We previously used a single nucleotide polymorphism (SNP) in the CHRNA5-A3-B4 gene cluster associated with heaviness of smoking within smokers to confirm the causal effect of smoking in reducing body mass index (BMI) in a Mendelian randomisation analysis. While seeking to extend these findings in a larger sample we found that this SNP is associated with 0.74% lower body mass index (BMI) per minor allele in current smokers (95% CI -0.97 to -0.51, P = 2.00×10−10), but also unexpectedly found that it was associated with 0.35% higher BMI in never smokers (95% CI +0.18 to +0.52, P = 6.38×10−5). An interaction test confirmed that these estimates differed from each other (P = 4.95×10−13). This difference in effects suggests the variant influences BMI both via pathways unrelated to smoking, and via the weight-reducing effects of smoking. It would therefore be essentially undetectable in an unstratified genome-wide association study of BMI, given the opposite association with BMI in never and current smokers. This demonstrates that novel associations may be obscured by hidden population sub-structure. Stratification on well-characterized environmental factors known to impact on health outcomes may therefore reveal novel genetic associations.
We found that a single nucleotide polymorphism in the CHRNA5-A3-B4 gene cluster, which is known to influence smoking heaviness, is associated with lower body mass index (BMI) in current smokers, but higher BMI in never smokers. This difference in effects suggests that the variant influences BMI both via pathways other than smoking, and via the weight-reducing effects of smoking, in opposite directions. The overall effect on BMI would therefore be undetectable in an unstratified genome-wide association study, indicating that novel associations may be obscured by hidden population sub-structure.
Objectives: This research investigates the associations between body mass index (BMI) at 21, 40–59, 60–79 years of age on cardiometabolic risk markers at 60–79 years.
Methods: A prospective study of 3464 British men with BMI measured at 40–59 and 60–79 years, when cardiometabolic risk was assessed. BMI at 21 years was ascertained from military records, or recalled from middle-age (adjusted for reporting bias); associations between BMI at different ages and later cardiometabolic risk markers were examined using linear regression. Sensitive period, accumulation and mobility life course models were devised for high BMI (defined as BMI≥75th centile) and compared with a saturated BMI trajectory model.
Results: At ages 21, 40–59 and 60–79 years, prevalences of overweight (BMI≥25 kg/m2) were 12%, 53%, 70%, and obesity (≥30 kg/m2) 1.6%, 6.6%, and 17.6%, respectively. BMI at 21 years was positively associated with serum insulin, blood glucose, and HbA1c at 60–79 years, with increases of 1.5% (95%CI 0.8,2.3%), 0.4% (0.1,0.6%), 0.3% (0.1,0.4%) per 1 kg/m2, respectively, but showed no associations with blood pressure or blood cholesterol. However, these associations were modest compared to those between BMI at 60–79 years and serum insulin, blood glucose and HbA1c at 60–79 years, with increases of 8.6% (8.0,9.2%), 0.7% (0.5,0.9%), and 0.5% (0.4,0.7%) per 1 kg/m2, respectively. BMI at 60–79 years was also associated with total cholesterol and blood pressure. Associations for BMI at 40–59 years were mainly consistent with those of BMI at 60–79 years. None of the life course models fitted the data as well as the saturated model for serum insulin. A sensitive period at 50 years for glucose and HbA1c and sensitive period at 70 years for blood pressure were identified.
Conclusions: In this cohort of men who were thin compared to more contemporary cohorts, BMI in later life was the dominant influence on cardiovascular and diabetes risk. BMI in early adult life may have a small long-term effect on diabetes risk.
To examine associations between sarcopenia, obesity, and sarcopenic obesity and risk of cardiovascular disease (CVD) and all-cause mortality in older men.
Prospective cohort study.
British Regional Heart Study.
Men aged 60–79 years (n = 4,252).
Baseline waist circumference (WC) and midarm muscle circumference (MAMC) measurements were used to classify participants into four groups: sarcopenic, obese, sarcopenic obese, or optimal WC and MAMC. The cohort was followed for a mean of 11.3 years for CVD and all-cause mortality. Cox regression analyses assessed associations between sarcopenic obesity groups and all-cause mortality, CVD mortality, CVD events, and coronary heart disease (CHD) events.
There were 1,314 deaths, 518 CVD deaths, 852 CVD events, and 458 CHD events during follow-up. All-cause mortality risk was significantly greater in sarcopenic (HR = 1.41, 95% CI = 1.22–1.63) and obese (HR = 1.21, 95% CI = 1.03–1.42) men than in the optimal reference group, with the highest risk in sarcopenic obese (HR = 1.72, 95% CI = 1.35–2.18), after adjustment for lifestyle characteristics. Risk of CVD mortality was significantly greater in sarcopenic and obese but not sarcopenic obese men. No association was seen between sarcopenic obesity groups and CHD or CVD events.
