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Background <p>Heme oxygenase 1 (HO-1), encoded by the <i>HMOX1</i> gene is a highly inducible enzyme with multiple cardiovascular protective properties. Polymorphisms of the <i>HMOX1</i> 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 <i>HMOX1</i> polymorphisms and HO-1 serum concentrations with vascular complications and all-cause mortality in individuals with type 1 diabetes (T1D).</p> Methods <p>The study population consists of individuals with T1D participating in the Finnish Diabetic Nephropathy Study (FinnDiane). We genotyped the <i>HMOX1</i> GTn repeat (<i>n</i> = 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; <i>n</i> = 4278), and measured the serum HO-1 concentrations (<i>n</i> = 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.</p> Results <p>In men, the LL genotype was associated with ischemic cardiac events (LL 22.9% vs. SS/SL 17.0%, <i>p</i> = 0.001) and all-cause mortality (<i>p</i> = 0.031). The association was detected in all individuals (LL 19.5% vs. SS/SL 16%, <i>p</i> = 0.006) but not in women (LL 15.7% vs. SS/SL 14.9%, <i>p</i> = 0.657). For the -413A/T SNP, men with the AA genotype experienced ischemic cardiac events more frequently (21.0% vs. 17.4%, <i>p</i> = 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&#xa0;ng/ml vs. 2.64 ± 1.04&#xa0;ng/ml, <i>p</i> &lt; 0.001). In women, higher HO-1 serum concentrations were associated with cardiovascular disease and need for antihypertensive and lipid lowering medications.</p> Conclusions <p>The LL genotype of the <i>HMOX1</i> 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 <i>HMOX1</i> genotype may influence the development of cardiovascular complications in individuals with T1D in a sex-dependent manner.</p>

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

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  • 发表日期：

    2025年8月18日

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  • Heli Segersvärd,
  • Niina Sandholm,
  • Valma Harjutsalo,
  • Heidi Tikkanen,
  • Riikka Kosonen,
  • Mika Laine,
  • Ilkka Tikkanen,
  • Per-Henrik Groop,
  • Päivi Lakkisto

摘要

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.