A New Biophysical Metric for Interrogating the Information Content in Human Genome Sequence Variation: Proof of Concept

Various studies have shown an association between single nucleotide polymorphisms (SNPs) and common disease. We hypothesize that information encoded in the structure of SNP haploblock variation illumines molecular pathways and cellular mechanisms involved in the regulation of host adaptation to the environment. We developed and utilized the normalized information content (NIC), a novel metric based on SNP haploblock variation. We found that all SNP haploblocks with statistically low information content contained putative transcription factor binding sites and microRNA motifs. We were able to translate a biophysical, mathematical measure of common variants into a deeper understanding of the life sciences through analysis of biochemical patterns associated with SNP haploblock variation. We submit that this new metric, NIC, may be useful in decoding the functional significance of common variation in the human genome and in analyzing the regulation of molecular pathways involved in host adaptation to environmental pathogens.Comment: 13 page

Prostate Cancer Susceptibility Loci Identified on Chromosome 12 in African Americans

Prostate cancer (PCa) is a complex disease that disproportionately affects African Americans and other individuals of African descent. A number of regions across the genome have been associated to PCa, most of them with moderate effects. A few studies have reported chromosomal changes on 12p and 12q that occur during the onset and development of PCa but to date no consistent association of the disease with chromosome 12 polymorphic variation has been identified. In order to unravel genetic risk factors that underlie PCa health disparities we investigated chromosome 12 using ancestry informative markers (AIMs), which allow us to distinguish genomic regions of European or West African origin, and tested them for association with PCa. Additional SNPs were genotyped in those areas where significant signals of association were detected. The strongest signal was discovered at the SNP rs12827748, located upstream of the PAWR gene, a tumor suppressor, which is amply expressed in the prostate. The most frequent allele in Europeans was the risk allele among African Americans. We also examined vitamin D related genes, VDR and CYP27B1, and found a significant association of PCa with the TaqI polymorphism (rs731236) in the former. Although our results warrant further investigation we have uncovered a genetic susceptibility factor for PCa in a likely candidate by means of an approach that takes advantage of the differential contribution of parental groups to an admixed population

Prostate Cancer Susceptibility Loci Identified on Chromosome 12 in African Americans

Prostate cancer (PCa) is a complex disease that disproportionately affects African Americans and other individuals of African descent. A number of regions across the genome have been associated to PCa, most of them with moderate effects. A few studies have reported chromosomal changes on 12p and 12q that occur during the onset and development of PCa but to date no consistent association of the disease with chromosome 12 polymorphic variation has been identified. In order to unravel genetic risk factors that underlie PCa health disparities we investigated chromosome 12 using ancestry informative markers (AIMs), which allow us to distinguish genomic regions of European or West African origin, and tested them for association with PCa. Additional SNPs were genotyped in those areas where significant signals of association were detected. The strongest signal was discovered at the SNP rs12827748, located upstream of the PAWR gene, a tumor suppressor, which is amply expressed in the prostate. The most frequent allele in Europeans was the risk allele among African Americans. We also examined vitamin D related genes, VDR and CYP27B1, and found a significant association of PCa with the TaqI polymorphism (rs731236) in the former. Although our results warrant further investigation we have uncovered a genetic susceptibility factor for PCa in a likely candidate by means of an approach that takes advantage of the differential contribution of parental groups to an admixed population.</p

Genetic polymorphisms in IL-10 promoter are associated with smoking and prostate cancer risk in African Americans

Background/Aim: Even though prostate cancer (PCa) has good prognosis, there is a discrepancy in the risk among ethnic groups, with high morbidity in African American men. Single nucleotide polymorphisms (SNPs) in interleukin 10 (IL-10) have been associated with inflammation and cancer risk. We investigated the association of five SNPs in the IL-10 promoter with clinical features such as Gleason score and smoking. Materials and Methods: A total of 413 DNA samples were obtained from a nested case-control study of African American males who were genotyped for 5 SNPs utilizing pyrosequencing. Multiple and binary logistic regression models were applied to analyze the clinical and genotypic data. Results: rs12122923 and rs1800871 were associated with PCa risk. Smoking was also found to increase the risk of PCa by 1.6-fold. rs1800893 was found to be associated with lower grades for prostate cancer. Conclusion: IL-10 promoter polymorphisms might be a risk factor for PCa development in smoking subjects and PCa progression

Association of CD14 variant with prostate cancer in African American men

BACKGROUND. African American men have the highest rates of prostate cancer worldwide, and immunogenetic studies suggest that people of African descent have increased susceptibility to diseases of inflammation. Since genetic susceptibility is an etiological factor in prostate cancer, we hypothesize that sequence variants in the promoter region of the CD14 gene that regulate inflammation may modify individual susceptibility to this disease. METHODS. The CD14 promoter was screened for single-nucleotide polymorphisms (SNPs) using dHPLC. One variant, -260 C\u3eT (rs2569190), was genotyped via restriction digest in all study participants (264 cases and 188 controls). The association of disease status and the polymorphism was analyzed by unconditional logistic regression. Odds ratios with 95% confidence intervals were calculated, stratifying by ethnicity and adjusting for age. Two-sided P-values of ≤0.05 were considered as statistically significant. RESULTS. Eleven variants (four novel) were identified in the promoter region of CD14. A marginal association between the C genotypes (C/C + C/T) and prostate cancer was found (P=0.07). When stratified by age, among men ≥55 years of age, the C genotypes were significantly associated with prostate cancer (P \u3c0.05). When stratified by self-reported ethnicity, African American males who had the C genotypes were at a higher risk for prostate cancer (P \u3c0.05). CONCLUSIONS. This is the first study to show an association between the C genotypes of the CD14 (-260) variant and prostate cancer which supports the hypothesis that genetic variation in the inflammatory process can contribute to prostate cancer susceptibility in African American men. © 2009 Wiley-Liss, Inc