Sarcopenia and central adiposity were associated with greater cardiovascular mortality and all-cause mortality. Sarcopenic obese men had the highest risk of all-cause mortality but not CVD mortality. Efforts to promote healthy aging should focus on preventing obesity and maintaining muscle mass.
cardiovascular disease; mortality; muscle mass; obesity; sarcopenia
Falls affect approximately one third of community-dwelling older adults each year and have serious health and social consequences. Fear of falling (FOF) (lack of confidence in maintaining balance during normal activities) affects many older adults, irrespective of whether they have actually experienced falls. Both falls and fear of falls may result in restrictions of physical activity, which in turn have health consequences. To date the relation between (i) falls and (ii) fear of falling with physical activity have not been investigated using objectively measured activity data which permits examination of different intensities of activity and sedentary behaviour.
Cross-sectional study of 1680 men aged 71–92 years recruited from primary care practices who were part of an on-going population-based cohort. Men reported falls history in previous 12 months, FOF, health status and demographic characteristics. Men wore a GT3x accelerometer over the hip for 7 days.
Among the 12% of men who had recurrent falls, daily activity levels were lower than among non-fallers; 942 (95% CI 503, 1381) fewer steps/day, 12(95% CI 2, 22) minutes less in light activity, 10(95% CI 5, 15) minutes less in moderate to vigorous PA [MVPA] and 22(95% CI 9, 35) minutes more in sedentary behaviour. 16% (n = 254) of men reported FOF, of whom 52% (n = 133) had fallen in the past year. Physical activity deficits were even greater in the men who reported that they were fearful of falling than in men who had fallen. Men who were fearful of falling took 1766(95% CI 1391, 2142) fewer steps/day than men who were not fearful, and spent 27(95% CI 18, 36) minutes less in light PA, 18(95% CI 13, 22) minutes less in MVPA, and 45(95% CI 34, 56) minutes more in sedentary behaviour. The significant differences in activity levels between (i) fallers and non-fallers and (ii) men who were fearful of falling or not fearful, were mediated by similar variables; lower exercise self-efficacy, fewer excursions from home and more mobility difficulties.
Falls and in particular fear of falling are important barriers to older people gaining health benefits of walking and MVPA. Future studies should assess the longitudinal associations between falls and physical activity.
Falls; Fear of falls; Physical activity; Accelerometer; Older adults
Physical activity (PA) levels in older adults decline with age. The prevalence and correlates of adherence to current UK PA guidelines in older adults has not been studied using objectively measured PA, which can examine precisely whether PA is carried out in bouts of specified length and intensity.
Free living men and women aged 70–93 years from 25 towns in the United Kingdom, participating in parallel on-going population based cohort studies were invited (by post) to wear a GT3x accelerometer over the hip for one week in 2010–12. Adherence to UK PA guidelines was defined as ≥150 minutes/week of moderate or vigorous PA (MVPA) in bouts of ≥10 minutes; the effect of different intensities and durations were examined.
1593 men and 857 women participated (responses 51% and 29% respectively). 15% men and 10% women achieved ≥150 minutes/week of MVPA (defined as >1040 cpm) in bouts lasting ≥10 minutes. With MVPA defined as >1952 cpm, prevalences were 7% and 3% respectively. Those adhering to guidelines were younger, had fewer chronic health conditions, less depression, less severe mobility limitations, but higher exercise self-efficacy and exercise outcomes expectations. They rated their local environment more highly for social activities and leisure facilities, having somewhere nice to go for a walk and feeling safe after dark, They left the house on more days per week, were more likely to use active transport (cycle or walk) and to walk a dog regularly.
Few older adults attain current PA guidelines. Health promotion to extend the duration of moderate-intensity activity episodes to 10 minutes or more could yield important health gains among older adults. However future studies will need to clarify whether attaining guideline amounts of PA in spells lasting 10 minutes or more is critical for reducing chronic disease risks as well as improving cardiometabolic risk factors.
