Genetic and Bioinformatic Approaches To Identify Polymorphic Modulators of Transcription Factor Binding and Disease Phenotypes Including HIV-1 Viremia

(PROBLEM) The overall goal of this thesis is to identify polymorphic alleles that associate with elevated risk and disease progression. Two different approaches were used to achieve this goal. (METHODS AIM 1) A database resource called Delta-MATCH was created using a predictive computational approach. The aim of the Delta-MATCH program is to identify human polymorphic variants that may create allele-specific transcription factor binding sites. In this version (v 1.0) 4,547,844 high-value candidate polymorphisms have been scored and ranked by the Delta-MATCH algorithm. These polymorphisms were either positioned within a 10,000 base pair window of a refSeq gene, or located within a region of high conservation in the human genome. The major and minor alleles for each of these 4.5 million polymorphisms were independently evaluated by the MATCH algorithm against a library of 550 known transcription factor binding site motifs (BIOBASE TRANSFAC v10.2) to determine the "highest MATCH scores" for each allele and transcription factor pair. (CONCLUSIONS AIM 1) The ranked list of Delta-MATCH predictions for each transcription factor binding site (matrix name) can be queried online at http://deltamatch.org. Predictions have been ranked in descending order of importance by a statistic called the "Delta-MATCH potential score", which reflects the potential of a polymorphism to create an allele-specific transcription factor binding site. (METHODS AIM 2) The common genotypes and haplotypes of four candidate genes (CCR5, TLR9, IRF5, APOE) were investigated for their association with the phenotype of HIV-1 viremia levels in a population of HIV-infected Americans primarily derived from the San Francisco SCOPE cohort. (CONCLUSIONS AIM 2) TLR9 and IRF5 variants associated with HIV viremia levels in White Americans. Additionally, individuals infected with HIV should try to avoid chronic inflammation, which means avoiding other viral and bacteria coinfections, traumas, and other behaviors that promote a chronic inflammatory state. Furthermore, the magnitude of TLR9- and IRF5-dependant inflammatory responses during the acute phase of HIV-1 infection may partially determine the viremia level of chronic infection (CVL classification)