Influence of ethnicity on pharmacogenetics : evaluation of therapeutically important polymorphic genes in an African (Ghanaian) population
Pharmacogenetics involves research into the hereditary basis for the different responses of individuals to drugs or other environmental pollutants. Several functional genetic polymorphisms of drug metabolising enzymes, transporters, receptors and other drug targets have been identified and characterised and these polymorphisms may be responsible for interethnic differences in drug disposition and disease risk. Few studies have focussed on ethnic African populations. Several genes that have known genetic polymorphism and have clinical implications for disease risk and/or treatment of patients were evaluated in a sample of the Ghanaian (West African) population. Catechol-O-methyltransferase (COMT) catalyses the 0-methylation of neurotransmitters, catechol hormones and drugs such as levodopa and methyldopa. Ethnic differences in COMT activity have been observed in several populations. Previous studies suggest that the homozygous low activity allele (COMT*L) is less common in individuals of African origin than Caucasians. COMT genotyping was performed using a mini-sequencing method in 195 healthy Ghanaians. The frequency of the homozygous low activity allele was 6%. In Caucasians it is 31%. This study provides confirmation that the low activity COMT allele is less common in individuals of African origin. This finding may be important clinically with regards to the treatment of many neuropsychiatric disorders and in the pathophysiology of various human disorders including oestrogen-induced cancers, Parkinson's disease, depression and hypertension. This thesis aimed to determine the allele frequency of therapeutically important genetic polymorphisms in an African (Ghanaian) population. The data was then compared to other ethnic populations. The marked racial and ethnic differences in the frequency of functional polymorphisms in these drug- and xenobiotic-metabolising enzymes, transporters, receptors and other drug targets shows that ethnic origin needs to be considered in studies aimed at discovering whether specific genotypes or phenotypes are associated with disease risk or drug toxicity. Genotyping prior to treatment may be essential, as 95% of the Ghanaian subjects genotyped had between one and four mutations in the therapeutically important genes analysed. Genotyping assays specific for predominant mutant alleles should be used in different ethnic groups.