) with rs316006 (c.1502-529A>T) among those randomized to varenicline (OR = 1.420, 95% CI = 1.038-1.944, p = .028, OR = 1.362, 95% CI = 1.001-1.853, p = .04) at end of treatment and 6 months. Individuals randomized to NRT from a seventh trial were genotyped for rs316019; rs316019 was associated with a nominally statistically significant effect on abstinence overall at 6 months among 2,233 participants (OR = 1.249, 95% CI = 1.007-1.550, p = .043). CONCLUSIONS: The functional OCT2 Ser270Ala polymorphism is nominally statistically significantly associated with abstinence among European-ancestry treatment-seeking smokers after adjustments for pharmacotherapy, demographics, population genetics, and without adjustment for multiple testing of 7 SNPs. Replication of these preliminary findings in additional randomized controlled trials of smoking cessation therapies and from multiple continental populations would describe another pharmacogenetic role for SLC22A2/OCT2.

Nicotinic acetylcholine receptor variation and response to smoking cessation therapies.

OBJECTIVE: To evaluate the association of nicotinic acetylcholine receptor (nAChR) single nucleotide polymorphism (SNP) with 7-day point prevalence abstinence (abstinence) in randomized clinical trials of smoking cessation therapies in individuals grouped by pharmacotherapy randomization to inform the development of personalized smoking cessation therapy. MATERIALS AND METHODS: We quantified association of four SNPs at three nAChRs with abstinence in eight randomized clinical trials. Participants were 2633 outpatient treatment-seeking, self-identified European ancestry individuals smoking at least 10 cigarettes/day, recruited through advertisement, prescribed pharmacotherapy, and provided with behavioral therapy. Interventions included nicotine replacement therapy (NRT), bupropion, varenicline, placebo (PLA), or combined NRT and bupropion, and five modes of group and individual behavioral therapy. Outcome measures tested in multivariate logistic regression were end of treatment and 6 month (6MO) abstinence, with demographic, behavioral, and genetic covariates. RESULTS: 'Risk' alleles previously associated with smoking heaviness were significantly (P<0.05) associated with reduced abstinence in the PLA pharmacotherapy group (PG) at 6MO [for rs588765, odds ratio (95% confidence interval) 0.41 (0.17-0.99)], and at end of treatment and at 6MO [for rs1051730, 0.42 (0.19-0.93) and 0.31 (0.12-0.80)], and with increased abstinence in the NRT PG at 6MO [for rs588765, 2.07 (1.11-3.87) and for rs1051730, 2.54 (1.29-4.99)]. We observed significant heterogeneity in rs1051730 effects (F=2.48, P=0.021) between PGs. CONCLUSION: chr15q25.1 nAChR SNP risk alleles for smoking heaviness significantly increase relapse with PLA treatment and significantly increase abstinence with NRT. These SNP-PG associations require replication in independent samples for validation, and testing in larger sample sizes to evaluate whether similar effects occur in other PGs.

The Twin Research Registry at SRI International.

The Twin Research Registry (TRR) at SRI International is a community-based registry of twins established in 1995 by advertising in local media, mainly on radio stations and in newspapers. As of August 2012, there are 3,120 same- and opposite-sex twins enrolled; 86% are 18 years of age or older (mean age 44.9 years, SD 16.9 years) and 14% less than 18 years of age (mean age 8.9 years, SD 4.5); 67% are female, and 62% are self-reported monozygotic (MZ). More than 1,375 twins have participated in studies over the last 15 years in collaboration with the University of California Medical Center in San Francisco, the University of Texas MD Anderson Cancer Center, and the Stanford University School of Medicine. Each twin completes a registration form with basic demographic information either online at the TRR Web site or during a telephone interview. Contact is maintained with members by means of annual newsletters and birthday cards. The managers of the TRR protect the confidentiality of twin data with established policies; no information is given to other researchers without prior permission from the twins; and all methods and procedures are reviewed by an Institutional Review Board. Phenotypes studied thus far include those related to nicotine metabolism, mutagen sensitivity, pain response before and after administration of an opioid, and a variety of immunological responses to environmental exposures, including second-hand smoke and vaccination for seasonal influenza virus and Varicella zoster virus. Twins in the TRR have participated in studies of complex, clinically relevant phenotypes that would not be feasible to measure in larger samples.

Depression and self-focused language in structured interviews with older men.

The association between depression and self-focused language has been found to varying extents across studies. The presence or absence of the association may depend on the communicative context. Based on Beck's depression model, a broad, evaluative self-focused question was predicted more likely to elicit a stronger association than a full interview containing a more heterogeneous question set of items. The spontaneous speech obtained during structured interviews of 26 depressed and nondepressed older men, an as-yet little studied population, was analyzed. Results were consistent with the hypothesis that association between self-focused language and depression was demonstrated in the target question but not across the entire interview. The results may explain some of the aforementioned discrepancies in prior studies.

