Mark N. Upton

Intergenerational 20 year trends in the prevalence of asthma and hay fever in adults: the Midspan family study surveys of parents and offspring.

Abstract Objective: To estimate trends between 1972–6 and 1996 in the prevalences of asthma and hay fever in adults. Design: Two epidemiological surveys 20 years apart. Identical questions were asked about asthma, hay fever, and respiratory symptoms at each survey. Setting: Renfrew and Paisley, two towns in the west of Scotland. Subjects: 1477 married couples aged 45–64 participated in a general population survey in 1972-6; and 2338 offspring aged 30–59 participated in a 1996 survey. Prevalences were compared in 1708 parents and 1124 offspring aged 45-54. Main outcome measures: Prevalences of asthma, hay fever, and respiratory symptoms. Results: In never smokers, age and sex standardised prevalences of asthma and hay fever were 3.0% and 5.8% respectively in 1972-6, and 8.2% and 19.9% in 1996. In ever smokers, the corresponding values were 1.6% and 5.4% in 1972–6 and 5.3% and 15.5% in 1996. In both generations, the prevalence of asthma was higher in those who reported hay fever (atopic asthma). In never smokers, reports of wheeze not labelled as asthma were about 10 times more common in 1972–6 than in 1996. With a broader definition of asthma (asthma and/or wheeze), to minimise diagnostic bias, the overall prevalence of asthma changed little. However, diagnostic bias mainly affected non-atopic asthma. Atopic asthma increased more than twofold (prevalence ratio 2.52 (95% confidence interval 1.01 to 6.28)) whereas the prevalence of non-atopic asthma did not change (1.00 (0.53 to 1.90)). Conclusion: The prevalence of asthma in adults has increased more than twofold in 20 years, largely in association with trends in atopy, as measured indirectly by the prevalence of hay fever. No evidence was found for an increase in diagnostic awareness being responsible for the trend in atopic asthma, but increased awareness may account for trends in non-atopic asthma.

Height and risk of death among men and women: aetiological implications of associations with cardiorespiratory disease and cancer mortality

OBJECTIVES Height is inversely associated with cardiovascular disease mortality risk and has shown variable associations with cancer incidence and mortality. The interpretation of findings from previous studies has been constrained by data limitations. Associations between height and specific causes of death were investigated in a large general population cohort of men and women from the West of Scotland. DESIGN Prospective observational study. SETTING Renfrew and Paisley, in the West of Scotland. SUBJECTS 7052 men and 8354 women aged 45–64 were recruited into a study in Renfrew and Paisley, in the West of Scotland, between 1972 and 1976. Detailed assessments of cardiovascular disease risk factors, morbidity and socioeconomic circumstances were made at baseline. MAIN OUTCOME MEASURES Deaths during 20 years of follow up classified into specific causes. RESULTS Over the follow up period 3347 men and 2638 women died. Height is inversely associated with all cause, coronary heart disease, stroke, and respiratory disease mortality among men and women. Adjustment for socioeconomic position and cardiovascular risk factors had little influence on these associations. Height is strongly associated with forced expiratory volume in one second (FEV1) and adjustment for FEV1 considerably attenuated the association between height and cardiorespiratory mortality. Smoking related cancer mortality is not associated with height. The risk of deaths from cancer unrelated to smoking tended to increase with height, particularly for haematopoietic, colorectal and prostate cancers. Stomach cancer mortality was inversely associated with height. Adjustment for socioeconomic position had little influence on these associations. CONCLUSION Height serves partly as an indicator of socioeconomic circumstances and nutritional status in childhood and this may underlie the inverse associations between height and adulthood cardiorespiratory mortality. Much of the association between height and cardiorespiratory mortality was accounted for by lung function, which is also partly determined by exposures acting in childhood. The inverse association between height and stomach cancer mortality probably reflectsHelicobacter pylori infection in childhood resulting in—or being associated with—shorter height. The positive associations between height and several cancers unrelated to smoking could reflect the influence of calorie intake during childhood on the risk of these cancers.