Older adults; Physical activity; Accelerometer; Physical health; Depression; Self-efficacy
Although diet quality is implicated in cardiovascular disease (CVD) risk, few studies have investigated the relation between diet quality and the risks of CVD and mortality in older adults. This study examined the prospective associations between dietary scores and risk of CVD and all-cause mortality in older British men. A total of 3328 men (aged 60–79 y) from the British Regional Heart Study, free from CVD at baseline, were followed up for 11.3 y for CVD and mortality. Baseline food-frequency questionnaire data were used to generate 2 dietary scores: the Healthy Diet Indicator (HDI), based on WHO dietary guidelines, and the Elderly Dietary Index (EDI), based on a Mediterranean-style dietary intake, with higher scores indicating greater compliance with dietary recommendations. Cox proportional hazards regression analyses assessed associations between quartiles of HDI and EDI and risk of all-cause mortality, CVD mortality, CVD events, and coronary heart disease (CHD) events. During follow-up, 933 deaths, 327 CVD deaths, 582 CVD events, and 307 CHD events occurred. Men in the highest compared with the lowest EDI quartile had significantly lower risks of all-cause mortality (HR: 0.75; 95% CI: 0.60, 0.94; P-trend = 0.03), CVD mortality (HR: 0.63; 95% CI: 0.42, 0.94; P-trend = 0.03), and CHD events (HR: 0.66; 95% CI: 0.45, 0.97; P-trend = 0.05) but not CVD events (HR: 0.79; 95% CI: 0.60, 1.05; P-trend = 0.16) after adjustment for sociodemographic, behavioral, and cardiovascular risk factors. The HDI was not significantly associated with any of the outcomes. The EDI appears to be more useful than the HDI for assessing diet quality in relation to CVD and morality risk in older men. Encouraging older adults to adhere to the guidelines inherent in the EDI criteria may have public health benefits.
We have investigated the role of muscle mass, natriuretic peptides and adipokines in explaining the obesity paradox.
The obesity paradox relates to the association between obesity and increased survival in patients with coronary heart disease (CHD) or heart failure (HF).
Prospective study of 4046 men aged 60–79 years followed up for a mean period of 11 years, during which 1340 deaths occurred. The men were divided according to the presence of doctor diagnosed CHD and HF: (i) no CHD or HF ii), with CHD (no HF) and (iii) with HF.
Overweight (BMI 25–9.9 kg/m2) and obesity (BMI ≥ 30 kg/m2) were associated with lower mortality risk compared to men with normal weight (BMI 18.5–24.9 kg/m2) in those with CHD [hazards ratio (HR) 0.71 (0.56,0.91) and 0.77 (0.57,1.04); p = 0.04 for trend] and in those with HF [HR 0.57 (0.28,1.16) and 0.41 (0.16,1.09; p = 0.04 for trend). Adjustment for muscle mass and NT-proBNP attenuated the inverse association in those with CHD (no HF) [HR 0.78 (0.61,1.01) and 0.96 (0.68,1.36) p = 0.60 for trend) but made minor differences to those with HF [p = 0.05]. Leptin related positively to mortality in men without HF but inversely to mortality in those with HF; adjustment for leptin abolished the BMI mortality association in men with HF [HR 0.82 (0.31,2.20) and 0.99 (0.27,3.71); p = 0.98 for trend].
The lower mortality risk associated with excess weight in men with CHD without HF may be due to higher muscle mass. In men with HF, leptin (possibly reflecting cachexia) explain the inverse association.
NT-proBNP, N-terminal pro-brain natriuretic peptide; HF, Heart failure; MI, Myocardial infarction; CHD, Coronary heart disease; CRP, C-reactive protein; WC, Waist circumference; BMI, Body mass index; MAMC, Mid arm muscle circumference; Obesity; Mortality; Cardiovascular disease; Leptin; Heart failure
Background The extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain.
Methods We calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual–participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies.
Results For people born between 1900 and 1960, mean adult height increased 0.5–1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96–0.99) for death from any cause, 0.94 (0.93–0.96) for death from vascular causes, 1.04 (1.03–1.06) for death from cancer and 0.92 (0.90–0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12–1.42) for risk of melanoma death to 0.84 (0.80–0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators.
Conclusion Adult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases.
Height; cardiovascular disease; cancer; cause-specific mortality; epidemiological study; meta-analysis
To determine how much physical activity (PA) is needed to protect against diabetes onset in older adults, whether protection is greater among overweight individuals, and whether taking up moderate activity in later life is beneficial.
RESEARCH DESIGN AND METHODS
Men (4,252) from a U.K. population-based cohort self-reported usual PA (regular walking and cycling, recreational activity, and sport) in 1996 and in 1998–2000, alongside other health behaviors and medical history. Fasting blood lipids were measured. Median follow-up was 7.1 years, during which 135 cases of type 2 diabetes (validated self-report) occurred.
