Understanding associations between smoking behaviour and poorer health: conventional and Mendelian randomization approaches

Background: Cigarette smoking is the leading preventable risk factor of morbidity and mortality in the world. Many studies have examined the association between smoking and health outcomes. Observational, cross-sectional studies can be confounded, and hence the casualty of associations between smoking and health outcomes cannot be established. A genetic epidemiological approach such as Mendelian randomization (MR) can be informative concerning potential causal associations between smoking and health outcomes. MR leverages the availability of genetic data on smoking and health outcomes to estimate confounder-free associations. The current thesis was carried out to investigate the observational and causal associations between smoking behaviour and cardiometabolic diseases, stroke, and lipid biomarkers. Methods: Firstly, detailed reviews of prior research were conducted, highlighting that the majority of previous research was observational in nature. The thesis utilised the relatively large sample of UK Biobank (N=~502k) to conduct observational as well as MR-based analyses. The observational approach was based on self-report for multiple smoking phenotypes (smoking status, smoking intensity, and age at smoking initiation), clinical diagnoses for cardiometabolic diseases (CMDs; coronary heart disease (CHD), hypertension (HTN), and diabetes mellitus (DM)), stroke, and lipid biomarkers (total cholesterol, low-density lipoproteins, triglycerides, and high-density lipoproteins). The genetic analysis was based on 14 single-nucleotide polymorphisms (SNPs) for smoking intensity (cigarettes smoked per day: CperD) and 15 SNPs for smoking history. The genetic analysis was conducted in the UK Biobank sample (one-sample MR) as well as publicly available ‘summary statistic’ genetic data (two-sample MR). The analyses were conducted using R software and the MR-Base platform. Results: Observationally (analysis: chapter four), current smokers had a higher risk of CHD (odds ratio [OR]: 1.61, P0.05, and HTN: 1.01, P0.05, TG: β=-0.01 mmol/L, P<0.001, HDL: β=0.04 mmol/L, P