We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10⁻⁷); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent ‘false leads’ with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.

The controversy about determining the body mass index (BMI) that is associated with lowest all-cause mortality has been fuelled by differences in analytical approaches.^1-3 Depending on how the exposure is defined or which populations or subgroups are analyzed, it is possible to estimate different BMI values to be associated with lowest all-cause mortality.^4-11 The U-shaped pattern of the association of BMI with mortality has been a point of contention; the increased risk of mortality observed with BMI in the low normal range has been suggested to be caused by residual confounding due to concurrent disease or decline in BMI due to disease,¹ while others have suggested this is caused by a detrimental effect of low BMI.^2,3 However, whether the association has changed over time in the general population has not been addressed adequately. Previous findings indicate that while average BMI has increased over time in most countries, the prevalence of cardiovascular risk factors may be decreasing among obese individuals over time.¹² Thus, the BMI associated with lowest all-cause mortality may have changed over time. The few studies addressing this question have used subgroups from differently recruited cohorts with limited or incomplete follow-up, with conflicting results making firm conclusions difficult.^13,14

Coronary atherosclerosis may develop at an early age and remain latent for many years. To define characteristics of subclinical coronary atherosclerosis associated with the development of myocardial infarction. Prospective observational cohort study. Copenhagen General Population Study, Denmark. 9533 asymptomatic persons aged 40 years or older without known ischemic heart disease. Subclinical coronary atherosclerosis was assessed with coronary computed tomography angiography conducted blinded to treatment and outcomes. Coronary atherosclerosis was characterized according to luminal obstruction (nonobstructive or obstructive [≥50% luminal stenosis]) and extent (nonextensive or extensive [one third or more of the coronary tree]). The primary outcome was myocardial infarction, and the secondary outcome was a composite of death or myocardial infarction. A total of 5114 (54%) persons had no subclinical coronary atherosclerosis, 3483 (36%) had nonobstructive disease, and 936 (10%) had obstructive disease. Within a median follow-up of 3.5 years (range, 0.1 to 8.9 years), 193 persons died and 71 had myocardial infarction. The risk for myocardial infarction was increased in persons with obstructive (adjusted relative risk, 9.19 [95% CI, 4.49 to 18.11]) and extensive (7.65 [CI, 3.53 to 16.57]) disease. The highest risk for myocardial infarction was noted in persons with obstructive-extensive subclinical coronary atherosclerosis (adjusted relative risk, 12.48 [CI, 5.50 to 28.12]) or obstructive-nonextensive (adjusted relative risk, 8.28 [CI, 3.75 to 18.32]). The risk for the composite end point of death or myocardial infarction was increased in persons with extensive disease, regardless of degree of obstruction-for example, nonobstructive-extensive (adjusted relative risk, 2.70 [CI, 1.72 to 4.25]) and obstructive-extensive (adjusted relative risk, 3.15 [CI, 2.05 to 4.83]). Mostly White persons were studied. In asymptomatic persons, subclinical, obstructive coronary atherosclerosis is associated with a more than 8-fold elevated risk for myocardial infarction. AP Møller og Hustru Chastine Mc-Kinney Møllers Fond.

Rationale: Asthma is associated with complications, cardiovascular comorbidities, and higher mortality in some individuals. Objectives: To test the hypothesis that, among individuals with asthma, never-smokers have different characteristics and a better prognosis than smokers. Methods: We recruited 94,079 individuals aged 20–100 years from the Copenhagen General Population Study, a prospective cohort study. Among these individuals, 5,691 (6%) had self-reported asthma (2,304 never-smokers, 2,467 former smokers, and 920 current smokers). We examined respiratory symptoms, lung function, and levels of inflammatory and allergic biomarkers in systemic circulation. Furthermore, we assessed prospectively the risk of asthma or chronic obstructive pulmonary disease (COPD) exacerbations, pneumonias, lung cancer, ischemic heart disease, ischemic stroke, and all-cause mortality during 4.5 years of follow-up. Measurements and Main Results: Compared with never-smokers without asthma, individuals with asthma had more respiratory symptoms and airflow limitation and higher levels of inflammatory and allergic biomarkers, which were most pronounced in smokers. Among individuals with asthma compared with never-smokers without asthma, multivariable adjusted hazard ratios for asthma exacerbations were 11 (95% confidence interval: 5.8–22) in never-smokers, 13 (6.2–29) in former smokers, and 18 (8.2–39) in current smokers. The corresponding values for other endpoints were, respectively, 8.9 (2.1–38), 23 (8.8–58), and 36 (12–105) for COPD exacerbations; 1.5 (0.9–2.2), 1.6 (1.0–2.4), and 2.4 (1.6–3.7) for pneumonias; 0.6 (0.1–5.1), 4.0 (1.3–12), and 13 (4.3–41) for lung cancer; 1.2 (0.9–1.6), 1.5 (1.2–2.0), and 2.0 (1.4–2.9) for ischemic heart disease; 1.4 (0.9–2.1), 1.2 (0.8–1.9), and 3.0 (1.7–5.3) for ischemic stroke; and 0.9 (0.6–1.3), 1.5 (1.1–2.0), and 2.7 (1.9–3.7) for all-cause mortality. Conclusions: Never-smokers with asthma had an increased risk of asthma and COPD exacerbations, and possibly pneumonias. Importantly, the risks for lung cancer, cardiovascular comorbidities, and death were restricted to smokers with asthma. Thus, tobacco smoking was the main explanation for poor prognosis in asthma.