The Haptoglobin (Hp) 2-2 genotype has been shown to increase the risk of coronary artery disease (CAD), kidney dysfunction and mortality from cardiovascular and renal causes in type 1 diabetes (T1D), although similar associations have not been observed in nondiabetic persons. However, whether the Hp 2 allele is associated with cardiac autonomic neuropathy (CAN), a CAD predictor, has not been previously studied. We thus assessed the presence of such an association in participants with childhood onset T1D (EDC study, n=216, mean 51 years) and age and gender matched nondiabetic controls (RETRO HDLc study, n=200). CAN was defined as a history of abnormal heart rate response to deep breathing (expiration-inspiration ratio < 1.1). The proportion of Hp 2 allele carriers did not differ by T1D (87% in T1D vs. 84% in controls, p=0.13), although participants with T1D had a greater CAN prevalence compared with controls (49% vs. 12%, respectively, p<0.0001). In multivariable logistic regression models, adjusting for traditional risk factors (age, BMI, hypertension, HDL and non-HDL cholesterol, albumin to creatinine ratio, estimated glomerular filtration rate (eGFR), white blood cell count), and T1D status, participants with any Hp 2 allele had significantly higher odds of CAN compared with participants with the Hp 1-1 genotype (OR=2.91, p=0.01). Age (OR=1.04, p=0.02), the presence of T1D (OR=5.17, p<0.0001), hypertension (OR=1.76, p=0.05) and eGFR (OR=0.98, p=0.003) were also associated with CAN. No significant interaction was found between T1D and Hp genotype (p=0.73); thus, stratifying by T1D, Hp 2 increased the odds of CAN in both T1D (OR=2.50, p=0.07) and controls (OR=6.70, p=0.08).

In conclusion, unlike the restriction of the Hp - kidney disease association to individuals with diabetes, the Hp 2 allele appears to be independently associated with greater odds of CAN in both T1D and nondiabetic controls.


J. Ju: None. E.L. Tomaszewski: None. T.J. Orchard: Consultant; Self; Boehringer Ingelheim International GmbH. T. Costacou: None.


National Institutes of Health (R01HL130153, DK34818)

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