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

Abstract

Background: 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. We studied the association of HMOX1 polymorphisms and HO-1 serum concentrations with vascular complications and all-cause mortality in individuals with type 1 diabetes (T1D). Methods: The study population consists of individuals with T1D participating in the 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 serum HO-1 concentrations (n = 861) from blood samples taken during their study visit. The GTn repeats were divided into short (S) and long (L) alleles where the cutoff point was L ≥ 30 repeats. Results: In men, the LL genotype was associated with ischemic cardiac events (LL 22.9% vs. SS/SL 17.0%, p = 0.001) and all-cause mortality (p = 0.031). The association was detected in all individuals (LL 19.5% vs. SS/SL 16%, p = 0.006) but not in women (LL 15.7% vs. SS/SL 14.9%, p = 0.657). For the -413A/T SNP, men with the AA genotype experienced ischemic cardiac events more frequently (21.0% vs. 17.4%, p = 0.044), but no differences were found for women or for men and women together. There were no differences between different genotypes of the + 99G/C variant regarding cardiovascular complications. Also, there was no difference in HO-1 serum concentrations between different genotypes (GTn repeat, -413A/T or + 99G/C). Men had higher HO-1 serum concentrations compared to women (3.12 ± 1.23 ng/ml vs. 2.64 ± 1.04 ng/ml, p < 0.001). In women, higher HO-1 serum concentrations were associated with cardiovascular disease and need for antihypertensive and lipid lowering medications. Conclusions: The LL genotype of the HMOX1 GTn repeat and the AA genotype of -413A/T SNP were associated with ischemic cardiac complications and all-cause mortality in men, but not in women. Thus, the HMOX1 genotype may influence the development of cardiovascular complications in individuals with T1D in a sex-dependent manner.