Among 3,012 men free from cardiovascular disease and diabetes in 1998–2000, 9% reported no usual leisure-time PA, 23% occasional PA, and 15% vigorous PA. Compared with men reporting no activity, men reporting occasional, light, moderate, moderately vigorous, and vigorous PA had lower diabetes risks: hazard ratio (HR) 0.58 (95% CI 0.33–1.02), 0.39 (0.20–0.74), 0.38 (0.19–0.73), 0.39 (0.20–0.77), and 0.33 (0.16–0.70), respectively; P (trend) = 0.002, adjusted for age, social class, tobacco, alcohol, diet, and blood lipids. Adjustment for BMI, waist circumference, or fasting insulin attenuated HRs. HRs were stronger in men with BMI ≥28 vs. <28 kg/m2 (interaction P = 0.02). Compared with men reporting light activity or less in 1996 and 2000, men who became at least moderately active by 2000 or remained at least moderately active at both times had adjusted HRs of 0.62 (0.34–1.12) and 0.51 (0.31–0.82), respectively.
Even light PA markedly reduced diabetes risk in older men, especially among the overweight or obese. Taking up or maintaining at least moderate PA in older adulthood strongly protected against diabetes.
► IL-18 is hypothesized to destabilise atherosclerotic plaques, leading to thrombotic events. ► We prospectively studied serum IL-18 and CHD or stroke onset in older men and women. ► IL-18 was positively associated with adverse lipid and inflammatory profile. ► Results did not suggest independent associations between IL-18 and CHD or stroke risk.
IL-18 is hypothesized to destabilise atherosclerotic plaques, leading to thrombotic events and epidemiologic studies suggest that IL-18 may increase risk of CHD or CVD.
We examined prospective associations between levels of serum IL-18 and new CHD and stroke events in older men and women from a general population.
A case-control study was nested within a prospective cohort of men and women aged 60–79 years recruited from general practices in 25 British towns in 1998–2000 and followed-up for 7.5 years for fatal and non-fatal MI and stroke. Baseline IL-18 was measured in stored serum samples of incident cases of MI (n = 364) or stroke (n = 300) and two controls per case.
Geometric mean IL-18 levels were higher among the 364 MI cases than the 706 controls; 417.84 pg/mL (IQR 316.25, 537.44) compared to 386.90 pg/mL (IQR 296.54, 482.33), p(difference) = 0.002. IL-18 was positively associated with adverse lipid and inflammatory profiles. Men and women in the top third of baseline IL-18 levels had an age and sex-adjusted odds ratio (OR) for MI of 1.31 (95%CI 0.92, 1.85) compared with those in the lowest third; this attenuated to 1.05 (95%CI 0.72, 1.53) after additional adjustment for established vascular and inflammatory risk factors. Each doubling of IL-18 level was associated with an increased OR for MI 1.34 (95%CI 1.04, 1.72), which was attenuated on adjustment for established vascular and inflammatory risk factors; 1.09 (95%CI 0.83, 1.44).
Geometric mean IL-18 levels did not differ between stroke cases and controls. The OR for stroke associated with the highest compared to the lowest tertile of IL-18 was 1.24 (95%CI 0.84, 1.84). Results for MI and stroke did not differ by presence of pre-existing CVD, gender or age.
Circulating IL-18 levels were strongly associated with a range of established and novel risk factors but were not independently associated with risk of MI or stroke in our study.
Coronary heart disease; Stroke; Interleukin-18; Epidemiology; Cohort
Pulmonary function measures reflect respiratory health and predict mortality, and are used in the diagnosis of chronic obstructive pulmonary disease (COPD). We tested genome-wide association with the forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) in 48,201 individuals of European ancestry, with follow-up of top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P<5×10−8) with pulmonary function, in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1, and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
Rationale: Genomic loci are associated with FEV1 or the ratio of FEV1 to FVC in population samples, but their association with chronic obstructive pulmonary disease (COPD) has not yet been proven, nor have their combined effects on lung function and COPD been studied.
Objectives: To test association with COPD of variants at five loci (TNS1, GSTCD, HTR4, AGER, and THSD4) and to evaluate joint effects on lung function and COPD of these single-nucleotide polymorphisms (SNPs), and variants at the previously reported locus near HHIP.
Methods: By sampling from 12 population-based studies (n = 31,422), we obtained genotype data on 3,284 COPD case subjects and 17,538 control subjects for sentinel SNPs in TNS1, GSTCD, HTR4, AGER, and THSD4. In 24,648 individuals (including 2,890 COPD case subjects and 13,862 control subjects), we additionally obtained genotypes for rs12504628 near HHIP. Each allele associated with lung function decline at these six SNPs contributed to a risk score. We studied the association of the risk score to lung function and COPD.
