Investigating the causal effect of smoking on hay fever and asthma: a Mendelian randomization meta-analysis in the CARTA consortium.

Observational studies on smoking and risk of hay fever and asthma have shown inconsistent results. However, observational studies may be biased by confounding and reverse causation. Mendelian randomization uses genetic variants as markers of exposures to examine causal effects. We examined the causal effect of smoking on hay fever and asthma by using the smoking-associated single nucleotide polymorphism (SNP) rs16969968/rs1051730. We included 231,020 participants from 22 population-based studies. Observational analyses showed that current vs never smokers had lower risk of hay fever (odds ratio (OR) = 0·68, 95% confidence interval (CI): 0·61, 0·76; P < 0·001) and allergic sensitization (OR = 0·74, 95% CI: 0·64, 0·86; P < 0·001), but similar asthma risk (OR = 1·00, 95% CI: 0·91, 1·09; P = 0·967). Mendelian randomization analyses in current smokers showed a slightly lower risk of hay fever (OR = 0·958, 95% CI: 0·920, 0·998; P = 0·041), a lower risk of allergic sensitization (OR = 0·92, 95% CI: 0·84, 1·02; P = 0·117), but higher risk of asthma (OR = 1·06, 95% CI: 1·01, 1·11; P = 0·020) per smoking-increasing allele. Our results suggest that smoking may be causally related to a higher risk of asthma and a slightly lower risk of hay fever. However, the adverse events associated with smoking limit its clinical significance.

Lower respiratory tract infection in the first year of life is associated with worse lung function in adult life: prospective results from the Barry Caerphilly Growth study.

PURPOSE: We examined the association between childhood respiratory infections and adult lung function and how this association varies depending on the age at infection. METHODS: The Barry Caerphilly Growth study collected information on childhood upper and lower respiratory tract infections (URTI, LRTI) from birth to 5 years on 14 occasions. Subjects were traced prospectively and had lung function measured at age 25 years. RESULTS: A total of 581 subjects had acceptable data for both forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). Childhood LRTIs (0-5 years) but not URTIs were negatively associated with all lung function measures except FVC and showed a dose-response effect. In the first year of life, a two-fold increase in the number of LRTIs experienced was associated with a reduction in FEV1 (78 mL; 95% confidence interval [95% CI], 3-153), FEV1/FVC (1.23%; 95% CI 0.25-2.22), forced expiratory flow 25%-75% (0.25 l/sec; 95% CI 0.08-0.41), and peak expiratory flow (0.30 l/sec; 95% CI 0.11-0.49) after adjustment for confounders. Few associations were found after the first year of life. There was evidence that age at infection effect modifies the association between LRTIs and FEV1, forced expiratory flow 25%-75%, and peak expiratory flow. CONCLUSIONS: LRTIs are associated with an obstructive lung function deficit. Furthermore, the first year of life may be a sensitive period for experiencing LRTIs.

Parental height in relation to offspring coronary heart disease: examining transgenerational influences on health using the west of Scotland Midspan Family Study.

BACKGROUND: Adult height is known to be inversely related to coronary heart disease (CHD) risk. We sought to investigate transgenerational influence of parental height on offspring's CHD risk. METHODS: Parents took part in a cardiorespiratory disease survey in two Scottish towns during the 1970s, in which their physical stature was measured. In 1996, their offspring were invited to participate in a similar survey, which included an electrocardiogram recording and risk factor assessment. RESULTS: A total of 2306 natural offspring aged 30-59 years from 1456 couples were subsequently flagged for notification of mortality and followed for CHD-related hospitalizations. Taller paternal and/or maternal height was associated with socio-economic advantage, heavier birthweight and increased high-density lipoprotein cholesterol in offspring. Increased height in fathers, but more strongly in mothers (risk ratio for 1 SD change in maternal height = 0.85; 95% confidence interval: 0.76 to 0.95), was associated with a lower risk of offspring CHD, adjusting for age, sex, other parental height and CHD risk factors. CONCLUSION: There is evidence of an association between taller parental, particularly maternal, height and lower offspring CHD risk. This may reflect an influence of early maternal growth on the intrauterine environment provided for her offspring.

Association between genetic variants on chromosome 15q25 locus and objective measures of tobacco exposure.

