Meta-analysis of the association of the haptoglobin genotype with cardiovascular outcomes and the pharmacogenomic interactions with vitamin E supplementation

Abstract

Objectives: The objectives of the study were to compile and summarize the data from all of the clinical trials designed to examine the association between haptoglobin (Hp) genotype and incidence of cardiovascular (CV) events in patients with diabetes mellitus (DM) and to assess the impact of vitamin E treatment on CV outcomes according to the Hp genotype.

Background: The Hp genotype could serve as a predictive biomarker to DM patients who may benefit from vitamin E therapy.

Methods: The electronic databases MEDLINE, PubMed, EMBASE and the Cochrane Library for Central Register of Clinical Trials were searched systematically using the following MESH terms: "haptoglobin genotype", "diabetes mellitus" and "cardiovascular events".

Results: Overall, 13 studies fit the inclusion criteria for this analysis, yielding a large study population that included 6,161 patients without Hp 2-2 and 4,684 patients with Hp 2-2. The analysis of these studies showed that the incidence of CV events in DM patients with the Hp 2-2 genotype was significantly increased as compared to non-Hp 2-2 patients in all three subgroups of case-control (OR: 2.2, 95% CI: 1.3-3.6; P=0.003), cohort (OR: 1.3, 95% CI: 1.2-1.5; P=0.001) and randomized controlled trials (OR: 1.6, 1.2-2.2; P=0.005). Among patients with the Hp 2-2 genotype, administration of vitamin E was associated with lower rates of CV events (OR: 0.66, 95% CI: 0.45-0.95; P=0.025). Further investigation into the association between Hp 2-2 and myocardial infarction, stroke, mortality and end-stage renal disease was also performed.

Conclusion: The Hp genotype is a risk factor for CV events in patients with DM, and administration of vitamin E appears to offer a low cost and accessible means of reducing CV events and mortality in this population.

Keywords: HDL dysfunction; antioxidants; cardiovascular disease; diabetes mellitus; haptoglobin genotype; vitamin E.

Figure 1

Search strategy for studies used in our meta-analysis.

Figure 2

Hp 2-2 genotype and risk of CV events and effect of vitamin E on major CV outcomes. Notes: (A) Random effect meta-analysis of cohort studies and RCTs for CV events between Hp 2-2 and non-Hp 2-2 genotypes. The figure presents number of events, number of patients in treatment and control groups, OR and 95% CI for each trial, overall OR estimate with 95% CI and P value for association test, P value for heterogeneity test and between trial inconsistency (I²) measures. (B) Random effect meta-analysis of the effects of vitamin E administration on CV events in diabetic patients with the Hp 2-2 genotype. (C) Random effect meta-analysis of the effects of vitamin E administration on CV events in diabetic patients without the Hp 2-2 genotype. Abbreviations: CV, cardiovascular; DCCT/EDIC, Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study; DHS, Diabetes Heart Study; EDC, Epidemiology of Diabetes Complications; HOPE, Heart Outcomes Prevention Evaluation; Hp, haptoglobin; HPFS, Health Professionals Followup Study; ICARE, Israeli Cardiovascular Vitamin E; NHS, Nurses’ Health Study; RCT, randomized controlled trial; SHS, Strong Heart Study; WHS, Women’s Health Study.

Figure 3

Hp 2-2 genotype and risk of MI and effect of vitamin E on MI risk. Notes: (A) Random effect meta-analysis of cohort studies and RCTs for MI between Hp 2-2 and non-Hp 2-2 genotypes. (B) Random effect meta-analysis of the effects of vitamin E administration on MI in diabetic patients with the Hp 2-2 genotype. Abbreviations: DCCT/EDIC, Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study; HOPE, Heart Outcomes Prevention Evaluation; Hp, haptoglobin; ICARE, Israeli Cardiovascular Vitamin E; MI, myocardial infarction; RCT, randomized controlled trial; WHS, Women’s Health Study.

Figure 4

Hp 2-2 genotype and risk of all-cause mortality. Note: Random effect meta-analysis of cohort studies and RCTs for all-cause mortality between Hp 2-2 and non-Hp 2-2 genotypes. Abbreviations: DHS, Diabetes Heart Study; Hp, haptoglobin; RCT, randomized controlled trial; WHS, Women’s Health Study.

Figure 5

Hp 2-2 genotype and risk of CV mortality and the effect of vitamin E on CV mortality risk. Notes: (A) Random effect meta-analysis of cohort studies and RCTs for CV mortality between Hp 2-2 and non-Hp 2-2 genotypes. (B) Random effect meta-analysis of the effects of vitamin E administration on CV mortality in diabetic patients with the Hp 2-2 genotype. Abbreviations: CV, cardiovascular; DHS, Diabetes Heart Study; HOPE, Heart Outcomes Prevention Evaluation; Hp, haptoglobin; ICARE, Israeli Cardiovascular Vitamin E; RCT, randomized controlled trial; WHS, Women’s Health Study.

Figure 6

Hp 2-2 genotype and risk of stroke and effect of vitamin E on stroke risk. Notes: (A) Random effect meta-analysis of cohort and randomized controlled studies for stroke between Hp 2-2 and non-Hp 2-2 genotypes. (B) Random effect meta-analysis of the effects of vitamin E administration on stroke in diabetic patients with the Hp 2-2 genotype. Abbreviations: HOPE, Heart Outcomes Prevention Evaluation; Hp, haptoglobin; ICARE, Israeli Cardiovascular Vitamin E; RCT, randomized controlled trial; WHS, Women’s Health Study.

Figure 7

Hp 2-2 genotype and risk of ESRD. Note: Random effect meta-analysis for ESRD between Hp 2-2 and non-Hp 2-2 genotypes. Abbreviations: DCCT, Diabetes Control and Complications Trial; EDC, Epidemiology of Diabetes Complications; ESRD, end-stage renal disease; Hp, haptoglobin; RCT, randomized controlled trial.

Figure 8

Mechanistic explanations of the increased risk of atherosclerosis CVD in patients with the Hp 2-2 genotype and the mechanistic rationale of using vitamin E to reduce CV burden in this cohort. Notes: Top right image shows an illustration of how the Hp 2-2 genotype in diabetic patients leads to decreased clearance of Hp–Hb complexes due to downregulation of the CD163 receptor. The higher steady state of the cell-free Hp–Hb complexes leads to the generation of ROS via the Fenton reaction subsequently to lipid peroxidation. It also leads to more binding of the Hp 2-2–Hb complexes to HDL and subsequent oxidation of lipoproteins. This renders HDL dysfunction causing increased inflammation, reduced antioxidant ability, reduced RCT, increased atherogenesis and an increased risk of CV events. The bottom right image shows how vitamin E therapy can reverse this cascade by maintaining the balance between antioxidant and ROS and remove the associated risk with the Hp 2-2 genotype. The figures on the left show how vitamin E therapy can cause an increased risk of hypertension, bleeding and increased CVD in DM patients with the non-Hp 2-2 genotype by disturbing the balance of antioxidants and ROS with administration of vitamin E. Abbreviations: CV, cardiovascular; CVD, cardiovascular disease; Hb, hemoglobin; HDL, high-density lipoprotein; Hp, haptoglobin; LDL, low-density lipoprotein; ROS, reactive oxygen species.