Haptoglobin Phenotype Modulates Lipoprotein-Associated Risk for Preeclampsia in Women with Type 1 Diabetes

Abstract

Preeclampsia (PE) occurs more frequently in pregnant diabetic than nondiabetic women (∼20% vs. ∼5%). Early identification of high risk women is needed. Dyslipidemia is implicated: we previously showed that early in pregnancy, increased cholesterol-rich lipoproteins are associated with subsequent PE in type 1 diabetes (T1D). Haptoglobin (Hp) is a plasma protein that binds free hemoglobin, and has two allelic forms, Hp-1, Hp-2, hence three phenotypes. Among people with diabetes, Hp 2-2 phenotype (present in ≈50%) has been associated with oxidative stress, cardiovascular risk and renal decline. We investigated whether maternal Hp phenotype is associated with PE in T1D, and/or modulates lipoprotein-related risks for PE. A prospective study of pregnancy included 23 T1DM women (cases) who developed PE, and 24 T1DM (controls) who remained normotensive. All were free of microalbuminuria and hypertension at enrolment. Hp phenotype was determined by ELISA (Savyon Diagnostics Ltd.). Lipid profiles were measured at three study visits (V1-V3), all preceding PE onset: (mean ± SD) 12.4 ± 1.8, 21.7 ± 1.4, and 31.3 ± 1.4 weeks gestation. Results: Hp phenotype did not differ between women with and without PE, and lipid profiles did not differ by Hp phenotype. In PE cases vs. controls, by univariate analysis, HDL-C was lower at V1 (1.9±0.4 vs. 2.2±0.5 mmol/l (mean ± SD)), while LDL-C was higher at V2 (3.1± 1.0 vs. 2.6± 0.8 mmol/l), as were triacylglycerols (1.6± 0.4 vs. 1.3± 0.4 mmol/l) (p<0.05). In Hp 2-2 women, these associations were stronger: in 2-2 cases (n=11) vs. 2-2 controls (n=9), HDL-C was lower at all visits (V1: p<0.05; V2, V3: p<0.01) and LDL-C was higher at V1 (p<0.01) and V2 (p<0.05). In contrast, in women with one or two Hp-1 alleles, no associations between lipids and PE were observed. Conclusion: In T1D women, lipoprotein-related risks for PE may be limited to those with Hp 2-2 phenotype. The data provide further evidence of a role for Hp phenotype as a modulator of vascular risk in diabetes. Disclosure C.B. Kelly: None. J. Yu: None. A. Jenkins: Research Support; Self; Medtronic, Mylan, Sanofi-Aventis. A.J. Nankervis: None. K.F. Hanssen: None. S.K. Garg: Research Support; Self; Dexcom, Inc., Eli Lilly and Company, Sanofi US. Advisory Panel; Self; Sanofi US. Research Support; Self; MannKind Corporation, Diasome Pharmaceuticals, Inc., Labstyle Innovations, Lexicon Pharmaceuticals, Inc., Medtronic. Advisory Panel; Self; Novo Nordisk A/S. C.E. Aston: None. T. Lyons: None.