Associations of height, leg length, and lung function with cardiovascular risk factors in the Midspan Family Study

Background: Taller people and those with better lung function are at reduced risk of coronary heart disease (CHD). Biological mechanisms for these associations are not well understood, but both measures may be markers for early life exposures. Some studies have shown that leg length, an indicator of pre-pubertal nutritional status, is the component of height most strongly associated with CHD risk. Other studies show that height-CHD associations are greatly attenuated when lung function is controlled for. This study examines (1) the association of height and the components of height (leg length and trunk length) with CHD risk factors and (2) the relative strength of the association of height and forced expiratory volume in one second (FEV1) with risk factors for CHD. Subjects and methods: Cross sectional analysis of data collected at detailed cardiovascular screening examinations of 1040 men and 1298 women aged 30–59 whose parents were screened in 1972–76. Subjects come from 1477 families and are members of the Midspan Family Study. Setting: The towns of Renfrew and Paisley in the West of Scotland. Results: Taller subjects and those with better lung function had more favourable cardiovascular risk factor profiles, associations were strongest in relation to FEV1. Higher FEV1 was associated with lower blood pressure, cholesterol, glucose, fibrinogen, white blood cell count, and body mass index. Similar, but generally weaker, associations were seen with height. These associations were not attenuated in models controlling for parental height. Longer leg length, but not trunk length, was associated with lower systolic and diastolic blood pressure. Longer leg length was also associated with more favourable levels of cholesterol and body mass index than trunk length. Conclusions: These findings provide indirect evidence that measures of lung development and pre-pubertal growth act as biomarkers for childhood exposures that may modify an individuals risk of developing CHD. Genetic influences do not seem to underlie height-CHD associations.

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.

Birth weight of offspring and mortality in the Renfrew and Paisley study: prospective observational study.

Abstract Objective: To investigate the association between birth weight of offspring and mortality among fathers and mothers in the west of Scotland. Design: Prospective observational study. Participants: 794 married couples in Renfrew district of the west of Scotland. Main outcome measures: Mortality from all causes and from cardiovascular disease over 15 year follow up. Results: Women who had heavier babies were taller, had higher body mass index and better lung function, and were less likely to be smokers than mothers of lighter babies. Fathers of heavier babies were taller and less likely to be smokers than fathers of lighter babies. Mortality was inversely related to offsprings birth weight for both mothers (relative rate for a 1 kg lower birth weight 1.82 (95% confidence interval 1.23 to 2.70)) and fathers (relative rate 1.35 (1.03 to 1.79)). For mortality from cardiovascular disease, inverse associations were seen for mothers (2.00 (1.18 to 3.33)) and fathers (1.52 (1.03 to 2.17)). Adjustment for blood pressure, plasma cholesterol, body mass index, height, social class, area based deprivation category, smoking, lung function, angina, bronchitis, and electrocardiographic evidence of ischaemia had little effect on these risk estimates, although levels of statistical significance were reduced. Conclusions: Birth weight of offspring was related inversely to mortality, from all causes and cardiovascular disease, in this cohort. The strength of this association was greater than would have been expected by the degree of concordance of birth weights across generations, but an extensive range of potential confounding factors could not account for the association. Mortality is therefore influenced by a factor related to birth weight that is transmissible across generations. Key messages Low birth weight is associated with increased mortality from cardiovascular disease in later life, and birth weight is associated across generations so that both maternal and paternal birth weights are associated with the offsprings birth weight In this observational study we found that lower birth weight of offspring was associated with higher parental mortality from all causes and from cardiovascular disease This elevated mortality could not be explained by a range of social, environmental, behavioural, and physiological risk factors The strength of the association was greater than would have been expected by the degree of concordance of birth weights across generations We conclude that mortality is influenced by a factor that is related to birth weight and is transmissible across generations

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). Conclusion—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.

