Abstract 931: Innate immunity-related sequence variants (TOLLIP, TLR2) as predictors of prostate cancer risk among men of African descent

Emerging genome-wide association studies suggest genome variation plays a rather important, yet largely uncharacterized, role in dissecting the genetic underpinnings of prostate cancer (PCa) health disparities. Moreover, recent advances in molecular and genetic studies demonstrate a relationship between chronic/recurrent inflammation and complex diseases. In terms of prostate cancer, it is speculated that chronic or recurrent inflammation, attributed to persistent exposure to pathogens may alter the tissue microenvironment that favors tumor growth. Despite the fact that men of African descent suffer disproportionately from PCa and may have a natural selection advantage toward inheriting innate immunity signaling loci linked with pro-inflammatory response, it remains to be determined whether variant innate immunity-related alleles will explain the higher PCa risk and disease severity in this sub-group. With the ultimate goal of understanding the genetic underpinnings of PCa health disparities, we set out to systematically evaluate the impact of innate immunity-related single nucleotide polymorphisms (SNPs) in relation to PCA risk among 3,200 men of African and European descent. We hypothesized that individuals inheriting high-risk innate immunity loci (linked with elevated pro-inflammatory response) will have an increased risk of developing PCa relative to those with the referent genotypes. In order to evaluate the effects of innate immunity sequence variants on PCa we used SNP profile data collected from 2277 European participants of the Cancer Genetic Markers of Susceptibility (CGEMS) project (1176 cases, 1101 controls) and 923 men of African descent (224 cases, 699 controls). Using a case-control study design, we evaluated the independent effects of 19 variant innate immunity genes (e.g., TLR 1-4, CD14, IRAK2, IRF3, TOLLIP) in relation to PCa risk using logistic regression and multi-factor dimensionality reduction (MDR) modeling. Inheritance of at least one minor TOLLIP rs5743899G (p = 0.002) and the TLR-2 rs4696480A allele (linked with enhanced cytokine production) was significantly associated with a 2.1-4.5 fold increase prostate cancer susceptibility among men of African descent. Notably, the TOLLIP marker remained significant even after adjusting for multiple comparisons following MDR with permutation testing (p = 0.01). These markers were not associated with PCa among European participants. In summary, variations in genes involved in the innate immunity signaling may play a role in PCa risk among men of African Descent in the current study. However, these findings require validation in larger and ethnically diverse sub-populations. Such efforts will help to identify and validate new genetic fingerprints with the capacity to unravel the genetic contributions of prostate cancer incidence and mortality disparities among high-risk subgroups. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 931.