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Human Molecular Genetics Advance Access originally published online on July 28, 2004
Human Molecular Genetics 2004 13(19):2197-2205; doi:10.1093/hmg/ddh233
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Human Molecular Genetics, Vol. 13, No. 19 © Oxford University Press 2004; all rights reserved

A common haplotype at the CD36 locus is associated with high free fatty acid levels and increased cardiovascular risk in Caucasians

Xiaowei Ma1,2, Simonetta Bacci3, Wojciech Mlynarski1,2, Lucia Gottardo4, Teresa Soccio1,2, Claudia Menzaghi3, Elisabetta Iori4, Robert A. Lager2,5,{dagger}, Adhir R. Shroff2,5, Ernest V. Gervino2,5, Richard W. Nesto2,6, Michael T. Johnstone2,5, Nada A. Abumrad7, Angelo Avogaro4, Vincenzo Trischitta3,8 and Alessandro Doria1,2,*

1Research Division, Joslin Diabetes Center and 2Department of Medicine, Harvard Medical School, Boston, MA, USA, 3Endocrine Unit, Scientific Institute ‘Casa Sollievo della Sofferenza’, San Giovanni Rotondo, Italy, 4Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy, 5Cardiology Division, Beth Israel Deaconess Medical Center, Boston, MA, USA, 6Heart and Vascular Center, Lahey Clinic, Burlington, MA, USA, 7Department of Physiology and Biophysics, State University of New York, Stony Brook, NY, USA and 8Department of Clinical Sciences, University ‘La Sapienza’, Rome, Italy

Received April 22, 2004; Accepted June 22, 2004

CD36 is a class B scavenger receptor recognizing a variety of ligands including long-chain fatty acids and modified LDL. We investigated whether genetic variability at this locus is a determinant of free fatty acid (FFA) plasma levels and risk of coronary artery disease (CAD) in Caucasians. Typing of 21 polymorphic markers, evenly spanning the CD36 gene, revealed two linkage disequilibrium (LD) blocks that could be tagged by five polymorphisms (–33137A>G, –31118G>A, 25444G>A, 27645del>ins and 30294G>C). In 585 non-diabetic individuals of Caucasian origin, the 30294G>C polymorphism was significantly associated with FFA levels (P=0.02)—an effect that was especially visible among men (P=0.009). A similar association was observed in this gender at –33137 (P=0.008) and –31118 (P=0.028). When the five tag polymorphisms were considered together, men carrying the AGGIG haplotype had 31% higher FFA (P=0.0002) and 20% higher triglycerides (P=0.025) than non-carriers. The same haplotype was associated with increased risk of CAD in 197 type 2 diabetic individuals from the US (OR=2.3, 95% CI 1.2–4.2). A similar tendency was observed in a group of 321 type 2 diabetic individuals from Italy (OR=1.4, 0.9–2.3), resulting in an overall relative risk of 1.6 (1.1–2.3, P=0.015) in the two populations considered together. By targeted resequencing, we identified a common variant in the CD36 promoter that is in strong LD with the AGGIG haplotype and could be partly responsible for these findings. In conclusion, this comprehensive study of CD36 variability indicates that the common polymorphisms at this locus modulate lipid metabolism and cardiovascular risk in Caucasians.

* To whom correspondence should be addressed at: Section on Genetics and Epidemiology, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA. Tel: +1 6177322406; Fax: +1 6177322667; Email: alessandro.doria{at}joslin.harvard.edu


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