Influence of Smoking Status and Intensity on Discovery of Blood Pressure Loci Through Gene-Smoking Interactions.
ABSTRACT: Genetic variation accounts for approximately 30% of blood pressure (BP) variability but most of that variability has not been attributed to specific variants. Interactions between genes and BP-associated factors may explain some "missing heritability." Cigarette smoking increases BP after short-term exposure and decreases BP with longer exposure. Gene-smoking interactions have discovered novel BP loci, but the contribution of smoking status and intensity to gene discovery is unknown.We analyzed gene-smoking intensity interactions for association with systolic BP (SBP) in three subgroups from the Framingham Heart Study: current smokers only (N = 1,057), current and former smokers ("ever smokers," N = 3,374), and all subjects (N = 6,710). We used three smoking intensity variables defined at cutoffs of 10, 15, and 20 cigarettes per day (CPD). We evaluated the 1 degree-of-freedom (df) interaction and 2df joint test using generalized estimating equations.Analysis of current smokers using a CPD cutoff of 10 produced two loci associated with SBP. The rs9399633 minor allele was associated with increased SBP (5 mmHg) in heavy smokers (CPD > 10) but decreased SBP (7 mmHg) in light smokers (CPD ? 10). The rs11717948 minor allele was associated with decreased SBP (8 mmHg) in light smokers but decreased SBP (2 mmHg) in heavy smokers. Across all nine analyses, 19 additional loci reached P < 1 × 10(-6).Analysis of current smokers may have the highest power to detect gene-smoking interactions, despite the reduced sample size. Associations of loci near SASH1 and KLHL6/KLHL24 with SBP may be modulated by tobacco smoking.
Project description:Cardiovascular diseases are among the most significant health problems in the United States. Blood pressure (BP) variability has a genetic component, and most of the genetic variance remains to be identified. One promising strategy for gene discovery is genome-wide analysis of interactions between single nucleotide polymorphisms (SNPs) and environmental factors related to cardiovascular diseases.We investigated SNP-smoking interaction effects on BP in genome-wide data in 6,889 participants from the Framingham Heart Study. We performed the standard 1 degree of freedom (df) test of the interaction effect and the joint 2 df test of main and interaction effects. Three smoking measures were used: cigarettes per day (CPD), pack years of smoking, and smoking status.We identified 7 significant and 21 suggestive BP loci. Identified through the joint 2 df test, significant SBP loci include: rs12149862 (P = 3.65×10(-9)) in CYB5B, rs2268365 (P = 4.85×10(-8)) in LRP2, rs133980 (P = 1.71×10(-8) with CPD and P = 1.07×10(-8) with pack-years) near MN1, and rs12634933 (P = 4.05×10(-8)) in MECOM. Through 1 df interaction analysis, 1 suggestive SBP locus at SNP rs8010717 near NRXN3 was identified using all 3 smoking measures (P = 3.27×10(-7) with CPD, P = 1.03×10(-7) with pack-years, and P = 1.19×10(-7) with smoking status).Several of these BP loci are biologically plausible, providing physiological connection to BP regulation. Our study demonstrates that SNP-smoking interactions can enhance gene discovery and provide insight into novel pathways and mechanisms regulating BP.
Project description:An increasing proportion of US smokers smoke ?10 cigarettes per day (CPD) or do not smoke every day, yet the health effects of low-intensity smoking are poorly understood. We identified lifelong smokers of <1 or 1-10 CPD and evaluated risk of incident cancer among 238,525 cancer-free adults, aged 59-82, in the NIH-AARP Diet and Health Study. A questionnaire administered in 2004-2005 assessed CPD during nine age-periods (<15 to ?70). We estimated hazard ratios (HR) and 95% confidence intervals (CI) using multivariable-adjusted Cox proportional hazards regression with age as the underlying time metric. Of the 18,233 current smokers, (7.6%), 137 and 1,243 reported consistently smoking <1 CPD and 1-10 CPD, respectively. Relative to never smokers, current smokers who reported consistently smoking 1-10 CPD over their lifetime were 2.34 (95% CI?=?1.86-2.93) times more likely to develop smoking-related cancer. Current lifetime smokers of <1 CPD were 1.89 (95% CI?=?0.90-3.96) times more likely to develop tobacco-related cancer, although the association did not reach statistical significance. Associations were observed for lifelong smoking of ?10 CPD with lung cancer (HR?=?9.65, 95% CI?=?6.93-13.43); bladder cancer (HR?=?2.22, 95% CI?=?1.22-4.05); and pancreatic cancer (HR?=?2.03, 95%CI: 1.05-3.95). Among lifelong ?10 CPD smokers, former smokers had lower risks of smoking-related cancer with longer time since cessation and longer smoking duration. Lifelong <1 and 1-10 CPD smokers are at increased risk of incident cancer relative to never smokers and would benefit from cessation, providing further evidence that even low-levels of cigarette smoking cause cancer.
