Identification of potential prognosticators for sepsis through expression analysis of transcriptomic data from sepsis survivors and nonsurvivors

Background@#Infection can be severely complicated by a dysregulated, whole-body inflammatory response known as sepsis. While previous research showed that genetic predisposition is linked to outcome differences, current patient characterization fails to determine which septic patients have greater tendencies to develop into severe sepsis or go into septic shock. As such, the identification of prognostic biomarkers may assist in identifying these high-risk patients and help improve the clinical management of the disease.@*Objective@#In this study, we aimed to identify molecular patterns involved in sepsis. We also aimed to identify essential genes associated with the disease’s survival which could serve as potential prognosticators for the disease. @*Methods@#We used weighted gene co-expression analysis (WGCNA) to analyze GSE63042, an RNA expression dataset from 129 patients with systemic inflammatory response syndrome or sepsis, including 78 sepsis survivors and 28 sepsis nonsurvivors. This analysis included identifying gene modules that differentiate sepsis survivors from nonsurvivors and qualitatively assessing differentially expressed genes. We then used STRING’s protein-protein interaction and gene ontology analysis to determine the functional and pathway relationships of the genes in the top modules. Lastly, we assessed the prognosticator abilities of the hub genes using ROC analysis. @*Results@#We found four diverse co-expression gene modules significantly associated with sepsis survival. Our differential gene expression analysis, combined with protein-protein interaction and gene ontology analysis, revealed that the hub genes of these modules – TAF10, SNAPIN, PSME2, PSMB9, JUNB, and CEBPD – may serve as candidate markers for sepsis prognosis. These markers were significantly downregulated in sepsis nonsurvivors compared with sepsis survivors.@*Conclusion@#Weighted gene co-expression analysis, gene ontology enrichment analysis, and proteinprotein network interaction analysis of transcriptomic data from sepsis survivors and nonsurvivors revealed TAF10, SNAPIN, PSME2, PSMB9, JUNB, and CEBPD as potential biomarkers for sepsis prognosis. These genes are associated with functions related to proper immune response, and their downregulation in sepsis nonsurvivors suggests eventual immune exhaustion in late sepsis. Further analyses, however, are necessary to validate their roles in sepsis progression and patient survival.

A genetic polymorphism in GCKR may be associated with low high-density lipoprotein cholesterol phenotype among Filipinos: A case-control study

@#<p style="text-align: justify;"><strong>Background.</strong> Low levels of high-density lipoprotein cholesterol (HDL-c) is a well-recognized risk factor in the development of cardiovascular diseases. Associated gene variants for low HDL-c have already been demonstrated in various populations. Such associations have yet to be established among Filipinos who reportedly have a much higher prevalence of low HDL-c levels compared to other races.</p><p style="text-align: justify;"><strong>Objective.</strong> To determine the association of selected genetic variants and clinical factors with low HDL-c phenotype in Filipinos.</p><p style="text-align: justify;"><strong>Methods.</strong> An age- and sex-matched case-control study was conducted among adult Filipino participants with serum HDL-c concentration less than 35 mg/dL (n=61) and those with HDL-c levels of more than 40 mg/dL (n=116). Genotyping was done using DNA obtained from blood samples. Candidate variants were correlated with the low HDL-c phenotype using chi-squared test and conditional logistic regression analysis.</p><p style="text-align: justify;"><strong>Results.</strong> Twelve single nucleotide polymorphisms (SNPs) were associated with low HDL-c phenotype among Filipinos with univariate regression analysis. The variant rs1260326 of glucokinase regulator (GCKR) (CT genotype: adjusted OR=5.17; p-value=0.007; TT genotype: adjusted OR=6.28; p-value=0.027) remained associated with low HDL-c phenotype, together with hypertension and elevated body mass index, after multiple regression analysis.</p><p style="text-align: justify;"><strong>Conclusion.</strong> The variant rs1260326 near GCKR is associated with low HDL-c phenotype among Filipinos. Its role in the expression of low HDL-c phenotype should be further investigated prior to the development of possible clinical applications.</p>

Variants near CETP, MTTP and BUD13-ZPR1-APOA5 may be nominally associated with poor statin response among Filipinos