Whole-Genome Differentially Hydroxymethylated DNA Regions among Twins Discordant for Cardiovascular Death.

Epigenetics is a mechanism underlying cardiovascular disease. It is unknown whether DNA hydroxymethylation is prospectively associated with the risk for cardiovascular death independent of germline and common environment. Male twin pairs middle-aged in 1969-1973 and discordant for cardiovascular death through December 31, 2014, were included. Hydroxymethylation was quantified in buffy coat DNA collected in 1986-1987. The 1893 differentially hydroxymethylated regions (DhMRs) were identified after controlling for blood leukocyte subtypes and age among 12 monozygotic (MZ) pairs (Benjamini-Hochberg False Discovery Rate < 0.01), of which the 102 DhMRs were confirmed with directionally consistent log2-fold changes and p < 0.01 among additional 7 MZ pairs. These signature 102 DhMRs, independent of the germline, were located on all chromosomes except for chromosome 21 and the Y chromosome, mainly within/overlapped with intergenic regions and introns, and predominantly hyper-hydroxymethylated. A binary linear classifier predicting cardiovascular death among 19 dizygotic pairs was identified and equivalent to that generated from MZ via the 2D transformation. Computational bioinformatics discovered pathways, phenotypes, and DNA motifs for these DhMRs or their subtypes, suggesting that hydroxymethylation was a pathophysiological mechanism underlying cardiovascular death that might be influenced by genetic factors and warranted further investigations of mechanisms of these signature regions in vivo and in vitro.

Validity of recall of tobacco use in two prospective cohorts.

This project studied the convergent validity of current recall of tobacco-related health behaviors, compared with prospective self-report collected earlier at two sites. Cohorts were from the Oregon Research Institute at Eugene (N = 346, collected 19.5 years earlier) and the University of Pittsburgh, Pennsylvania (N = 294, collected 3.9 years earlier). Current recall was examined through computer-assisted interviews with the Lifetime Tobacco Use Questionnaire from 2005 through 2008. Convergent validity estimates demonstrated variability. Validity estimates of some tobacco use measures were significant for Oregon subjects (age at first cigarette, number of cigarettes/day, quit attempts yes/no and number of attempts, and abstinence symptoms at quitting; all P < 0.03). Validity estimates of Pittsburgh subjects' self-reports of tobacco use and abstinence symptoms were significant (P < 0.001) for all tobacco use and abstinence symptoms and for responses to initial use of tobacco. These findings support the utility of collecting recalled self-report information for reconstructing salient lifetime health behaviors and underscore the need for careful interpretation.

Test-retest reliability of web-based retrospective self-report of tobacco exposure and risk.

BACKGROUND: Retrospectively collected data about the development and maintenance of behaviors that impact health are a valuable source of information. Establishing the reliability of retrospective measures is a necessary step in determining the utility of that methodology and in studying behaviors in the context of risk and protective factors. OBJECTIVE: The goal of this study was to examine the reliability of self-report of a specific health-affecting behavior, tobacco use, and its associated risk and protective factors as examined with a Web-based questionnaire. METHODS: Core tobacco use and risk behavior questions in the Lifetime Tobacco Use Questionnaire-a closed, invitation-only, password-controlled, Web-based instrument-were administered at a 2-month test-retest interval to a convenience sample of 1229 respondents aged 18 to 78 years. Tobacco use items, which covered cigarettes, cigars, smokeless tobacco, and pipe tobacco, included frequency of use, amount used, first use, and a pack-years calculation. Risk-related questions included family history of tobacco use, secondhand smoke exposure, alcohol use, and religiosity. RESULTS: Analyses of test-retest reliability indicated modest (.30 to .49), moderate (.50 to .69), or high (.70 to 1.00) reliability across nearly all questions, with minimal reliability differences in analyses by sex, age, and income grouping. Most measures of tobacco use history showed moderate to high reliability, particularly for age of first use, age of first weekly and first daily smoking, and age at first or only quit attempt. Some measures of family tobacco use history, secondhand smoke exposure, alcohol use, and religiosity also had high test-retest reliability. Reliability was modest for subjective response to first use. CONCLUSIONS: The findings reflect the stability of retrospective recall of tobacco use and risk factor self-report responses in a Web-questionnaire context. Questions that are designed and tested with psychometric scrutiny can yield reliable results in a Web setting.

Genetic association of daytime sleepiness and depressive symptoms in elderly men.