Project description:OBJECTIVE:Our objective was to investigate the influence of gene by smoking (GxS) interaction on hypertension and blood pressure (BP) using genome-wide linkage analysis in Mexican-Americans, followed by single nucleotide polymorphism (SNP) fine mapping of candidate genes in the linked chromosomal region. METHODS:We used nonparametric methods to test for linkage of microsatellites with hypertension and BP measures in smokers, nonsmokers, and the combined group. To begin fine mapping of a major quantitative trait locus (QTL) for systolic blood pressure (SBP) on chromosome 15q that showed strong evidence for GxS interaction, we genotyped 55 SNPs in nine candidate genes for association studies using two population-based statistical methods. RESULTS:The strongest evidence for GxS interaction (P = 0.0004) was found for SBP on chromosome 15q, where a major QTL (LOD = 3.36) was identified only in nonsmokers. Follow-up studies identified three SNPs in three genes (ANPEP, IGF1R, and SLCO3A1) that showed associations with SBP only in nonsmokers, cumulatively accounting for a 7 mmHg increase in SBP. However, conditional linkage analyses that accounted for phenotypic effects of these SNPs only slightly reduced the original LOD score. CONCLUSION:The detection of a major QTL on chromosome 15q for SBP in nonsmokers indicates the presence of loci that influence BP via GxS interactions. However, identification of the genes that underlie such QTL effects remains a challenge. Although we found three candidate genes that showed significant associations with SBP in nonsmokers, further studies are required to identify the gene(s) that underlie the chromosome 15q QTL that influences SBP via GxS interactions.
Project description:<h4>Background</h4>The CHRNA5-CHRNA3-CHRNB4 gene cluster on 15q25 has consistently been associated with smoking quantity, nicotine dependence and lung cancer. Recent research also points towards its involvement in cardiovascular homeostasis, but studies in large human samples are lacking, especially on the role of the gene cluster in blood pressure regulation.<h4>Methodology/principal findings</h4>We studied the associations between 18 single nucleotide polymorphisms (SNPs) in CHRNA5-CHRNA3-CHRNB4 and systolic blood pressure (SBP), diastolic blood pressure (DBP), and body mass index (BMI) in 5402 young adults from the Northern Finland Birth Cohort 1966. We observed some evidence for associations between two SNPs and SBP and between six SNPs and BMI; the evidence for associations with DBP was weaker. The associations with the three phenotypes were driven by different loci with low linkage disequilibrium with each other. The associations appeared more pronounced in smokers, such that the smoking-increasing alleles would predict lower SBP and BMI. Each additional copy of the rs1948 G-allele and the rs950776 A-allele reduced SBP on average by -1.21 (95% CI -2.01, -0.40) mmHg in smokers. The variants associated with BMI included rs2036534, rs6495309, rs1996371, rs6495314, rs4887077 and rs11638372 and had an average effect size of -0.38 (-0.68, -0.08) kg/m(2) per an additional copy of the risk allele in smokers. Formal assessments of interactions provided weaker support for these findings, especially after adjustment for multiple testing.<h4>Conclusions</h4>Variation at 15q25 appears to interact with smoking status in influencing SBP and BMI. The genetic loci associated with SBP were in low linkage disequilibrium with those associated with BMI suggesting that the gene cluster might regulate SBP through biological mechanisms that partly differ from those regulating BMI. Further studies in larger samples are needed for more precise evaluation of the possible interactions, and to understand the mechanisms behind.
