Heme oxygenase-1 (HO-1) plays a critical role in protecting the cardiovascular system from the damaging effects of oxidative stress. The anti-inflammatory, antioxidant, antiproliferative and vasodilatory effects of its reaction products (carbon monoxide, free ferrous iron, and bilirubin) mediate cardiovascular protection. Two promoter polymorphisms found in HMOX1, the gene encoding HO-1, are reported to have contrasting effects on gene transcription. The A allele of the single nucleotide polymorphism (SNP) located at base −413 has been shown to increase transcriptional activity, while a (GT)n microsatellite promoter polymorphism has been shown to decrease HMOX1 transcription when the GT repeat number exceeds 25. These polymorphisms have been associated with cardiovascular disease, and have different frequency distributions based upon ethnicity.
The main goal of the experiments in this dissertation was to examine the relationship between the HMOX1 promoter polymorphisms and cardiovascular disease, while placing special emphasis on the African American ethnic group. Genotyping of the polymorphisms was performed by sequence analysis of the HMOX1 promoter. The microsatellite allele was classified as large (L) if the GT repeat was < 26 and small (S) if the GT repeat was < 26. The HMOX1 SNP-413 was genotyped according to the bases present at position −413 of the sequences. In general, the African American subjects were significantly associated with the large repeat microsatellite polymorphism and the T allele of the SNP-413. The Caucasian subjects were significantly associated with the small repeat microsatellite polymorphism and the A allele of the SNP-413. The L microsatellite allele and A SNP-413 allele was the most frequent allele combination seen in all subjects. Coronary artery disease was significantly associated with the LL microsatellite genotype in African Americans and the AA SNP-413 genotype in Caucasians. Congestive heart failure was significantly associated with the LL microsatellite genotype and TT SNP-413 genotype in African Americans. The author concludes that the large microsatellite polymorphism of HMOX1 is associated with cardiovascular disease in the African American population, and these subjects are possibly more susceptible to diseases resulting from oxidative stress due to deficient HO-1 activity.