Measurements and Main Results: Association with COPD was significant for three loci (TNS1, GSTCD, and HTR4) and the previously reported HHIP locus, and suggestive and directionally consistent for AGER and TSHD4. Compared with the baseline group (7 risk alleles), carrying 10–12 risk alleles was associated with a reduction in FEV1 (β = –72.21 ml, P = 3.90 × 10−4) and FEV1/FVC (β = –1.53%, P = 6.35 × 10−6), and with COPD (odds ratio = 1.63, P = 1.46 × 10−5).
Conclusions: Variants in TNS1, GSTCD, and HTR4 are associated with COPD. Our highest risk score category was associated with a 1.6-fold higher COPD risk than the population average score.
FEV1; FVC; genome-wide association study; modeling risk
The incidence of myocardial infarction (MI) in Britain has fallen markedly in recent years. Few studies have investigated the extent to which this decline can be explained by concurrent changes in major cardiovascular risk factors.
Methods and Results
The British Regional Heart Study examined changes in cardiovascular risk factors and MI incidence over 25 years from 1978 in a cohort of 7735 men. During this time, the age-adjusted hazard of MI decreased by 3.8% (95% confidence interval 2.6% to 5.0%) per annum, which corresponds to a 62% decline over the 25 years. At the same time, after adjustment for age, cigarette smoking prevalence, mean systolic blood pressure, and mean non–high-density lipoprotein (HDL) cholesterol decreased, whereas mean HDL cholesterol, mean body mass index, and physical activity levels rose. No significant change occurred in alcohol consumption. The fall in cigarette smoking explained the greatest part of the decline in MI incidence (23%), followed by changes in blood pressure (13%), HDL cholesterol (12%), and non-HDL cholesterol (10%). In combination, 46% (approximate 95% confidence interval 23% to 164%) of the decline in MI could be explained by these risk factor changes. Physical activity and alcohol consumption had little influence, whereas the increase in body mass index would have produced a rise in MI risk.
Modest favorable changes in the major cardiovascular risk factors appear to have contributed to considerable reductions in MI incidence. This highlights the potential value of population-wide measures to reduce exposure to these risk factors in the prevention of coronary heart disease.
myocardial infarction; risk factors; population; epidemiology; prevention
To investigate the role of medication in 20-year trends in blood pressure (BP) and blood lipids in older British men.
Methods and results
BP and lipids were measured in 4231 men from a representative cohort at baseline (1978–1980, aged 40–59 years) and after 20 years (1998–2000). Cohort-wide age-adjusted 20-year mean changes were as follows: systolic BP − 7.6 mmHg (95% confidence interval: − 9.7 to − 5.4); diastolic BP + 3.3 mmHg ( + 2.2 to + 4.5); non-high-density lipoprotein (HDL)-cholesterol − 0.4 mmol/l ( − 0.5 to − 0.2); HDL-cholesterol + 0.16 mmol/l ( + 0.13 to + 0.19). Much (79%) of the systolic BP fall occurred only among 1561 men (37%) reporting the use of BP-lowering medication during the follow-up; systolic BP changed by − 12.3 mmHg ( − 14.7 to − 9.9) and − 1.6 mmHg ( − 3.7 to + 0.5) among medication users and men not using medication, respectively (P < 0.001 for medication–time interaction). One-third of the non-HDL-cholesterol fall occurred only among 302 men (8%) reporting the use of lipid-regulating drugs; non-HDL-cholesterol changed by − 1.8 mmol/l ( − 2.0 to − 1.6) and − 0.2 mmol/l ( − 0.4 to − 0.1) among medication users and men not using medication, respectively (P< 0.001 for interaction). The HDL-cholesterol increase was not associated with lipid-regulating drug use (P=0.15 for interaction).
Decreases in BP were largely confined to medication users and overall changes in non-HDL-cholesterol were modest, suggesting the need for greater efforts to reduce BP and cholesterol among the general population. HDL-cholesterol increased among all men, likely reflecting cohort-wide improvements in associated health behaviours.
antihypertensive medication; blood pressure; cholesterol; epidemiology; lipid-regulating medication; time trends
We prospectively examined the relationship between lung function and risk of type-2 diabetes and fatal and nonfatal coronary heart disease (CHD) events and investigated the hypothesis that inflammation may underlie these associations.
RESEARCH DESIGN AND METHODS
A prospective study of 4,434 men aged 40–59 years with no history of cardiovascular disease (CHD or stroke) or diabetes drawn from general practices in 24 British towns and followed up for 20 years.
