Abstract
BackgroundChemokine and chemokine receptors play an essential role in tumorigenesis. Although chemokine-associated single nucleotide polymorphisms (SNPs) are associated with various cancers, their impact on prostate cancer (PCA) among men of African descent is unknown. Consequently, this study evaluated 43 chemokine-associated SNPs in relation to PCA risk. We hypothesized inheritance of variant chemokine-associated alleles may lead to alterations in PCA susceptibility, presumably due to variations in antitumor immune responses.MethodsSequence variants were evaluated in germ-line DNA samples from 814 African-American and Jamaican men (279 PCA cases and 535 controls) using Illumina’s Goldengate genotyping system.ResultsInheritance of CCL5 rs2107538 (AA, GA+AA) and rs3817655 (AA, AG, AG+AA) genotypes were linked with a 34-48% reduction in PCA risk. Additionally, the recessive and dominant models for CCR5 rs1799988 and CCR7 rs3136685 were associated with a 1.52-1.73 fold increase in PCA risk. Upon stratification, only CCL5 rs3817655 and CCR7 rs3136685 remained significant for the Jamaican and U.S. subgroups, respectively.ConclusionsIn summary, CCL5 (rs2107538, rs3817655) and CCR5 (rs1799988) sequence variants significantly modified PCA susceptibility among men of African descent, even after adjusting for age and multiple comparisons. Our findings are only suggestive and require further evaluation and validation in relation to prostate cancer risk and ultimately disease progression, biochemical/disease recurrence and mortality in larger high-risk subgroups. Such efforts will help to identify genetic markers capable of explaining disproportionately high prostate cancer incidence, mortality, and morbidity rates among men of African descent.
Highlights
Chemokine and chemokine receptors play an essential role in tumorigenesis
Prevalence of minor alleles/genotype frequency comparing men of African Descent from the U.S and Jamaica Overall, the chemokine-related Single nucleotide polymorphism (SNP) were fairly common among disease-free individuals from the entire sub-population of U.S and Jamaica, with average minor frequencies of 26-27% and a standard deviation of 14%, respectively
Five SNPs detected in CCL5, CCR5 and CCR7 were significantly associated with prostate cancer risk among all study participants; only three markers survived adjustments for potential confounders and multiple hypothesis testing
Summary
Chemokine-associated single nucleotide polymorphisms (SNPs) are associated with various cancers, their impact on prostate cancer (PCA) among men of African descent is unknown. This study evaluated 43 chemokine-associated SNPs in relation to PCA risk. We hypothesized inheritance of variant chemokine-associated alleles may lead to alterations in PCA susceptibility, presumably due to variations in antitumor immune responses. Prostate cancer (PCA) is one of the leading causes of cancer and cancer-related deaths among men in the U.S and Caribbean and its disparities are well documented [1,2,3]. Established risk factors for PCA include older age, black race, and family history of the disease. Other plausible contributors of prostate tumorigenesis include endocrine, lifestyle, environmental, and genetic factors as well as imbalances in inflammatory, immune surveillance, and angiogenesis pathways
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