STUDY OBJECTIVES: Clinical rating scales, self-reports, and diagnostic instruments measuring depression often inquire about daytime fatigue and tiredness. Excessive daytime sleepiness refers specifically to the tendency to feel drowsy or fall asleep during waking hours and is considered conceptually and operationally independent from the fatigue, tiredness, and sleeping difficulties that characterize depression. The objective of this study was to examine whether daytime sleepiness assessed using the Epworth Sleepiness Scale and depressive symptoms assessed using the Geriatric Depression Scale are genetically related. DESIGN/SETTING: Cross-sectional data were collected via questionnaire in 1998-2000. PARTICIPANTS: Population-based sample of more than 5,000 male elderly twins aged 69-82 years old at the time of survey. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: There was evidence for moderate heritability for daytime sleepiness (36.9%) and depressive symptoms (30.7%). There was evidence for a significant genetic correlation (0.40) between the 2 measures, suggesting that both daytime sleepiness and depressive symptoms have some genes in common. The genetic correlation was reduced to 0.21 after adjustment for several covariates. CONCLUSIONS: The results showed that the often reported phenotypic correlation between daytime sleepiness and depressive symptoms is due, in part, to modest overlap in genetic factors, at least in elderly men. However, the majority of individual variation in daytime sleepiness and depressive symptoms, in particular after covariate adjustment, was attributable to individual-specific environmental factors.

Genetic and environmental sources of variation in heart rate response to infused nicotine in twins.

The heart rate response to nicotine may be an important component of the process leading to dependence. The present study is the first to determine the extent to which genetic and environmental sources play a role in various components of the heart rate response. One hundred and ten monozygotic and 29 dizygotic twin pairs received an i.v. infusion of nicotine and cotinine over 30 min. Before, during, and for 30 min after infusion, heart rate was measured via an electronic monitor. The clearance of nicotine was determined as a measure of the rate of nicotine metabolism. Average resting heart rate before infusion was 64.7 beats per minutes (bpm), and at the termination of infusion, heart rate had increased to an average of 72.7 bpm. At 30 min after infusion, heart rate had decreased to 67.5 bpm. Age, current smoking status, body mass index, and nicotine clearance were associated significantly with heart rate levels over the full 60 min of measurement. After adjustment for several covariates, including dose of administered nicotine and rate of nicotine clearance, the variance in several characteristics of the heart rate response curve was examined for the relative contribution from genetic and environmental sources. In the total sample, as much as 30.3% of the variance in the acceleration of heart rate was due to additive genetic sources. In nonsmokers, 34.8% and 31.0% of variance in the acceleration and deceleration of heart rate, respectively, was due to genetic sources. Heart rate acceleration and deceleration may be a reflection of central nervous system responsiveness to nicotine. The contribution from genetic sources to heart rate response characteristics should be investigated further as a potential endophenotype for use in genetic studies of nicotine dependence.

Does the sex of one's co-twin affect height and BMI in adulthood? A study of dizygotic adult twins from 31 cohorts.

BACKGROUND: The comparison of traits in twins from opposite-sex (OS) and same-sex (SS) dizygotic twin pairs is considered a proxy measure of prenatal hormone exposure. To examine possible prenatal hormonal influences on anthropometric traits, we compared mean height, body mass index (BMI), and the prevalence of being overweight or obese between men and women from OS and SS dizygotic twin pairs. METHODS: The data were derived from the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) database, and included 68,494 SS and 53,808 OS dizygotic twin individuals above the age of 20 years from 31 twin cohorts representing 19 countries. Zygosity was determined by questionnaires or DNA genotyping depending on the study. Multiple regression and logistic regression models adjusted for cohort, age, and birth year with the twin type as a predictor were carried out to compare height and BMI in twins from OS pairs with those from SS pairs and to calculate the adjusted odds ratios and 95% confidence intervals for being overweight or obese. RESULTS: OS females were, on average, 0.31 cm (95% confidence interval (CI) 0.20, 0.41) taller than SS females. OS males were also, on average, taller than SS males, but this difference was only 0.14 cm (95% CI 0.02, 0.27). Mean BMI and the prevalence of overweight or obesity did not differ between males and females from SS and OS twin pairs. The statistically significant differences between OS and SS twins for height were small and appeared to reflect our large sample size rather than meaningful differences of public health relevance. CONCLUSIONS: We found no evidence to support the hypothesis that prenatal hormonal exposure or postnatal socialization (i.e., having grown up with a twin of the opposite sex) has a major impact on height and BMI in adulthood.

Higher usual alcohol consumption was associated with a lower 41-y mortality risk from coronary artery disease in men independent of genetic and common environmental factors: the prospective NHLBI Twin Study.