There were 680 major CHD events (276 fatal, 404 nonfatal) and 256 incident type 2 diabetes during the 20 years follow-up. Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) but not FEV1-to-FVC ratio were significantly and inversely associated with incident type 2 diabetes and fatal CHD events (not nonfatal events) after adjustment for age, potential confounders, and metabolic risk factors. The adjusted relative risk (RR) for type 2 diabetes (Quartile 1 vs. Quartile 4) were 1.59 (1.07–2.56) and 1.74 (1.16–2.61) for FVC and FEV1, respectively (P = 0.03 and P = 0.04 for trend). The corresponding RR for fatal CHD were 1.48 (1.00–2.21) and 1.81 (1.19–2.76) (P = 0.002 and P = 0.0003 for trend). Lung function was significantly and inversely associated with C-reactive protein and interleukin-6; the inverse associations with type 2 diabetes for FVC and FEV1 were attenuated after further adjustment for these factors (P = 0.14 and P = 0.11 for trend) but remained significant for fatal CHD (P = 0.03 and P = 0.01, respectively).
Restrictive rather than obstructive impairment of lung function is associated with incident type 2 diabetes (and fatal CHD) with both associations partially explained by traditional and metabolic risk factors and inflammation.
To estimate the extent to which increasing BMI may explain the rise in type 2 diabetes incidence in British men from 1984 to 2007.
RESEARCH DESIGN AND METHODS
A representative cohort ratio of 6,460 British men was followed-up for type 2 diabetes incidence between 1984 (aged 45–65 years) and 2007 (aged 67–89 years). BMI was ascertained at regular intervals before and during the follow-up.
Between 1984–1992 and 1999–2007, the age-adjusted hazard of type 2 diabetes more than doubled (hazard ratio 2.33 [95% CI 1.75–3.10]). Mean BMI rose by 1.42 kg/m2 (95% CI 1.10–1.74) between 1984 and 1999; this could explain 26% (95% CI 17–38) of the type 2 diabetes increase.
An appreciable portion of the rise in type 2 diabetes can be attributed to BMI changes. A substantial portion remains unexplained, possibly associated with other determinants such as physical activity. This merits further research.
Previous studies suggest that circulating levels of interleukin-18 (IL-18) may be prospectively related to risk of coronary heart disease (CHD) in the general population. We report new data from the largest prospective study to date, which are combined with data from all published prospective studies in a meta-analysis.
We measured baseline IL-18 levels in stored serum samples of subjects from a case–control study nested within a prospective study of 5661 men aged 40–59 years recruited from general practices in 18 British towns in 1978–1980 and followed-up for up to 16 years (median time to event 8.4 years) for fatal CHD and non-fatal myocardial infarction (595 cases, 1238 controls).
IL-18 concentrations were strongly related to cigarette smoking, triglyceride, HDL-cholesterol (inversely) and to circulating levels of several inflammatory and haemostatic markers. Men in the top third of baseline IL-18 levels had an age-adjusted odds ratio (OR) for CHD of 1.55 (95% CI 1.21, 1.98) compared with those in the lowest third; this was reduced to 1.30 (95% CI 0.99, 1.69) after additional adjustment for vascular risk factors and 1.12 (95% CI 0.84, 1.49) after further adjustment for CRP and IL-6. In meta-analyses of CVD, associations (or effect sizes) were consistent between studies; RRs were 1.63 (95% CI 1.46, 1.82) after age adjustment, 1.39 (95% CI 1.24, 1.55) after additional risk factor adjustment and 1.34 (95% CI 1.17, 1.54) after additional adjustment for inflammatory markers.
Circulating IL-18 is prospectively and independently associated with CVD risk.
Coronary heart disease; Epidemiology; Interleukin-18; Cohort; Meta-analysis
To examine the relationship between dietary fiber and the risk of type 2 diabetes in older men and the role of hepatic and inflammatory markers.
RESEARCH DESIGN AND METHODS
The study was performed prospectively and included 3,428 nondiabetic men (age 60–79 years) followed up for 7 years, during which there were 162 incident cases of type 2 diabetes.
Low total dietary fiber (lowest quartile ≤20 g/day) was associated with increased risk of diabetes after adjustment for total calorie intake and potential confounders (relative risk −1.47 [95% CI 1.03–2.11]). This increased risk was seen separately for both low cereal and low vegetable fiber intake. Dietary fiber was inversely associated with inflammatory markers (C-reactive protein, interleukin-6) and with tissue plasminogen activator and γ-glutamyl transferase. Adjustment for these markers attenuated the increased risk (1.28 [0.88–1.86]).
