This dissertation examined two distinct phenotypes, on the hypothesis that they have a common pathway of etiology related to the Pro12Ala polymorphism of the peroxisome proliferator activated receptor (PPAR) γ2 gene, a transcription factor involved in adipogenesis. Mild reduction in transcription activity was observed for a common, nonconservative substitution at codon 12 (Pro12Ala).
In the first paper, the association between PPARγ2 Pro12Ala polymorphism and the risk of type 2 diabetes was investigated in the Atherosclerosis Risks in Community (ARIC) study. In the prevalence analysis at baseline, Ala/- genotype was associated with decreased risk of diabetes, while no association was observed in the incidence analysis over a seven year follow-up period. Ala/- genotype is also associated with a lower insulin resistance index at baseline. The association between three adipocytokines (adiponectine, interleukin-6, and leptin) and Pro12Ala resulted in a null association. Thus, the study did not show any evidence that the relationship between PPARγ2 Pro12Ala and diabetes is through adipocytokines.
In the second paper, the association between PPARγ2 Pro12Ala polymorphism and the risk of HIV lipodystrophy syndrome was investigated in the Women's Interagency HIV Study (WIHS) cohort. Abnormal fat distribution was classified as lipoatrophy and lipohypertrophy for peripheral and central sites based on self-reporting and confirmation with anthropometric measurements. The analysis revealed that there was no association between the development of lipodystrophy and Pro12Ala genotype. Next, the association between metabolic syndrome and insulin resistance with Pro12Ala genotype was examined. Neither showed significant correlation with polymorphism. Further investigation of the anthropometrics and factors in the criteria of metabolic syndrome did not show any significant difference in terms of polymorphism. Research in a genetic determinant for diabetes, a common, complex disease which is epidemic in many countries, and HIV related lipodystrophy, possibly an adverse effect of anti-retroviral medication, has implications for public health and clinical medicine. Areas for future research related to this parallel study design are discussed.
|School:||The Johns Hopkins University|
|School Location:||United States -- Maryland|
|Source:||DAI-B 68/04, Dissertation Abstracts International|
|Keywords:||Diabetes, HIV, Insulin resistance, Lipodystrophy, PPARgamma|
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