Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.484852
Title: Molecular genetic epidemiological studies of smoking behaviour and growth promoting genes
Author: Huang, Shuwen
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2007
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Abstract:
Objectives: 1. Smoking is a major cause of death and often initiates in adolescence. Raploinsufficiency 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 associations 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 OR 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-CSHgene 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 *lA, *IB, *2, *4, *5, *9 and *12 to classify predicted nicotine metabolism rate. DBB, MAOA, DRD4 and 5HT2A markers were also studied. 2. Microsatellites CSHI.OI and IGFI(CA)n were genotyped and analysed in relation to birthweight and other metabolic traits in the SHHS cohort. 3. Combined analyses ofACEYD and GH-CSHBgl IlB 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. Linkage disequilibrium (LD) analysis and other genetic statistical analysis were carried out. Results: 1. Those predicted to be half normal metabolisers due to haploinsufficiency ofCYP2A6 (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 CSHI.OI IT genotype in the SHHS boys showed a higher birthweight compared with those DIDI or D2D2 genotype. There was no evidence for association ofthe IGFI(CA)n genotype with birthweight in the SHHS, but boys of 1921192bp genotype did show a leg length 0.65cm greater (p=0.05) than those not homozygous for allele I92bp. 3. A significant association between GH-CSHBgl lIB and ACE activity was detected but only through its LD with ACEYD. No association between GH-CSHBgl lIB and LVM change was found. Conclusions: 1. CYP2A6 haploinsufficiency increases likelihood of continuing smoking in teenagers. 2. My study provides evidence for effects ofGH-CSHon birthweight in males. Complexities ofmy data relative to previous data are discussed. 3. Cardiac muscle growth response to exercise and ACE levels both appear to be attributable to ACE polymorphism and not to nearby GH-CSHpolymorphism, although this does not exclude otherACE attributed phenotypes being due to GH-CSHvariation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.484852  DOI: Not available
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