Dietary fiber is associated with reduced diabetes risk, which may be partly explained by inflammatory markers and hepatic fat deposition.
Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n ≤ 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n ≤ 883). We confirmed the reported locus at 4q31 and identified associations with FEV1 or FEV1/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 × 10−12), 4q24 in GSTCD (2.18 × 10−23), 5q33 in HTR4 (P = 4.29 × 10−9), 6p21 in AGER (P = 3.07 × 10−15) and 15q23 in THSD4 (P = 7.24 × 10−15). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.
The endopeptidase matrix metalloproteinase-9 (MMP-9) is implicated in atherosclerotic plaque rupture. We investigate prospective associations between MMP-9 and MI or stroke in an older general population cohort, accounting for established and novel cardiovascular risk factors.
Baseline serum MMP-9 was measured in incident MI (n = 368) and stroke (n = 299) cases and two controls per case, ‘nested’ in prospective studies of 4252 men and 4286 women aged 60–79 years, sampled from General Practices in Britain in 1998–2000, with 7-year follow-up for fatal and non-fatal MI and stroke.
Geometric mean MMP-9 was 528 ng/mL (IQR 397, 743) in MI cases compared to 501 ng/mL (IQR 370, 743) in controls, p = 0.10. Participants in the top compared to bottom third of MMP-9 levels had an age-adjusted odds ratio for MI of 1.53 (95% CI 1.09, 2.13), which attenuated to 1.18 (95% CI 0.81, 1.70) after adjustment for established and novel cardiovascular risk factors. There was weak evidence that OR differed according to pre-existing CVD; the OR for MI in 187 participants with pre-existing CVD was 2.20 (1.04, 4.64) and 1.24 (0.84, 1.82) in 715 participants without (LR test for interaction p = 0.06). Geometric mean MMP-9 levels were higher in stroke cases than controls; 522 ng/mL (IQR 363, 673) vs 487 (IQR 393, 704), p = 0.045; however adjustments similarly attenuated the associations.
While serum MMP-9 is univariately associated with risk of MI and stroke, it is not a strong independent risk marker for either.
MMP-9, matrix metalloproteinase-9; MI, myocardial infarction; CVD, cardiovascular disease; CHD, coronary heart disease; OR, odds ratio; IQR, inter-quartile range; CI, confidence interval; CRP, C-reactive protein; IL-6, interleukin-6; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; t-PA, tissue plasminogen activator; LR, likelihood ratio; Myocardial infarction; Stroke; Inflammation; Epidemiology; MMP-9; Prospective; Cohort
Tumour necrosis factor alpha (TNFα) is a pro-inflammatory cytokine implicated in atherosclerotic plaque formation. We investigated whether circulating TNFα is prospectively associated with myocardial infarction (MI) or stroke in the older general population, independently of established cardiovascular risk factors and other inflammatory markers related to CHD risk.
We measured baseline TNFα concentrations in stored serum samples of 362 incident MI and 299 incident stroke cases and controls (2 per case, frequency matched by age, gender and town) who were ‘nested’ in parallel prospective studies of 4252 men and 4286 women aged 60–79 years assessed in general practices in 24 British towns in 1998–2000 and followed up for an average 7 years for fatal and non-fatal MI and stroke.
TNFα levels were 11.4% (95% CI 9.5, 13.3%) higher among MI cases than controls; geometric mean 1.84 pg/mL compared to 1.63 pg/mL, p (difference) < 0.001. Participants in the top third of baseline TNFα levels had an age-adjusted odds ratio (OR) for MI of 1.75 (95%CI 1.22, 2.49) compared with those in the bottom third, which was reduced to 1.47 (95%CI 1.01, 2.14) after adjustment for established cardiovascular risk factors. However, further adjustment for C-reactive protein and interleukin-6 abolished the association OR 1.33 (95% CI 0.91, 1.66) and the linear trend. Excluding subjects with pre-existing CVD did not materially affect results. No significant association between TNFα and stroke was observed.
This study suggests that TNFα is not a strong independent risk marker for MI, and is not associated with risk of stroke.
TNFα, tumour necrosis factor alpha; MI, myocardial infarction; CVD, cardiovascular disease; CHD, coronary heart disease; OR, odds ratio; IQR, inter-quartile range; CI, confidence interval; CRP, C-reactive protein; IL-6, interleukin-6; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; t-PA, tissue plasminogen activator; LR, likelihood ratio; Myocardial infarction; Stroke; Inflammation; Epidemiology; TNFα; Prospective; Cohort
To examine long-term changes in environmental tobacco smoke (ETS) exposure in British men between 1978 and 2000, using serum cotinine.
