Studies towards stratified approaches to smoking cessation with a focus on South Asians and effectiveness of varenicline

Smoking is a preventable risk factor for many diseases and cancers. Pharmacotherapies such as varenicline have been utilised to aid quit smoking attempts. However, the genetic underpinnings of response to varenicline are not well understood. Despite reported genetic associations with smoking behaviours in European populations, very few efforts have been made to investigate the genetic underpinnings of smoking behaviours in other populations such as South Asians, the second largest population in the UK. This thesis aims to investigate the genetic basis of the long term effectiveness of varenicline in the EXCEED Study, and the genetic basis of smoking initiation in South Asians in UK Biobank.

In this thesis, I devised a phenotyping algorithm to study long term effectiveness of varenicline using linked primary care electronic health records. A candidate-gene case-control analysis of varenicline long term effectiveness was then performed which highlighted 7 SNPs across the nicotinic receptor subunit coding genes CHRNA7, CHRNA4, and CHRNB4 at nominal significance. The variant most significantly associated with successful cessation was in CHRNA4, the gene encoding the target receptor of varenicline. Finally, a genome-wide case-control analysis of smoking initiation (ever- vs never-smokers) in South Asians in the UK Biobank highlighted 11 SNPs in DIMT1-KIF2A-IPO11, RBM3, and BHLHE40 associated with smoking initiations with P < 5×10−6, signals not previously described in either South Asians or Europeans.

These findings, if replicated, could provide insights into the biological mechanisms underlying successful cessation using varenicline, and underlying smoking initiation in South Asians.