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Background: Observationally, reports on the association between milk intake and risk of ischaemic heart disease (IHD) and myocardial infarction (MI) have produced conflicting results; and no previous large-scale study using the lactase persistent/non-persistent LCT-13910 C/T genotype as a largely unconfounded proxy for milk intake free of reverse causation has been conducted. We tested the hypothesis that milk intake observationally and genetically through the LCT-13910 C/T genotype is associated with risk of IHD and MI in a Mendelian randomization design. Methods: We included 98 529 White individuals of Danish descent, aged 20-100 years, from three studies of the general population. Information on IHD (N=10 372) and MI (N=4188) were obtained from national Danish registries. First, we investigated observational associations between milk intake and incident IHD and MI. Second, we confirmed the association between the rs4988235 genetic variant LCT-13910 C/T, associated with lactase persistence/non-persistence, and milk intake. Finally, we tested whether LCT-13910 C/T genotype was associated with risk of IHD and MI as well as with cardiovascular risk factors. Results: During a mean follow-up time of 5.4 years, the observational hazard ratio for a 1 glass/week higher milk intake was 1.00 [95% confidence interval (CI): 1.00,1.01] for both IHD and MI. Median milk intake was 3 glasses/week (interquartile range: 0-7) in lactase CC non-persistent individuals compared with 5 glasses/week (0-10) in lactase TC/TT persistent individuals (P=3*10-60). In the dominant genetic model comparing lactase TC/TT persistent individuals with lactase CC non-persistent individuals, the odds ratio was 1.00 (0.92,1.09) for IHD and 0.96 (0.84,1.09) for MI. Finally, in the dominant genetic model genotype was not associated convincingly with plasma levels of total cholesterol, low density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides or glucose, nor with blood pressure. Conclusion: Milk intake was not associated with risk of IHD or MI, observationally orgenetically [ABSTRACT FROM AUTHOR]

Background: Conflicting evidence has been found regarding the association between high tobacco consumption and body weight among smokers. We tested the hypothesis that high tobacco consumption is causally associated with low body weight. Methods: We conducted a Mendelian randomization study with a genetic variant in CHRNA3 (rs1051730) as proxy for high tobacco consumption. The cohort consisted of 80 342 participants from the Copenhagen General Population Study, with details on body weight, smoking habits and CHRNA3 genotype, including 15 220 current smokers. Results: In observational analyses, high tobacco consumption was associated with high body weight, body mass index, waist circumference, hip circumference and waist-hip ratio. In multivariable adjusted models a 1-cigarette/day higher tobacco consumption was associated with 0.05 kg (95% confidence interval 0.02; 0.08) higher body weight, 0.02 kg/m² (0.01; 0.02) higher body mass index, 0.10cm (0.07; 0.12) higher waist circumference and 0.02cm (0.001; 0.03) higher hip circumference. In contrast, the per-allele increase inCHRNA3 rs1051730 associated with high tobacco consumption was associated with 0.59 kg (0.96; 0.22) lower body weight, 0.23 kg/m² (0.33; 0.13) lower body mass index, 0.32cm (0.74; 0.003) lower waist circumference and 0.45cm (0.66; 0.24) lower hip circumference. No association was found between tobacco consumption and waist-hip ratio in genetic analysis, or among CHRNA3 genotype and any of the outcome variables in former or never smokers. Conclusions: High tobacco consumption causes lower body weight among current smokers. However, smoking does not seem to affect body shape or fat distribution causally. The lack of association between CHRNA3 genotype and body weight among former smokers and never smokers favours smoking as the causal factor for the observed associations. [ABSTRACT FROM AUTHOR]

Background: High cumulative tobacco consumption is associated with short telomeres and with increased all-cause mortality. We tested the hypothesis that high tobacco consumption is causally associated with short telomeres and with increased all-cause mortality.Methods: We studied 55 568 individuals including 32 823 ever smokers from the Danish general population, of whom 3430 died during 10 years of follow-up. All had telomere length measured, detailed information on smoking history, and CHRNA3 rs1051730 genotype, which is associated with tobacco consumption, determined. In a Mendelian randomization study, we conducted observational, genetic, and mediation analyses.Results: First, tobacco consumption was 21.1 pack-years in non-carriers, 22.8 in heterozygotes and 24.8 in homozygotes (P-trend <0.001). Second, the observational multivariable adjusted hazard ratio for all-cause mortality was 1.12 [95% confidence interval (CI): 1.09, 1.15] per doubling in tobacco consumption. In Mendelian randomization analysis, the hazard ratio was 1.08 (1.02, 1.14) per minor CHRNA3 allele in ever smokers. Third, in observational analysis telomeres shortened with −13 base pairs (−18, −8) per doubling in tobacco consumption. In Mendelian randomization analysis, the estimate was +3 base pairs (−10, +15) per minor CHRNA3 allele. Finally, individuals with the shortest vs longest telomeres had a multivariable adjusted hazard ratio of 1.30 (1.13, 1.50) for all-cause mortality; however, in mediation analysis short telomeres explained only +0.4% (−3.5%, +4.3%) of the association between high tobacco consumption and increased all-cause mortality.Conclusions: High tobacco consumption is causally associated with increased all-cause mortality. High cumulative tobacco consumption is associated with short telomeres observationally, but there is no clear genetic association. [ABSTRACT FROM AUTHOR]