@#<p style="text-align: justify;"><strong>Objective.</strong> Several studies showed that genetic factors affect responsiveness to statins among different populations. This study investigated the associations of candidate genetic variants with poor response to statins among Filipinos.</p><p style="text-align: justify;"><strong>Methods.</strong> In this unmatched case-control study, dyslipidemic participants were grouped into statin responders and poor responders based on the degree of reduction in LDL-c from baseline. DNA from blood samples were genotyped and analyzed. The association of candidate variants with statin response was determined using chi-square and logistic regression analysis.</p><p style="text-align: justify;"><strong>Results.</strong> We included 162 adults on statins (30 poor responders as cases, 132 good responders as controls). The following variants are nominally associated with poor response to statin among Filipinos at a per-comparison error rate of 0.05: rs173539 near CETP (OR=3.05, p=0.015), rs1800591 in MTTP (OR=3.07, p=0.021), and rs1558861 near the BUD13-ZPR1-APOA5 region (OR=5.08, p=0.004).</p><p style="text-align: justify;"><strong>Conclusion.</strong> Genetic variants near CETP, MTTP and the BUD13-ZPR1-APOA5 region are associated with poor response to statins among Filipinos. Further study is recommended to test the external validity of the study in the general Filipino population.</p>

Genetic polymorphisms in NAT1, NAT2, GSTM1, GSTP1 and GSTT1 and susceptibility to colorectal cancer among Filipinos

@#Objectives. Polymorphisms in metabolic genes which alter rates of bioactivation and detoxification have been shown to modulate susceptibility to colorectal cancer. This study sought to evaluate the colorectal cancer risk from environmental factors and to do polymorphism studies on genes that code for Phase I and II xenobiotic metabolic enzymes among Filipino colorectal cancer patients and matched controls. Methods. A total of 224 colorectal cancer cases and 276 controls from the Filipino population were genotyped for selected polymorphisms in GSTM1, GSTP1, GSTT1, NAT1 and NAT2. Medical and diet histories, occupational exposure and demographic data were also collected for all subject participants.Results. Univariate logistic regression of non-genetic factors identified exposure to UV (sunlight) (OR 1.99, 95% CI: 1.16-3.39) and wood dust (OR 2.66, 95% CI: 1.21-5.83) and moldy food exposure (OR 1.61, 95% CI:1.11-2.35) as risk factors; while the NAT2*6B allele (recessive model OR 1.51, 95% CI :1.06-2.16; dominant model OR 1.87, 95% CI: 1.05-3.33) and homozygous genotype (OR 2.19, 95% CI: 1.19-4.03) were found to be significant among the genetic factors. After multivariate logistic regression of both environmental and genetic factors, only UV radiation exposure (OR 2.08, 95% CI: 1.21-3.58) and wood dust exposure (OR 2.08, 95% CI: 0.95-5.30) remained to be significantly associated with increasing colorectal cancer risk in the study population.Conclusion. This study demonstrated that UV sunlight and wood dust exposure play a greater role in influencing colorectal cancer susceptibility than genotype status from genetic polymorphisms of the GST and the NAT` genes.

The prevalence of CYP2D6 Gene Polymorphisms among Filipinos and their use as biomarkers for lung cancer risk

Objectives@#The highly polymorphic nature of the CYP2D6 gene and its central role in the metabolism of commonly used drugs make it an ideal candidate for pharmacogenetic screening. This study aims to determine the prevalence of CYP2D6 polymorphisms among Filipinos and their association to lung cancer. @*Method@#Forty seven single nucleotide polymorphisms (SNPs) of the CYP2D6 gene were genotyped from DNA samples of 115 cases with lung cancer and age- and sex-matched 115 controls. @*Results@#Results show that 18 out of 47 polymorphisms have significant genotypic variability (>1% for at least 2 genotypes). No variant is associated with lung cancer. However, rs1135840, rs16947 and rs28360521, were found to be highly variable among Filipinos. @*Conclusion@#This study demonstrated that CYP2D6 polymorphisms are present among Filipinos, which, although not found to be associated with lung cancer, can be useful biomarkers for future pharmacogenetic studies. The SNP rs16947 is found to be associated with cancer and timolol-induced bradycardia; the SNP rs1135840, on the other hand, is only shown to be linked with cancer. The genetic variant rs28360521 is known to be associated with low-dose aspirin-induced lower gastrointestinal bleeding.