TY - JOUR
T1 - A common haplotype at the CD36 locus is associated with high free fatty acid levels and increased cardiovascular risk in Caucasians
AU - Ma, Xiaowei
AU - Bacci, Simonetta
AU - Mlynarski, Wojciech
AU - Gottardo, Lucia
AU - Soccio, Teresa
AU - Menzaghi, Claudia
AU - Iori, Elisabetta
AU - Lager, Robert A.
AU - Shroff, Adhir R.
AU - Gervino, Ernest V.
AU - Nesto, Richard W.
AU - Johnstone, Michael T.
AU - Abumrad, Nada A.
AU - Avogaro, Angelo
AU - Trischitta, Vincenzo
AU - Doria, Alessandro
N1 - Funding Information:
This research was supported by National Institutes of Health Grants HL73168 and HL71981 (A.D.), DK60837 (Diabetes Genome Anatomy Project), and DK36836 (Genetics Core of the Diabetes and Endocrinology Research Center at the Joslin Diabetes Center), a Grant-in-Aid from the American Heart Association (A.D.), and by Italian Ministry of Health grants RC0303ED19 and RC0201ED02 (E.T.). X.M. was the recipient of a Charles A. King Trust Post-Doctoral Research Fellowship. W.M. was supported by a Mentor-Based PostDoctoral Fellowship from the American Diabetes Association. We are grateful to David Poznik for computational help, Maya Becker, Aviva Bashan, David Nolan and Jill Duffy for assistance with the recruitment of study subjects. We acknowledge the invaluable contribution by the individuals who participated in this study.
PY - 2004/10/1
Y1 - 2004/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=5444230644&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddh233
DO - 10.1093/hmg/ddh233
M3 - Article
C2 - 15282206
AN - SCOPUS:5444230644
SN - 0964-6906
VL - 13
SP - 2197
EP - 2205
JO - Human molecular genetics
JF - Human molecular genetics
IS - 19
ER -