Molecular genetic epidemiological studies of smoking behaviour and growth promoting genes

Huang, Shuwen (2007) Molecular genetic epidemiological studies of smoking behaviour and growth promoting genes. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

Objectives: 1. Smoking is a major cause of death and often initiates in adolescence. Haploinsufficiency of CYP2A6 in adults is associated with lower cigarette consumption, lower cotinine level and higher quit rates. Other genes are also implicated in smoking behaviour. I explored genotypes of CYP2A6 and other genes in relation to smoking behaviour and cotinine levels in the UK-wide School Heart and Health Study (SHHS). 2. The association between low birthweight and adult disorders have been widely investigated. Environmental factors have been widely investigated but there has been less focus on genetic factors. There is however evidence that GH-CSH influences adult GH level, one year weight, metabolic syndrome traits and bone loss. I focused on major growth genes in relation to birthweight and other metabolic traits in the SHHS cohort. 3. Results from previous studies led to the hypothesis that some ACE D allele phenotypic associations may represent proxy marking of causal factors located in the GH-CSH gene cluster. I tested this hypothesis for cardiac muscle growth response to exercise and ACE level in a British army heart study cohort.

Methods: 1. 1,520 subjects from the SHHS were genotyped for CYP2A6 alleles *1A, *1B, *2, *4, *5, *9 and *12 to classify predicted nicotine metabolism rate. DBH, MAOA, DRD4 and 5HT2A markers were also studied. 2. Microsatellites CSH1.01 and IGF2(CA)n were genotyped and analysed in relation to birthweight and other metabolic traits in the SHHS cohort. 3. Combined analyses of ACE I/D and GH-CSH Bgl IIB in relation to exercise induced left ventricular mass (LVM) change and serum ACE activity were investigated in a group of Caucasian males in the UK.

Results: 1. Those predicted to be half normal metabolisers due to haploinsufficiency of CYP2A6 (carriers of one fully inactive allele, i.e. *2, *4, or *5) were more likely to be a current smoker at age 18 years. Current versus ever odds ratio was 1.95 (95% C.I. 1.03-3.68). Salivary cotinine levels in current smokers were significantly lower in the ‘normal’ group compared with ‘slow’ or ‘very slow’ group. 2. The CSH1.01 TT genotype in the SHHS boys showed a higher birthweight compared with those D1D1 or D2D2 genotype. There was no evidence for association of the IGF1(CA)n genotype with birthweight in the SHHS, but boys of 192/192bp genotype did show a leg length 0.65cm greater (p=0.05) than those not homozygous for allele 192bp. 3. A significant association between GH-CSH Bgl IIB and ACE activity was detected but only through its LD with ACE I/D. No association between GH-CSH Bgl IIB and LVM change was found.