BACKGROUND: Evidence that alcohol consumption is inversely associated with long-term coronary artery disease (CAD) mortality independent of genetic and early life environmental factors is lacking. OBJECTIVE: We evaluated whether alcohol consumption was prospectively associated with CAD mortality risk independent of familial factors. DESIGN: In total, 843 male twins (396 pairs and 51 unpaired twins) aged 42-55 y (mean: 48 y) without baseline CAD reported beer, wine, and spirits consumption at baseline (1969-1973) and were followed up to 2010 in the prospective National Heart, Lung, and Blood Institute Twin Study. Data on usual alcohol consumption over the past year were collected. Outcome was time to event, where the primary event was death from CAD and secondary events were death from cardiovascular disease and all causes. HRs were estimated by using frailty survival models, both overall and within-pair. RESULTS: There were 129 CAD deaths and 219 cardiovascular deaths during 41 y of follow-up. In the whole cohort, after adjustment for caloric intake and cardiovascular disease risk factors, overall HRs per 10-g increment in alcohol intake were 0.94 (95% CI: 0.89, 0.98) for CAD and 0.97 (95% CI: 0.93, 1.00) for cardiovascular mortality. The within-pair adjusted HRs for a twin with 10-g higher daily alcohol consumption than his co-twin were 0.90 (95% CI: 0.84, 0.97) for CAD and 0.95 (95% CI: 0.90, 1.00) for cardiovascular disease mortality in the cohort pooled by zygosity, which remained similar among monozygotic twins. All 3 beverage types tended to be associated with lower CAD mortality risk within-pair to a similar degree. Alcohol consumption was not associated with total mortality risk overall or within-pair. CONCLUSION: Higher usual alcohol consumption is associated with lower CAD mortality risk, independent of germline and early life environment and adulthood experience shared among twins, supporting a possible causal role of alcohol consumption in lowering CAD death risk. This trial was registered at clinicaltrials.gov as NCT00005124.

Drug Metabolizing Enzyme and Transporter Gene Variation, Nicotine Metabolism, Prospective Abstinence, and Cigarette Consumption.

The Nicotine Metabolite Ratio (NMR, ratio of trans-3'-hydroxycotinine and cotinine), has previously been associated with CYP2A6 activity, response to smoking cessation treatments, and cigarette consumption. We searched for drug metabolizing enzyme and transporter (DMET) gene variation associated with the NMR and prospective abstinence in 2,946 participants of laboratory studies of nicotine metabolism and of clinical trials of smoking cessation therapies. Stage I was a meta-analysis of the association of 507 common single nucleotide polymorphisms (SNPs) at 173 DMET genes with the NMR in 449 participants of two laboratory studies. Nominally significant associations were identified in ten genes after adjustment for intragenic SNPs; CYP2A6 and two CYP2A6 SNPs attained experiment-wide significance adjusted for correlated SNPs (CYP2A6 PACT=4.1E-7, rs4803381 PACT=4.5E-5, rs1137115, PACT=1.2E-3). Stage II was mega-regression analyses of 10 DMET SNPs with pretreatment NMR and prospective abstinence in up to 2,497 participants from eight trials. rs4803381 and rs1137115 SNPs were associated with pretreatment NMR at genome-wide significance. In post-hoc analyses of CYP2A6 SNPs, we observed nominally significant association with: abstinence in one pharmacotherapy arm; cigarette consumption among all trial participants; and lung cancer in four case:control studies. CYP2A6 minor alleles were associated with reduced NMR, CPD, and lung cancer risk. We confirmed the major role that CYP2A6 plays in nicotine metabolism, and made novel findings with respect to genome-wide significance and associations with CPD, abstinence and lung cancer risk. Additional multivariate analyses with patient variables and genetic modeling will improve prediction of nicotine metabolism, disease risk and smoking cessation treatment prognosis.

Relationship of endogenous sex hormones to coronary heart disease: a twin study.

We examined the association between endogenous sex hormones (estradiol, estrone, testosterone, and SHBG) and coronary heart disease (CHD) in white male twins. Stored plasma samples were available for 566 participants of the National Heart, Lung, and Blood Institute Twin Study, a longitudinal study of cardiovascular disease in male twins. Twenty-eight of these individuals were lost to follow-up, and outcome data were missing. Of the remaining 538 participants, 78 had CHD at baseline, and 154 subsequently developed CHD over 20 yr of follow-up. We observed no differences in mean unadjusted or age- and body mass index-adjusted log-transformed sex hormone concentrations for participants with and without CHD (all P > 0.08). Quartile and median split analyses revealed no significant association between any of the sex hormones and either prevalent or incident CHD. The discordant monozygotic twins showed no significant case-control group difference in estradiol, estrone, testosterone, and SHBG (all P > 0.3). The positive and negative concordant twin pairs had similar values for each of the sex hormones (all P > 0.3). We observed no relationship between endogenous sex hormone concentrations and prevalent or incident CHD in this sample of male twins.