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/m2 [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/m2 (95% CI: 0.13–0.31) lower BMI (P = 8 × 10−6). The effect size was larger in current [0.33 kg/m2 lower BMI per T-allele (95% CI: 0.18–0.48); P = 6 × 10−5], than in former smokers [0.16 kg/m2 (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.

How accurately do adult sons and daughters report and perceive parental deaths from coronary disease

OBJECTIVES To describe how adult sons and daughters report and perceive parental deaths from heart disease DESIGN Two generation family study. SETTING West of Scotland. SUBJECTS 1040 sons and 1298 daughters aged 30–59 from 1477 families, whose fathers and mothers were aged 45–64 in 1972–76 and have been followed up for mortality over 20 years. OUTCOME Perception of a “family weakness” attributable to heart disease. RESULTS 26% of sons and daughters had a parent who had died of coronary heart disease (CHD). The proportion was higher in older offspring (+18% per 10 year age difference) and in manual compared with non-manual groups (+37%). Eighty nine per cent of parental deaths from CHD were correctly reported by offspring. Only 23% of sons and 34% of daughters with at least one parent who had died of CHD considered that they had a family weakness attributable to heart disease. Perceptions of a family weakness were higher when one or both parents had died of CHD, when parental deaths occurred at a younger age, in daughters compared with sons and in offspring in non-manual compared with manual occupations. CONCLUSIONS Only a minority of sons and daughters with experience of a parent having died from CHD perceive this in terms of a family weakness attributable to heart disease. Although men in manual occupations are most likely to develop CHD, they are least likely to interpret a parental death from CHD in terms of a family weakness. Health professionals giving advice to patients on their familial risks need to be aware of the difference between clinical definitions and lay perceptions of a family history of heart disease.

Separating in-utero and postnatal influences on later disease

Associations of birthweight with leg length and trunk length are similar. Childhood exposures rather than in-utero programming may underlie specific associations seen between leg length and mortality.

Circulating 25OHD, Dietary Vitamin D, PTH, and Calcium Associations with Incident Cardiovascular Disease and Mortality: The MIDSPAN Family Study

CONTEXT Observational studies relating circulating 25-hydroxyvitamin D (25OHD) and dietary vitamin D intake to cardiovascular disease (CVD) have reported conflicting results. OBJECTIVE Our objective was to investigate the association of 25OHD, dietary vitamin D, PTH, and adjusted calcium with CVD and mortality in a Scottish cohort. DESIGN AND SETTING The MIDSPAN Family Study is a prospective study of 1040 men and 1298 women from the West of Scotland recruited in 1996 and followed up for a median 14.4 yr. PARTICIPANTS Locally resident adult offspring of a general population cohort were recruited from 1972-1976. MAIN OUTCOME MEASURES CVD events (n = 416) and all-cause mortality (n = 100) were evaluated. RESULTS 25OHD was measured using liquid chromatography-tandem mass spectrometry in available plasma (n = 2081). Median plasma 25OHD was 18.6 ng/ml, and median vitamin D intake was 3.2 μg/d (128 IU/d). Vitamin D deficiency (25OHD <15 ng/ml) was present in 689 participants (33.1%). There was no evidence that dietary vitamin D intake, PTH, or adjusted calcium were associated with CVD events or with mortality. Vitamin D deficiency was not associated with CVD (fully adjusted hazard ratio = 1.00; 95% confidence interval = 0.77-1.31). Results were similar after excluding patients who reported an activity-limiting longstanding illness at baseline (18.8%) and those taking any vitamin supplements (21.7%). However, there was some evidence vitamin D deficiency was associated with all-cause mortality (fully adjusted hazard ratio = 2.02; 95% confidence interval = 1.17-3.51). CONCLUSION Vitamin D deficiency was not associated with risk of CVD in this cohort with very low 25OHD. Future trials of vitamin D supplementation in middle-aged cohorts should be powered to detect differences in mortality outcomes as well as CVD.