Genetic association of the CCR5 region with lipid levels in at-risk cardiovascular patients.
BACKGROUND
There is mounting evidence to suggest that chemokine receptor 5 (CCR5) plays an important role in the development and progression of atherosclerosis. A naturally occurring variant of the CCR5 gene CCR532, exists at allele frequencies of typically 10% in European populations and results in a nonfunctional CCR5 receptor.


RESULTS
The CCR5Delta32 deletion and 26 other variants within the chemokine receptor 2-CCR5-chemokine receptor-like protein 2 (CCRL2) gene cluster spanning 59 kilobases of chromosome 3 were genotyped in 5748 subjects from the Treating to New Targets atorvastatin trial to determine whether genetic associations could be identified with circulating lipid values and cardiovascular disease. Our results demonstrate an association between the CCR5Delta32 deletion and increased plasma high-density lipoprotein cholesterol and decreased plasma triglycerides, both of which are beneficial from a cardiovascular perspective. Three single-nucleotide polymorphisms (rs1154428, rs6808835, and rs6791599) in CCRL2 in linkage disequilibrium (r(2)> or =0.65) with CCR5Delta32 and located up to 45 kilobases distal to it were associated with high-density lipoprotein cholesterol. The high-density lipoprotein cholesterol and triglycerides findings were replicated in an additional set of >6000 individuals from the Incremental Decrease in Endpoints through Aggressive Lipid Lowering atorvastatin trial.


CONCLUSIONS
Our study provides evidence that a locus within the region of the genome encompassing the CCR5-CCRL2 region is associated with lipid levels and suggests that chemokine activity influences lipid levels in populations with preexisting cardiovascular disease. CLINICAL TRIAL REGISTRATION- clinicaltrials.gov. Identifier: TNT, NCT00327691; IDEAL, NCT00159835.
Molecular Medicine and Clinical Research Statistics, Pfizer Global Research and Development, Groton, CT 06340, USA.
Craig L
CL
Hyde
Alan
A
Macinnes
Frances A
FA
Sanders
John F
JF
Thompson
Richard A
RA
Mazzarella
Ole
O
Faergeman
Diederik F
DF
van Wijk
Linda
L
Wood
Maruja
M
Lira
Sara A
SA
Paciga
D000368:Aged; D000069059:Atorvastatin; D002318:Cardiovascular Diseases / Q000235:genetics*; D008076:Cholesterol, HDL / Q000097:blood* / Q000235:genetics; D002893:Chromosomes, Human, Pair 3; D005260:Female; D017353:Gene Deletion; D005787:Gene Frequency; D005838:Genotype; D006538:Heptanoic Acids / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011758:Pyrroles / Q000627:therapeutic use; D054388:Receptors, CCR / Q000235:genetics; D019713:Receptors, CCR5 / Q000235:genetics*; D012189:Retrospective Studies; D012307:Risk Factors; D019821:Simvastatin / Q000627:therapeutic use; D014280:Triglycerides / Q000097:blood* / Q000235:genetics
C487531:CCRL2 protein, human; D008076:Cholesterol, HDL; D006538:Heptanoic Acids; D011758:Pyrroles; D054388:Receptors, CCR; D019713:Receptors, CCR5; D014280:Triglycerides; D000069059:Atorvastatin; D019821:Simvastatin