title: The CXCL16 A181V mutation selectively inhibits monocyte adhesion to CXCR6 but is not associated with human coronary heart disease.
abstract: OBJECTIVE
  The chemokine CXCL16 serves as a scavenger receptor for oxidized low-density lipoprotein and as an adhesion molecule and chemoattractant for cells expressing the receptor CXCR6. A commonly occurring CXCL16 allele has been described containing 2 nonsynonymous single-nucleotide polymorphisms in complete linkage disequilibrium, although the effects on CXCL16 function are unknown. Here, we examined the effect of the single-nucleotide polymorphisms on CXCL16 function and assessed the association of the mutant allele with coronary heart disease (CHD).
  
  
  RESULTS
  Both wild-type and mutant T123V181-CXCL16 were readily expressed in vitro and were similarly functional in assays of oxidized low-density lipoprotein scavenging and chemotaxis. However, unlike wild-type CXCL16, T123V181-CXCL16 was unable to promote adhesion of CXCR6(+) cells. Findings were confirmed ex vivo, with monocytes from donors homozygous for the T123V181 allele unable to facilitate adhesion of CXCR6 transfectants. In the London Life Sciences Prospective Population cohort (n = 2797), we found that the T123V181 allele was not associated with protection or susceptibility to CHD (adjusted odds ratio, 1.01; 95% CI, 0.95 to 1.10; P = 0.74).
  
  
  CONCLUSIONS
  CXCL16-mediated cell adhesion plays at best a modest role in CHD, and the scavenging and chemotactic properties of the chemokine are more likely to be more important in disease pathogenesis.
authors.affiliation: Leukocyte Biology Section, Division, Faculty of Medicine, National Heart and Lung Institute, Imperial College London, Exhibition Rd, SW7 2AZ London, United Kingdom.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Petit
authors.forename: Emma L
authors.initials: EL
authors.lastname: Wise
authors.forename: John C
authors.initials: JC
authors.lastname: Chambers
authors.forename: Jobanpreet
authors.initials: J
authors.lastname: Sehmi
authors.forename: Naomi E
authors.initials: NE
authors.lastname: Chayen
authors.forename: Jaspal S
authors.initials: JS
authors.lastname: Kooner
authors.forename: James E
authors.initials: JE
authors.lastname: Pease
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D002448:Cell Adhesion; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC / Q000235:genetics* / Q000378:metabolism; D002633:Chemotaxis; D018920:Coculture Techniques; D003327:Coronary Disease / Q000235:genetics* / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006720:Homozygote; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D016015:Logistic Models; D008131:London; D008297:Male; D051379:Mice; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology*; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D051116:Receptors, Scavenger / Q000235:genetics* / Q000378:metabolism; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D014162:Transfection
chemical_list: C423727:CXCL16 protein, human; C106330:CXCR6 protein, human; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC; D008077:Lipoproteins, LDL; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine; D051116:Receptors, Scavenger; D011991:Receptors, Virus; C099252:oxidized low density lipoprotein