Mendelian randomization analysis to assess a causal effect of haptoglobin on macroangiopathy in Chinese type 2 diabetes patients

Abstract

Background: Haptoglobin (Hp) functions as an antioxidant by binding with haemoglobin. We investigated whether serum Hp has a causal effect on macroangiopathy via Mendelian randomization (MR) analysis with common variants of the Hp gene in Chinese patients with type 2 diabetes.

Methods: A total of 5687 type 2 diabetes patients were recruited and genotyped for the Hp gene. Clinical features and vascular imaging tests were applied to diagnose macroangiopathy. The association between common Hp genotypes and macroangiopathy was analyzed in the whole population. Serum Hp levels were measured by enzyme-linked immunosorbent assay in a subset of 935 patients. We individually analyzed the correlations among Hp levels, Hp genotypes and macroangiopathy. Further, 8-hydroxy-2'-deoxyguanosine (8-OHdG), an oxidative marker of DNA damage, was examined to evaluate the levels of oxidative stress.

Results: Common Hp genotypes were correlated with macroangiopathy (OR = 1.140 [95% CI 1.005-1.293], P = 0.0410 for the Hp 1 allele). Serum Hp levels were associated with both common Hp genotypes (P = 3.55 × 10^-31) and macroangiopathy (OR = 2.123 [95% CI 1.098-4.102], P = 0.0252) in the subset of 935 patients. In the MR analysis, the directional trends of the observed and predicted relationships between common Hp genotypes and macroangiopathy were the same (OR 1.357 and 1.130, respectively). Furthermore, common Hp genotypes and Hp levels were associated with serum 8-OHdG levels (P = 0.0001 and 0.0084, respectively).

Conclusions: Our study provides evidence for a causal relationship between serum Hp levels and macroangiopathy in Chinese type 2 diabetes patients by MR analysis.

Keywords: Haptoglobin; Macroangiopathy; Mendelian randomization; Type 2 diabetes.

Fig. 1

Serum haptoglobin (Hp) levels in 935 patients grouped by Hp genotype. The Hp levels are shown in dot plots; the median is indicated by the middle of the black solid line. The lower and upper quartiles are shown by the bottom and top of the black solid line, respectively. a Presents a comparison of serum Hp levels between non-Hp del (common Hp genotypes) and Hp del carriers, P = 2.61 × 10⁻³⁰; b presents a comparison of the serum Hp levels among different common Hp genotypes (P = 3.55 × 10⁻³¹) based on a multiple linear regression analysis

Fig. 2

Framework of the Mendelian randomization analysis used in this study. The solid lines represent the observed associations in the three-way study: β₁ for the effect size estimate of common variants of the Hp (haptoglobin) gene on serum Hp levels, OR₂ for the association between Hp levels and diabetic macroangiopathy, and OR₃ for the observed association between common variants of the Hp gene and diabetic macroangiopathy. The dashed line represents the predicted association between common variants of the Hp gene and diabetic macroangiopathy: OR₄ was calculated as exp(β₁ × log_e OR₂). OR₃ for the observed association and OR₄ for the predicted association between common variants of the Hp gene and diabetic macroangiopathy in the current study were both larger than 1

Fig. 3

Serum 8-OHdG levels in 935 patients grouped by Hp genotype. 8-OHdG 8-hydroxy-2′-deoxyguanosine, Hp haptoglobin. The 8-OHdG levels are shown in dot plots; the median is indicated by the middle of the black solid line. The lower and upper quartiles are shown by the bottom and top of the black solid line, respectively. a Presents a comparison of serum 8-OHdG levels between non-Hp del (common Hp genotypes) and Hp del carriers, P = 0.0548; b presents comparisons of serum 8-OHdG levels among common Hp genotypes, P = 0.0001, based on multiple linear regression analysis