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

Abstract

BackgroundHaptoglobin (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.MethodsA 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.ResultsCommon 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).ConclusionsOur study provides evidence for a causal relationship between serum Hp levels and macroangiopathy in Chinese type 2 diabetes patients by MR analysis.Electronic supplementary materialThe online version of this article (10.1186/s12933-018-0662-7) contains supplementary material, which is available to authorized users.

Haptoglobin polymorphisms in Latin American populations

“…It is speculated that rs5471 A, rs5472 A, HP 1 , and rs2000999 G alleles and the A-1-G haplotype were prevalent, and HP 2 and G-1-G haplotypes (this means HP 1F and mainly migrations from Europe and Africa) were rare in Native Americans. Interestingly, all of the alleles with higher frequency in the Latin Americans are associated with higher serum HP and lower cholesterol levels 5,23,24,[27][28][29][30] . In addition, the genetic influx from populations of other continents into Peruvians seems to be relatively lower than into other Latin Americans, as suggested by previous studies on autosomal, X-, or Y-chromosomal and mitochondrial markers or SNPs or our FUT2 data on the same subjects [39][40][41] .…”

“…In addition, associations between these polymorphisms as well as rs2000999 and serum cholesterol levels were reported 5,23,24,[27][28][29][30] . Each allele of the polymorphisms that correlated with a higher HP level was associated with lower cholesterol levels despite the population, although no report is available for rs5471 yet.…”

“…In addition, gender, age, smoking, plasma Hb levels, serum lipids, and some genetic factors were shown to be associated with circulating HP levels 21 , 22 . Serum HP concentrations are reported to be associated with the common HP genotypes and HP del 3 , 12 , 23 . A SNP located in HPR intron 2 (rs2000999), which was originally identified as one of the genetic determinants of serum total cholesterol by a genome-wide association study (GWAS) 24 , was thereafter reported to be associated with the serum HP level 12 , 21 – 23 , 25 .…”

“…Serum HP concentrations are reported to be associated with the common HP genotypes and HP del 3 , 12 , 23 . A SNP located in HPR intron 2 (rs2000999), which was originally identified as one of the genetic determinants of serum total cholesterol by a genome-wide association study (GWAS) 24 , was thereafter reported to be associated with the serum HP level 12 , 21 – 23 , 25 . A promoter SNP at position − 61 (rs5471), a characteristic SNP of Africans, was identified as a causal polymorphism of HP 2-1 modified phenotypes due to a decreased amount of HP2 polypeptide relative to that of HP1 polypeptide 6 .…”

Obesity and diabetes as comorbidities for COVID-19: Underlying mechanisms and the role of viral–bacterial interactions

“…On the other hand, plasma levels of LPS binding protein are increased in obesity and T2D, demonstrating a positive correlation with BMI ( Sato et al, 2014 ); CD14 expression is enhanced in obese humans ( Fernández-Real et al, 2011 ), and the serum levels of haptoglobin are increased both in diabetic rats ( Jelena et al, 2013 ) and in T2D patients ( McMillan, 1989 ). Enhanced expression of haptoglobin correlates with serum viscosity and was causally connected with the appearance of various microangiopathies in T2D patients ( Wang et al, 2018 ). Importantly, micro-thrombosis is very common in COVID-19 pneumonia ( Price et al, 2020 ).…”