BACKGROUND: Two single-nucleotide polymorphisms, rs1051730 and rs16969968, located within the nicotinic acetylcholine receptor gene cluster on chromosome 15q25 locus, are associated with heaviness of smoking, risk for lung cancer, and other smoking-related health outcomes. Previous studies have typically relied on self-reported smoking behavior, which may not fully capture interindividual variation in tobacco exposure. METHODS: We investigated the association of rs1051730 and rs16969968 genotype (referred to as rs1051730-rs16969968, because these are in perfect linkage disequilibrium and interchangeable) with both self-reported daily cigarette consumption and biochemically measured plasma or serum cotinine levels among cigarette smokers. Summary estimates and descriptive statistical data for 12 364 subjects were obtained from six independent studies, and 2932 smokers were included in the analyses. Linear regression was used to calculate the per-allele association of rs1051730-rs16969968 genotype with cigarette consumption and cotinine levels in current smokers for each study. Meta-analysis of per-allele associations was conducted using a random effects method. The likely resulting association between genotype and lung cancer risk was assessed using published data on the association between cotinine levels and lung cancer risk. All statistical tests were two-sided. RESULTS: Pooled per-allele associations showed that current smokers with one or two copies of the rs1051730-rs16969968 risk allele had increased self-reported cigarette consumption (mean increase in unadjusted number of cigarettes per day per allele = 1.0 cigarette, 95% confidence interval [CI] = 0.57 to 1.43 cigarettes, P = 5.22 × 10(-6)) and cotinine levels (mean increase in unadjusted cotinine levels per allele = 138.72 nmol/L, 95% CI = 97.91 to 179.53 nmol/L, P = 2.71 × 10(-11)). The increase in cotinine levels indicated an increased risk of lung cancer with each additional copy of the rs1051730-rs16969968 risk allele (per-allele odds ratio = 1.31, 95% CI = 1.21 to 1.42). CONCLUSIONS: Our data show a stronger association of rs1051730-rs16969968 genotype with objective measures of tobacco exposure compared with self-reported cigarette consumption. The association of these variants with lung cancer risk is likely to be mediated largely, if not wholly, via tobacco exposure.

Intergenerational change and familial aggregation of body mass index.

The relationship between parental BMI and that of their adult offspring, when increased adiposity can become a clinical issue, is unknown. We investigated the intergenerational change in body mass index (BMI) distribution, and examined the sex-specific relationship between parental and adult offspring BMI. Intergenerational change in the distribution of adjusted BMI in 1,443 complete families (both parents and at least one offspring) with 2,286 offspring (1,263 daughters and 1,023 sons) from the west of Scotland, UK, was investigated using quantile regression. Familial correlations were estimated from linear mixed effects regression models. The distribution of BMI showed little intergenerational change in the normal range (<25 kg/m(2)), decreasing overweightness (25-<30 kg/m(2)) and increasing obesity (≥30 kg/m(2)). Median BMI was static across generations in males and decreased in females by 0.4 (95% CI: 0.0, 0.7) kg/m(2); the 95th percentile increased by 2.2 (1.1, 3.2) kg/m(2) in males and 2.7 (1.4, 3.9) kg/m(2) in females. Mothers' BMI was more strongly associated with daughters' BMI than was fathers' (correlation coefficient (95% CI): mothers 0.31 (0.27, 0.36), fathers 0.19 (0.14, 0.25); P = 0.001). Mothers' and fathers' BMI were equally correlated with sons' BMI (correlation coefficient: mothers 0.28 (0.22, 0.33), fathers 0.27 (0.22, 0.33). The increase in BMI between generations was concentrated at the upper end of the distribution. This, alongside the strong parent-offspring correlation, suggests that the increase in BMI is disproportionally greater among offspring of heavier parents. Familial influences on BMI among middle-aged women appear significantly stronger from mothers than fathers.

Genetic variation at CHRNA5-CHRNA3-CHRNB4 interacts with smoking status to influence body mass index.

BACKGROUND: Cigarette smoking is associated with lower body mass index (BMI), and a commonly cited reason for unwillingness to quit smoking is a concern about weight gain. Common variation in the CHRNA5-CHRNA3-CHRNB4 gene region (chromosome 15q25) is robustly associated with smoking quantity in smokers, but its association with BMI is unknown. We hypothesized that genotype would accurately reflect smoking exposure and that, if smoking were causally related to weight, it would be associated with BMI in smokers, but not in never smokers. METHODS: We stratified nine European study samples by smoking status and, in each stratum, analysed the association between genotype of the 15q25 SNP, rs1051730, and BMI. We meta-analysed the results (n = 24,198) and then tested for a genotype × smoking status interaction. RESULTS: There was no evidence of association between BMI and genotype in the never smokers {difference per T-allele: 0.05 kg/m(2) [95% confidence interval (95% CI): -0.05 to 0.18]; P = 0.25}. However, in ever smokers, each additional smoking-related T-allele was associated with a 0.23 kg/m(2) (95% CI: 0.13-0.31) lower BMI (P = 8 × 10(-6)). The effect size was larger in current [0.33 kg/m(2) lower BMI per T-allele (95% CI: 0.18-0.48); P = 6 × 10(-5)], than in former smokers [0.16 kg/m(2) (95% CI: 0.03-0.29); P = 0.01]. There was strong evidence of genotype × smoking interaction (P = 0.0001). CONCLUSIONS: Smoking status modifies the association between the 15q25 variant and BMI, which strengthens evidence that smoking exposure is causally associated with reduced BMI. Smoking cessation initiatives might be more successful if they include support to maintain a healthy BMI.

