Haptoglobin Genotype as a Determinant of Benefit or Harm from Niacin in the AIM HIGH Study

Rabea Asleh ¹ Nina S. Levy ² Gheorge Doros ³ Tina Costacou ⁴ Jennifer G. Robinson ⁵ William E. Boden ⁶ Debra L. Simmons ⁷ Patrice Desvigne-Nickens ⁸ George Grunberger ⁹ Todd J. Anderson ¹⁰ Andrew P. Levy ²

¹Department of Cardiology, Rambam Medical Center and Laboratory of Vascular Medicine, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa
²Laboratory of Vascular Medicine, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa
³Department of Epidemiology, Harvard Clinical Research Institute and Boston University School of Public Health, Boston, MA
⁴Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA
⁵Colleges of Public Health and Medicine, University of Iowa, Iowa City, IA
⁶Department of Medicine, Albany Stratton Veteran Affairs Medical Center, Albany, NY
⁷Utah Diabetes and Endocrinology Center, University of Utah, Salt Lake City, UT
⁸Division of Cardiovascular Sciences, National Heart Lung and Blood Institute, NIH, Bethesda, MD
⁹Department of Endocrinology and Metabolism, Grunberger Diabetes Institute, Bloomfield Hills, MI
¹⁰Department of Cardiac Sciences, Libin Cardiovascular Institute, Calgary, Alberta

Background: HDL raising therapy has not shown any benefit on cardiovascular outcomes. Raising HDL in individuals in whom the HDL is dysfunctional may promote atherogenesis. Haptoglobin (Hp) is a serum protein which is part of the HDL proteome. The Hp 1 and Hp 2 alleles at the Hp genetic locus produce marked differences in HDL structure and function. HDL structure and function are abnormal in individuals with the Hp 2-2 genotype.

Objectives: This study sought to determine if there was a pharmacogenomic interaction between the Hp genotype and niacin on changes in HDL functional metrics.

Methods: Serum induced reverse cholesterol transport function and HDL antioxidant function were measured in 70 Hp 1-1 and 70 Hp 2-2 participants from the AIM HIGH study at baseline and at one year after randomization to placebo or niacin.

Results: Niacin was associated with a significant increase in reverse cholesterol transport function only in study participants with the Hp 1-1 genotype. HDL antioxidant function was significantly improved in Hp 1-1 study participants with niacin but was significantly worsened in Hp 2-2 study participants who received niacin (p=0.0001 for interaction between Hp genotype and niacin on HDL function). In nearly half of the Hp 2-2 cohort HDL promoted rather than inhibited oxidation.

Conclusions: There is a pharmacogenomic interaction between the Hp genotype and niacin on HDL functional metrics.

Please upload your file