title: Genome-wide association replicates the association of Duffy antigen receptor for chemokines (DARC) polymorphisms with serum monocyte chemoattractant protein-1 (MCP-1) levels in Hispanic children.
abstract: Obesity is associated with a chronic low inflammatory state characterized by elevated levels of chemokines. Monocyte chemoattractant protein-1 (MCP-1) is a member of the cysteine-cysteine (CC) chemokine family and is increased in obesity. The purpose of this study was to identify loci regulating serum MCP-1 in obese Hispanic children from the Viva La Familia Study. A genome-wide association (GWA) analysis was performed in 815 children, ages 4-19 years, using genotypes assayed with the Illumina HumanOmni1-Quad v1.0 BeadChips. All analyses were performed in SOLAR using a linear regression-based test under an additive model of allelic effect, while accounting for the relatedness of family members via a kinship variance component. The strongest association for MCP-1 levels was found with a non-synonymous single nucleotide polymorphism (SNP), rs12075, resulting in an amino acid substitution (Asp42Gly) in the Duffy antigen receptor for chemokines (DARC) gene product (minor allele frequency=43.6%, p=1.3 × 10(-21)) on chromosome 1. Four other DARC SNPs were also significantly associated with MCP-1 levels (p<10(-16)-10(-6)). The Asp42Gly variant was associated with higher levels of MCP-1 and accounted for approximately 10% of its variability. In addition, MCP-1 levels were significantly associated with SNPs in chemokine receptor 3 (CCR3) and caspase recruitment domain family, member 9 (CARD9). In summary, the association of the DARC Asp42Gly variant with MCP-1 levels replicates previous GWA results substantiating a potential role for DARC in the regulation of pro-inflammatory cytokines.
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX 78245-0549, USA. saroja@TxBiomedgenetics.org
authors.forename: V Saroja
authors.initials: VS
authors.lastname: Voruganti
authors.forename: Sandra
authors.initials: S
authors.lastname: Laston
authors.forename: Karin
authors.initials: K
authors.lastname: Haack
authors.forename: Nitesh R
authors.initials: NR
authors.lastname: Mehta
authors.forename: C Wayne
authors.initials: CW
authors.lastname: Smith
authors.forename: Shelley A
authors.initials: SA
authors.lastname: Cole
authors.forename: Nancy F
authors.initials: NF
authors.lastname: Butte
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Comuzzie
mesh_terms: D000293:Adolescent; D019943:Amino Acid Substitution; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics; D018932:Chemokine CCL2 / Q000097:blood* / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004375:Duffy Blood-Group System / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006630:Hispanic or Latino / Q000235:genetics*; D006801:Humans; D008297:Male; D009765:Obesity / Q000097:blood / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D054397:Receptors, CCR3 / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics*; D055815:Young Adult
chemical_list: C473745:ACKR1 protein, human; D053468:CARD Signaling Adaptor Proteins; C505855:CARD9 protein, human; C111835:CCL2 protein, human; C515350:CCR3 protein, human; D018932:Chemokine CCL2; D004375:Duffy Blood-Group System; D054397:Receptors, CCR3; D011956:Receptors, Cell Surface