Project description:Importance:A growing proportion of US smokers now smoke fewer than 10 cigarettes per day (CPD), and that proportion will likely rise in the future. The health effects of smoking only a few CPD over one's lifetime are less understood than are the effects of heavier smoking, although many smokers believe that their level is modest. Objective:To evaluate the associations of long-term smoking of fewer than 1 or 1 to 10 CPD (low intensity) with all-cause and cause-specific mortality compared with never smoking cigarettes. Design, Setting, and Participants:Prospective cohort study of 290?215 adults in the National Institutes of Health-AARP (formerly known as the American Association of Retired Persons) Diet and Health Study who were aged 59 to 82 years in calendar years 2004-2005 (baseline). Data were gathered with a questionnaire assessing lifetime cigarette smoking history. Hazard ratios (HRs) and 95% CIs were determined for all-cause mortality and cause-specific mortality through the end of 2011. Hazard ratios and 95% CIs were estimated using Cox proportional hazards regression models using age as the underlying time metric and adjusted for sex, race/ethnicity, educational level, physical activity, and alcohol intake. Data analysis was conducted from December 15, 2015, to September 30, 2016. Exposures:Current and historical smoking intensity during 9 previous age periods (from <15 years to ?70 years) over the lifetime assessed on the 2004-2005 questionnaire. Main Outcomes and Measures:All-cause and cause-specific mortality among current, former, and never smokers. Results:Of the 290?215 cohort participants who completed the 2004-2005 questionnaire, 168?140 were men (57.9%); the mean (SD) age was 71 (5.3) years (range, 59-82 years). Most people who smoked fewer than 1 or 1 to 10 CPD at baseline reported smoking substantially higher numbers of CPD earlier in their lives. Nevertheless, 159 (9.1%) and 1493 (22.5%) of these individuals reported consistently smoking fewer than 1 or 1 to 10 CPD in each age period that they smoked, respectively. Relative to never smokers, consistent smokers of fewer than 1 CPD (HR, 1.64; 95% CI, 1.07-2.51) and 1 to 10 CPD (HR, 1.87; 95% CI, 1.64-2.13) had a higher all-cause mortality risk. Associations were similar in women and men for all-cause mortality and were observed across a range of smoking-related causes of death, with an especially strong association with lung cancer (HR, 9.12; 95% CI, 2.92-28.47, and HR, 11.61; 95% CI, 8.25-16.35 for <1 and 1-10 CPD, respectively). Former smokers who had consistently smoked fewer than 1 or 1 to 10 CPD had progressively lower risks with younger age at cessation. For example, the HRs for consistent smokers of fewer than 1 and 1 to 10 CPD who quit at 50 years or older were 1.44 (95% CI, 1.12-1.85) and 1.42 (95% CI, 1.27-1.59), respectively. Conclusions and Relevance:This study provides evidence that individuals who smoke fewer than 1 or 1 to 10 CPD over their lifetime have higher mortality risks than never smokers and would benefit from cessation. These results provide further evidence that there is no risk-free level of exposure to tobacco smoke.
Project description:Cigarette smoking is influenced by nicotine's effects on dopaminergic activity, which appear to be moderated by genetic variation, particularly a variable number tandem repeat (VNTR, 48 bp) polymorphism in the third exon of the dopamine receptor gene (DRD4). Smokers with the VNTR ?7 repeats (long, L allele) report markedly increased participation in some smoking behaviors; hence, our aim was to evaluate the association of the L allele in Mexican Mestizo smokers with and without COPD. The DRD4 VNTR 48 bp was genotyped in 492 Mexican Mestizo smokers: 164 COPD patients (?20 cigarettes per day, cpd), 164 heavy smokers without COPD (HS, ?20 cpd) and 164 light smokers without COPD (LS, 1-10 cpd). In the dominant model analysis (SL + LL vs. SS), men in the COPD and HS groups showed a statistical difference compared to LS (p = 0.01, OR = 2.06, CI 95% 1.17-3.64 and p = 0.05, OR = 1.88, CI 95% 1.03-3.45, respectively). In addition, by clustering smokers >20 cpd (COPD + HS) and comparing with the LS group, we found an association with increased risk of higher tobacco smoking p = 0.01, OR = 1.99, CI 95% 1.18-3.34. In conclusion, the long allele (L) in the VNTR of the DRD4 gene is associated with the risk of presenting higher tobacco smoking in male Mexican Mestizo smokers.
Project description:INTRODUCTION Prevalence of light daily smoking, <10 cigarettes per day (CPD), and non-daily smoking has increased in the US population. This analysis examined the heterogeneity in past-year smoking behavior, current tobacco use behaviors, and smoking cessation behaviors among light and/or non-daily smokers. METHODS Current adult (?18 years old) smokers (N=26196) participated in the 2010–2011 US Current Population Survey – Tobacco Use Supplement, which reported current (T1) and past 12-month (T0) smoking behaviors. Responses were categorized by intensity (light ?10 CPD vs heavy >10 CPD) and frequency (non-daily vs daily). Combinations of T0 and T1 smoking behaviors resulted in 15 smoking trajectories ending in light/non-daily smoking and a 16th category of heavy daily smokers at T1. Differences in demographics, tobacco use, and smoking cessation behaviors were assessed by using weighted multivariable regression models. RESULTS Overall, 46.1% of US smokers were heavy smokers, 24.6% remained light daily smokers and 12.5% remained light non-daily smokers between T0 and T1. Current cigar, smokeless tobacco, and pipe use differed by smoking trajectories (p<0.05). All light and/or non-daily smokers were more likely than heavy daily smokers to have made a quit attempt (p<0.05) but use of cessation treatments varied. Smokers in many light and/or non-daily smoking trajectories were less likely than heavy daily smokers to be aided by healthcare providers for smoking cessation (p<0.05). CONCLUSIONS Among heavy daily smokers who became light non-daily smokers, the mismatch between intent to quit (80.9%) and receiving advice to set a quit date (33.7%) is one example of a potential opportunity for a clinical intervention.
