The Haptoglobin 2-2 genotype is associated with major adverse vascular events in type 2 diabetes mellitus: a longitudinal follow-up study

Abstract Background The haptoglobin (Hp) genotype consists of 2 alleles, with the Hp2-2 genotype associated with increased oxidative stress and cardiovascular disease in type 2 diabetes mellitus (T2DM)1,2. Major adverse vascular events (MAVE) is a composite outcome measure of macrovascular complications capturing peripheral vascular disease. The association between Hp genotype and MAVE, particularly in Asian populations, is unclear. We examined whether the Hp 2-2 genotype is associated with MAVE in a multiethnic T2DM cohort. Methods We conducted a prospective observational study of 355 adults with T2DM from January 2014 to June 2018 at a tertiary Diabetes clinic and followed up till June 2025. Hp genotype determined by real-time PCR (Taqman assay). Baseline demographics, anthropometrics and cardiometabolic profiles were obtained. Incident MAVE was ascertained through electronic medical records. Time-to-event analysis and Cox proportional hazards models were performed. Results The Hp2-2 haptoglobin genotype was present in 54% (191/355), with higher prevalence in Indian versus Chinese participants (70.1% vs 45.6%, p0.01). Hp2-2 individuals had lower haptoglobin (113 vs 139 mg/dL, p0.01) and higher non-HDL-cholesterol concentrations (3.38 vs 3.09 mmol/L, p=0.014) at baseline (Table 1). Over 8.3 years median follow-up, the cumulative MAVE event rate was 20.6% (69/335; lost to follow-up:20), with Hp2-2 individuals experiencing higher event rates (p=0.026) (Figure 1). Multivariate Cox regression revealed that the Hp2-2 genotype predicted MAVE risk (HR 1.72; 95% CI 1.02–2.91; p=0.04), independent of age, sex, ethnicity, BMI, systolic blood pressure, HbA1c, and non-HDL-cholesterol. Conclusion The Hp2-2 haptoglobin genotype is independently associated with myocardial and vascular events in T2DM. Future prospective and mechanistic studies are required to establish whether this genotype functions as an independent vascular risk enhancer in Asians.For image description, please refer to the figure legend and surrounding text. For image description, please refer to the figure legend and surrounding text.