Heme oxygenase-1 polymorphisms associate with ischemic cardiac complications and mortality in type 1 diabetes

Abstract

Abstract Background/Introduction Heme oxygenase-1 (HO-1), encoded by the HMOX1 gene is a highly inducible enzyme with multiple cardiovascular protective properties. Polymorphisms of the HMOX1 gene, especially a guanine-thymine dinucleotide repeat polymorphism (GTn), affects its transcriptional activity and is associated with cardiovascular complications in the general population. Purpose We studied the association of HMOX1 polymorphisms and HO-1 plasma levels with cardiovascular complications in patients with type 1 diabetes (DM1). Methods The study population consists of patients with DM1 participating in the nationwide, multicenter Finnish Diabetic Nephropathy Study (FinnDiane). We genotyped the HMOX1 GTn repeat (n=3990), extracted from genome-wide genotyping data two single nucleotide polymorphisms (SNPs) (−413A/T upstream variant rs2071746, and +99G/C p.Asp7Asn missense variant rs2071747; n=4278), and measured the plasma HO-1 levels (n=861) from blood samples taken during a regular visit to the study center. The GTn repeats were divided into short (S) and long (L) alleles where the cutoff point was L>29 repeats. Results In men, LL genotype was associated with ischemic cardiac events (LL 22.9% vs. SS/SL 17.0%, p=0.001, see figure) and mortality (p=0.031, see figure). The association was detected also when analyzing all patients (LL 19.5% vs. SS/SL 16%, p=0.006, see figure) but not women alone (LL 15.7% vs. SS/SL 14.9%, p=0.657). For −413A/T SNP, men with AA genotype had higher odds for ischemic cardiac events (21.0% vs. 17.4%, p=0.044, see figure) but no differences in women or all together were found. There were no differences between different genotypes of +99G/C for cardiovascular complications. There was no difference in HO-1 plasma levels between different genotypes (GTn repeat, −413A/T or +99G/C). Men had significantly higher HO-1 plasma levels compared to women (3.12±1.23 ng/l vs. 2.64±1.04 ng/l, p<0.001). Interestingly, in women, higher HO-1 plasma levels were associated with cardiovascular complications and the need for antihypertensive and lipid lowering medications. Conclusions In men, but not in women LL genotype of the HMOX1 GTn repeat and AA genotype of −413A/T SNP were associated with ischemic cardiac complications and mortality. Thus, HMOX1 genotype may influence the development of cardiovascular complications in DM1 patients in a gender-dependent manner. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The Finnish Foundation for Cardiovascular ResearchFinnish State Funding for university-level research