Project description:Racial/ethnic differences in the associations of smoking with uncontrolled blood pressure (BP) and its subtypes (isolated uncontrolled systolic BP (SBP), uncontrolled systolic-diastolic BP, and isolated uncontrolled diastolic BP (DBP)) have not been investigated among diagnosed hypertensive subjects.A sample of 7,586 hypertensive patients aged ?18 years were selected from the National Health and Nutrition Examination Survey 1999-2010. Race/ethnicity was classified into Hispanic, non-Hispanic white, and non-Hispanic black. Smoking was categorized as never smoking, ex-smoking, and current smoking. Uncontrolled BP was determined as SBP?140 or DBP?90 mm Hg. Isolated uncontrolled SBP was defined as SBP?140 and DBP<90 mm Hg, uncontrolled SDBP as SBP?140 and DBP?90 mm Hg, and isolated uncontrolled DBP as SBP<140 and DBP?90 mm Hg. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) of uncontrolled BP and its subtypes were calculated using weighted logistic regression models.The interaction effect of race and smoking was significant after adjustment for the full potential confounding covariates (Adjusted p = 0.0412). Compared to never smokers, current smokers were 29% less likely to have uncontrolled BP in non-Hispanic whites (OR = 0.71, 95% CI = 0.56-0.90), although the likelihood for uncontrolled BP is the same for smokers and never smokers in Hispanics and non-Hispanic blacks. Current smokers were 26% less likely than never smokers to have isolated uncontrolled SBP in non-Hispanic whites (OR = 0.74, 95% CI = 0.58-0.95). However, current smoking is associated with an increased likelihood of uncontrolled systolic-diastolic BP in non-Hispanic blacks, and current smokers in this group were 70% more likely to have uncontrolled systolic-diastolic BP than never smokers (OR = 1.70, 95% CI = 1.10-2.65).The associations between current smoking and uncontrolled BP differed over race/ethnicity. Health practitioners may need to be especially vigilant with non-Hispanic black smokers with diagnosed hypertension.
Project description:BACKGROUND: Data relating to the association between tea consumption and blood pressure change are inconsistent. The aim of this analysis was to investigate the association between tea consumption and the change in blood pressure (BP) in Chinese adults over a 5-year period. METHODS: Data from 1109 Chinese men (N=?472) and women (N=?637) who participated in the Jiangsu Nutrition Study (JIN) were analysed. BP was measured in 2002 and 2007. Tea (green, black and total tea) consumption was quantitatively assessed at the follow-up survey in 2007. RESULTS: Total tea and green tea consumption were inversely associated with 5-year diastolic BP (DBP) but not systolic BP (SBP) change. In the multivariable analysis, compared with no consumption of tea, those with daily total tea/green tea consumption of at least10 g had 2.41 mmHg and 3.68 mmHg smaller increase of DBP respectively. There was a significant interaction between smoking and total tea/green tea consumption and DBP change. The inverse association between total tea/green tea consumption and DBP change was significant only in non-smokers. Green tea consumption was inversely associated with SBP change only in non-smokers and those without central obesity. CONCLUSION: The consumption of green tea is inversely associated with 5-year BP change among Chinese adults, an effect abrogated by smoking.
Project description:Among cigarette smokers, lower levels of consumption, defined as smoking fewer cigarettes per day (CPD) or not smoking daily, are becoming more common. The relationship between cigarette consumption and smoking frequency (daily or nondaily) is not well characterized, and the natural history of light smoking (defined here as smoking < or =10 CPD) is poorly understood.We assessed changes in CPD and smoking frequency over time among light smokers (< or =10 CPD) and very light smokers (< or =5 CPD), using a population-based longitudinal survey of 3,083 adult smokers in Massachusetts who were interviewed three times over a 4-year follow-up period (in 2000-2001, 2002-2003, and 2005-2006). We used logistic regression to identify factors associated with light smokers' progression to heavier smoking or smoking reduction/quitting.Seventy percent of very light smokers were nondaily smokers. Very light nondaily smokers differed from very light daily smokers by younger age, higher socioeconomic status, a social smoking pattern, later smoking initiation, less evidence of nicotine addiction, and more recent and planned cessation efforts. Very light nondaily smokers and smokers consuming 6-10 CPD were more likely to remain in the same smoking category and were less likely to increase consumption than were very light daily smokers. Factors independently associated with increasing consumption among very light smokers were smoking daily, nicotine dependence, White ethnicity, social smoking, and having more friends who smoked; among smokers consuming 6-10 CPD, male gender and lack of quitting self-efficacy were associated with increasing consumption.Our findings indicate that most light smoking is not a gateway to heavier smoking.