Prospective cohort: British Regional Heart Study.
General practices in 24 towns in England, Wales and Scotland.
Non-smoking men: 2125 studied at baseline [questionnaire (Q1): 1978–80, aged 40–59 years], 3046 studied 20 years later (Q20: 1998–2000, aged 60–79 years) and 1208 studied at both times. Non-smokers were men reporting no current smoking with cotinine < 15 ng/ml at Q1 and/or Q20.
Serum cotinine to assess ETS exposure.
In cross-sectional analysis, geometric mean cotinine level declined from 1.36 ng/ml [95% confidence interval (CI): 1.31, 1.42] at Q1 to 0.19 ng/ml (95% CI: 0.18, 0.19) at Q20. The prevalence of cotinine levels ≤ 0.7 ng/ml [associated with low coronary heart disease (CHD) risk] rose from 27.1% at Q1 to 83.3% at Q20. Manual social class and northern region of residence were associated with higher mean cotinine levels both at Q1 and Q20; older age was associated with lower cotinine level at Q20 only. Among 1208 persistent non-smokers, cotinine fell by 1.47 ng/ml (95% CI: 1.37, 1.57), 86% decline. Absolute falls in cotinine were greater in manual occupational groups, in the Midlands and Scotland compared to southern England, although percentage decline was very similar across groups.
A marked decline in ETS exposure occurred in Britain between 1978 and 2000, which is likely to have reduced ETS-related disease risks appreciably before the introduction of legislation banning smoking in public places.
Cohort study; cotinine; environmental tobacco smoke; tobacco; trend
Objective—To assess the relation between alcohol intake and sudden cardiac death—ie, death within one hour of the onset of symptoms.
Design—Prospective study of a cohort of men followed up for eight years.
Setting—General practices in 24 towns in England, Wales, and Scotland.
Subjects—7735 men aged 40–59 at screening who were selected at randon from one general practice in each of 24 towns.
Main outcome measure—All deaths from ischaemic heart disease with particular reference to those that were sudden (death within one hour of the onset of symptoms).
Results—During the follow up period of eight years there were 217 deaths from ischaemic heart disease of which 117 (54%) were classified as sudden. Although heavy drinkers (more than six drinks daily) did not show a high incidence rate of fatal heart attack, they showed the highest incidence rate of sudden cardiac death. This was seen in both manual and non-manual workers and was most clearly seen in older (50–59) men. Death from ischaemic heart disease was more likely to be sudden in heavy drinkers than in other drinking groups; this phenomenon was seen irrespective of the presence or degree of pre-existing ischaemic heart disease. The positive association between heavy drinking and the incidence of sudden death was most apparent in men without pre-existing ischaemic heart disease, with heavy drinkers showing an increase of >60% compared with occasional or light drinkers. After adjustment for age, social class, and smoking, heavy drinkers free of pre-existing ischaemic heart disease had a marginally significantly higher incidence rates of sudden death than other drinkers combined (relative risk 2·00, 95% confidence interval 0·98 to 4·8). Additional adjustment for systolic blood pressure reduced the risk to 1·7.
Conclusions—This study suggests that heavy drinking is associated with an increased risk of sudden death. Studies that do not take pre-existing ischaemic heart disease into account are likely to underestimate the adverse effects of heavy drinking on the incidence of sudden death because the effects are not as evident in men with pre-existing ischaemic heart disease.
The drinking behaviour of 7735 middle-aged men drawn from general practices in 24 British towns was determined in 1978-80 and five years later in 1983-85. Those with heavier initial drinking were more likely to have reduced consumption after five years. At every level of consumption manual workers showed a greater tendency to decrease drinking than non-manual workers. Of those who became non-drinkers over the five years, 12% had been moderate or heavy drinkers. Men who were told by a doctor that they had developed ischaemic heart disease during the five years were more likely to reduce their alcohol consumption than men who remained free of ischaemic heart disease. Similarly, men who were put on regular medical treatment of any kind or who acquired two or more diagnoses of illness (including ischaemic heart disease) were more likely to become occasional or non-drinkers. Nondrinkers at both reviews had higher rates of diagnosed illness than drinkers. In particular, the ex-drinkers, who comprised 70% of non-drinkers at follow up, had higher rates of ischaemic heart disease and cardiovascular-related problems, such as high blood pressure and diabetes, than drinkers.
It is essential to be aware of the tendency for moderate or heavy drinkers to reduce or stop drinking over time, particularly if illness has been diagnosed. Non-drinkers and exdrinkers should not be used as a baseline in studies relating alcohol to disease.