Alcohol consumption behaviours and social mobility in men and women of the Midspan Family study.

AIMS: The aim of this study was to investigate relationships between alcohol consumption and social mobility in a cohort study in Scotland. METHODS: 1040 sons and 1298 daughters aged 30-59 from 1477 families reported their alcohol consumption from which was derived: weekly units (1 UK unit being 8 g ethanol), exceeding daily or weekly limits, binge drinking and consuming alcohol on 5+ days per week. Own and father's social class were available enabling social mobility to be investigated. RESULTS: More downwardly mobile men exceeded the weekly limit, the daily limit, were defined as binge drinkers and drank the most units per week of the four social mobility groups. Stable non-manual women were more likely to consume alcohol on 5+ days a week but very few were binge drinkers. Stable non-manual and upwardly mobile men and women were more likely to drink wine, and downwardly mobile men to drink beer. CONCLUSIONS: Downward mobility was associated with less favourable alcohol behaviours, especially in men. Wine consumption was more closely related to the social mobility groups than beer and spirits consumption. Drinking patterns could both influence and be influenced by social mobility.

Contribution of Midparental BMI and other determinants of obesity in adult offspring.

The aim of this study was to evaluate midparental BMI among intergenerational factors associated with obesity in adult offspring. The data was from an unusual two-generational observational design of 1,477 married couples from Renfrew and Paisley in Scotland who were aged 45-64 years when screened in 1972-1976, and 1,040 sons and 1,298 daughters aged 30-59 years when screened in 1996. BMI was categorized as normal (< 25 kg/m(2)), overweight (25-29.9 kg/m(2)), and obese (> or = 30 kg/m(2)) in offspring and parents. Midparental BMI was defined as the mean of the mother's and father's BMI. Low physical activity, nonsmoking status, higher cholesterol level, and manual social class were all associated with increased BMI in offspring. The effect of reported dietary intake was less clear. Offspring of obese parents (defined by midparental BMI) were over four times more likely to be obese than offspring of normal weight parents. Midparental BMI had a strong effect on offspring BMI, independent of social class, smoking habit, physical activity, and reported dietary intake. Adding midparental BMI to the regression model more than doubled the explained variation of offspring BMI from 7.7 to 17%. Every 1 kg/m(2) increment in midparental BMI was associated with a BMI greater by 0.51 kg/m(2) in offspring. We conclude that midparental BMI is a useful simple tool to predict offspring BMI. Whether it represents genetic or environmental family effects, it is easily ascertained by the individual and could be used in health promotion and clinical settings to target individuals who are at increased risk of becoming obese.

The accuracy of the Framingham risk-score in different socioeconomic groups: a prospective study.

BACKGROUND: The primary prevention of cardiovascular disease involves using the Framingham risk score to identify high risk patients and then prescribe preventive treatments. AIM: To examine the performance of the Framingham risk score in different socioeconomic groups in a population with high rates of cardiovascular disease. DESIGN OF STUDY: A prospective study. SETTING: West of Scotland. METHOD: The observed 10-year cardiovascular disease and coronary heart disease mortality rates in 5626 men and 6678 women free from cardiovascular disease from the Renfrew/Paisley Study were compared with predicted rates, stratified by socioeconomic class and by area deprivation score. RESULTS: The ratio of predicted to observed cardiovascular mortality rate in the 12 304 men and women with complete risk factor information was 0.56 (95% confidence interval [CI] = 0.52 to 0.60), a relative underestimation of 44%. Cardiovascular disease mortality was underestimated by 48% in manual participants (predicted over observed = 0.52, 95% CI = 0.48 to 0.56) compared to 31% in the non-manual participants (predicted over observed = 0.69, 95% CI = 0.60 to 0.81, P = 0.0005). Underestimation was also worse in participants from deprived areas (P = 0.0017). Only 4.8% of individuals had a 10-year cardiovascular risk of >40% (equivalent to >30% 10-year coronary risk), and 81% of deaths occurred in the rest. If the Framingham score had been recalibrated for manual and non-manual members of this population, an additional 3611 individuals mainly from manual social classes would have reached the treatment threshold. CONCLUSION: Currently recommended risk scoring methods underestimate risk in socioeconomically deprived individuals. The likely consequence is that preventive treatments are less available to the most needy.

