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Aims: The common copy number variant (CNV) in the haptoglobin (Hp) gene may influence the susceptibility to diabetic macrovascular diseases. We aimed to investigate the relationship of the genetic variant rs2000999, located in the haptoglobin-related protein (HPR) gene, with serum Hp levels and diabetic macrovascular diseases in Chinese type 2 diabetes patients.Methods: The Hp CNV and rs2000999 were genotyped in a group of 5457 Chinese patients with type 2 diabetes. Associations of rs2000999 with the common Hp CNV, susceptibility to diabetic macrovascular diseases and related metabolic traits were analysed. Furthermore, 886 patients were selected to detect serum Hp levels and to evaluate the correlation between rs2000999 and serum Hp levels.Results: The genetic variant rs2000999 was not associated with diabetic macrovascular diseases (P = 0.6109), while subjects carrying the A allele had higher levels of low-density lipoprotein cholesterol (P = 0.0578) and a smaller inter-adventitial diameter of the common carotid artery (P = 0.0266). Additionally, rs2000999 exhibited strong association with serum Hp levels (P = 2.03 × 10-21).Conclusions: The genetic variant rs2000999 was not associated with diabetic macrovascular diseases but showed an association with metabolic traits and serum Hp levels in Chinese patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

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 enzymelinked 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. [ABSTRACT FROM AUTHOR]