The Haptoglobin genotype predicts cardio-renal mortality in type 1 diabetes

Abstract

Aims The Haptoglobin (HP) 2-2 genotype increases cardiovascular diabetes complication incidence. In type 1 diabetes, HP 2-2 also predicts declining kidney function and end-stage renal disease. We investigated whether HP 2-2 predisposes to cardio-renal mortality, while considering other causes of death as competing risks. Methods Individuals with type 1 diabetes and HP data available (n=486; mean baseline age, 27 and duration, 19 years) were selected for study. Vital status was assessed as of 8/31/2014. The underlying cause of death was determined and classified based on standardized procedures. Results During 25 years of follow-up, 79 (16.3%) cardio-renal deaths and 43 (8.8%) deaths related to other causes occurred. Although total mortality did not differ by HP (25.4% with HP 1 versus 24.6% with HP 2-2, p=0.84), a greater proportion of HP 2-2 carriers exhibited a cardio-renal death (19.0 versus 14.2, p=0.05). In time-to-event analyses, HP 2-2 was associated with a statistically significant increase of the sub-distribution hazard ratio for cardio-renal mortality (HR=1.64, p=0.03), although this effect was somewhat attenuated after multivariable adjustment (HR=1.58, p=0.05). Conclusions Our results suggest that in addition to predicting the incidence of cardio-renal complications, HP 2-2 also increases susceptibility for cardio-renal mortality in type 1 diabetes. These findings require validation in other cohorts.

Haptoglobin 2–2 genotype and the risk of coronary artery disease in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study (DCCT/EDIC)

“…In type 1 diabetes, the Pittsburgh Epidemiology of Diabetes Complications (EDC) study has been the only thus far to evaluate the role of the Hp genotype in the development of CAD, providing similar evidence for an increased risk with the Hp 2-2 genotype (17). In EDC, the Hp 2-2 genotype was also a strong predictor of declining renal function and progression to end-stage renal disease (18), findings which were recently confirmed in the DCCT/EDIC study (19), as well as of mortality attributed to cardiovascular or renal causes (20). …”

Haptoglobin 2-2 Genotype, Patient, and Graft Survival in Renal Transplant Recipients

“…The distribution of Hp genotypes was similar to previous studies (Hp 1-1: 13.2%, Hp 2-1: 44.5%, Hp 2-2: 42.3%). 15 Haptoglobin Genotype and CVD…”

“…Previous reports indicate a positive association between Hp 2-2 genotype and decline in renal function and end-stage renal disease incidence in patients with diabetes. 15,20 Glomerular filtration of Hp 2-2 proteins increases iron deposition in and damage to renal proximal tubule cells. 21 In patients with end-stage renal disease, Hp 2-2 genotype was associated with higher high-sensitive C-reactive protein levels, indicating a relationship between Hp genotype and inflammation.…”

The protean role of haptoglobin and haptoglobin genotypes on vascular complications in diabetes mellitus

“…60 In the same cohort, an association of Hp2-2 individuals with an increase in cardio-renal mortality was also observed. 61 In the large T1DM DCCT/EDIC cohort with duration of follow-up median 26 years, a significant association of myocardial infarction was seen with Hp2-2 individuals in the secondary cohort (consisting of patients with duration of diabetes: 1–15 years with early minor complications, for example, retinopathy/microalbuminuria). 62 These data suggest that in individuals with advanced T1DM, the Hp2-2 genotypes confer a higher risk of cardiovascular complications.…”

“…We have summarized in Table 2 the human studies looking at association of Hp genotypes with complications in T1DM. 58–72 Studies have been conducted in three large cohorts of T1DM in the United States: 1. Coronary Artery Calcification in T1DM (CACTI); 2. the Pittsburgh Epidemiology of Diabetes Complications (EDC) study, and 3.…”