Inverse association between birth weight and C-reactive protein concentrations in the MIDSPAN Family Study.

OBJECTIVE: Inflammation markers and low birth weight each predict elevated risk of cardiovascular events and type 2 diabetes. However, potential associations between the low-grade inflammatory response as represented by C-reactive protein (CRP) concentrations and low birth weight have been sparsely examined. METHODS AND RESULTS: In the MIDSPAN Family Study, 1663 individuals had birth weight data and CRP concentrations measured as adults (age 30 to 59). The relationship between these parameters was examined after adjusting for factors known to influence CRP concentrations inclusive of age, body mass index, smoking, socio-economic deprivation, and hormone use in women. After adjusting for potential confounders, there was a negative association between birth weight and CRP, whereby a 1-kg increase in birth weight is associated with a 10.7% decrease in CRP (95% CI: 3.0% to 17.8% decrease). There was no strong evidence that the effects differed in men and women (P=0.32). CONCLUSIONS: Low birth weight contributes to elevated CRP concentration in adult life. Future studies are required to determine to what extent this association reflects catch-up centile crossing, in utero programming, or genetic factors.

Maternal and personal cigarette smoking synergize to increase airflow limitation in adults.

Susceptibility of the lungs to cigarette smoke is poorly understood. It is not known whether maternal smoking increases chronic obstructive pulmonary disease (COPD) risk. In 1998 we reported an inverse association between maternal smoking (prerecorded) and FEV(1) in adults. Because FEV(1) and FVC are strongly correlated, it is unclear whether the association in question reflects a link with lung volume, airflow limitation, or both. We extended our original analysis to investigate whether maternal and personal smoking synergize to increase airflow limitation. We estimated residual FEV(1) to express FEV(1) variation that was not associated with FVC. Maternal smoking was inversely associated with FVC and FEV(1) irrespective of personal smoking. It was inversely associated with FEV(1)/FVC, forced midexpiratory flow rates (FEF(25-75) [mean forced expiratory flow during the middle half of the FVC], FEF(25-75)/FVC), and residual FEV(1) in current smokers but not in never or former smokers (heterogeneity p = 0.016, 0.024, 0.021, and 0.016, respectively). We tested the clinical relevance of findings in ever smokers without asthma: 10 cigarettes/day maternal smoking increased prevalent COPD by 1.7 (95% confidence interval: 1.2-2.5) after adjustment for covariates. Maternal smoking impairs lung volume irrespective of personal smoking and appears to synergize with personal smoking to increase airflow limitation and COPD.

The Y chromosome effect on blood pressure in two European populations.

Higher blood pressure (BP) in males compared with females is well documented and is thought to be influenced in part by the Y chromosome. To examine whether there is an association between BP and a polymorphic HindIII biallelic marker in the nonrecombining region of the Y chromosome, we genotyped 155 males from a Polish study group and 762 males from a Scottish study group. We also tested for possible interaction between the Y chromosome and a mutation in the steroidogenic factor binding site of the aldosterone synthase gene by genotyping the same group from Scotland. There was no significant difference in age or body mass index between 2 Y chromosome genotypes in both study groups. Men with the HindIII(+) genotype had significantly higher systolic and diastolic pressures than those with the HindIII(-) genotype in both the Polish and Scottish studies. This difference between the genotypes was 5.27 mm Hg (P=0.0014) and 3.14 mm Hg (P=0.0005) for adjusted systolic BP and 2.6 mm Hg (P=0.0045) and 1.44 mm Hg (P=0.0084) for adjusted diastolic BP in the Polish and the Scottish studied, respectively. On binary logistic regression analysis, males with the HindIII(+)/TT SF1 genotype combination had an odds ratio for elevated BP of 3.92 (CI 1.21 to 12.68, P=0.023). Our results indicate that the Y chromosome harbors a locus or loci that contribute to BP variation in hypertensive and normotensive men. The polymorphism in the aldosterone synthase gene may interact with the Y chromosome to increase the odds of an individual's developing higher BP.