Cytochrome P450 polymorphisms : relevance in two South African disease populations

[摘要] ENGLISH ABSTRACT:With knowledge of the human genome increasing constantly we are continually facedwith new and potentially groundbreaking methods for managing, treating and/oridentifying diseases and predisposition to diseases and conditions at a genetic level.The human cytochrome P450 (CYP) super-family of genes code for enzymes that canparticipate in metabolism of drugs and foreign chemicals and in steroid synthesis andmetabolism. Mutations in these genes may contribute to clinically relevant diseases.In this study, the effects of mutations within four CYP genes were evaluated in twoSouth African disease groups - variegate porphyria and breast cancer.Variegate porphyria (VP) has an unusually high incidence in South Africa due to theR59W founder mutation in the protoporphyrinogen oxidase (PPOX) gene that causesa disruption in the haem biosynthetic pathway. VP presents with variable clinicalsymptoms and has a relatively low penetrance. It is expected that environmentalfactors and modifier genes play a role in the clinical expression of VP. CYP genesare implicated as candidate modifier genes for the expression of VP due to thefunction they have in metabolising many drugs contraindicated in porphyria patients,and the necessity of haem binding to the apoprotein to produce a functional CYPenzyme. This is the first study to investigate CYPs as possible modifier genes for VPclinical expression. Six CYP polymorphisms (CYPIAlml, CYPIAlm2, CYPIA2 -734 C>A, CYPIBI 8372 A>C, CYP2D6*3, CYP2D6*4), associated with four CYPloci, were genotyped in a VP population and a suitable control population. Theresults observed are suggestive of CYPIAlml and CYPIBI playing a role asmodifiers for the clinical expression of VP as they were significantly associated(PA and CYPIBI 8372 A>C). Thisrepresents the first investigation of the potential role of CYPs as breast cancer riskmodifiers in the two South African populations. Significant differences wereobserved (PC polymorphism in the population ofmixed ancestry. Vast differences in allele frequencies were also observed betweenthe two groups of breast cancer populations. These results emphasize the importanceof population-based risk assessment when genetic testing and counselling for complexdisease susceptibility is offered.The results of this study provide the first evidence suggesting a role for CYPs inmodifying the clinical expression of VP and in acting as risk factors for developingbreast cancer in a South African population.

[发布机构] Stellenbosch University