Single Nucleotide Polymorphisms In Key Genes Research Articles

Impact of SLCO1B3 polymorphisms on clinical outcomes in lung allograft recipients receiving mycophenolic acid.

Single nucleotide polymorphisms (SNPs) in genes involved in mycophenolic acid (MPA) metabolism have been shown to contribute to variable MPA exposure, but their clinical effects are unclear. We aimed to determine if SNPs in key genes in MPA metabolism affect outcomes after lung transplantation. We performed a retrospective cohort study of 275 lung transplant recipients, 228 receiving mycophenolic acid and a control group of 47 receiving azathioprine. Six SNPs known to regulate MPA exposure from the SLCO, UGT and MRP2 families were genotyped. Primary outcome was one-year survival. Secondary outcomes were 3-year survival, nonminimal (≥A2 or B2) acute rejection, and chronic lung allograft dysfunction (CLAD). Statistical analyses included time-to-event Kaplan Meier with log-rank test and Cox regression modeling. We found that SLCO1B3 SNPs rs4149117 and rs7311358 were associated with decreased one-year survival [rs7311358 HR 7.76 (1.37–44.04), p=0.021; rs4149117 HR 7.28 (1.27–41.78), p=0.026], increased risk for nonminimal acute rejection [rs4149117 TT334/T334G: OR 2.01(1.06–3.81), p=0.031; rs7311358 GG699/G699A: OR 2.18(1.13–4.21) p=0.019] and lower survival through three years for MPA patients but not for azathioprine patients. MPA carriers of either SLCO1B3 SNP had shorter survival after CLAD diagnosis (rs4149117 p=0.048, rs7311358 p=0.023). For the MPA patients, Cox regression modelling demonstrated that both SNPs remained independent risk factors for death. We conclude that hypofunctional SNPs in the SLCO1B3 gene are associated with an increased risk for acute rejection and allograft failure in lung transplant recipients treated with MPA.

Abstract P3-07-40: Pharmacogenetic study of exemestane and everolimus in metastatic breast cancer patients progressing on prior non-steroidal aromatase inhibitors

Abstract Background: Activation of the mTOR pathway has been observed in patients (pts) with metastatic breast cancer (MBC) progressing on endocrine therapy. BOLERO-2 trial demonstrated a significant increase in progression free survival (PFS) obtained with everolimus (EVE) and exemestane (EXE) versus EXE alone in pts refractory to a prior non-steroidal aromatase inhibitors (NSAI). However, there is large interindividual variability in toxicity and efficacy profiles of EXE-EVE treatment. Single Nucleotide Polymorphisms (SNPs) have been proposed to explain some of these differences. The objective of this study was to perform a pharmacogenetic analysis to identify SNPs associated with EVE toxicity and activity. Methods: This is a prospective unicentric clinical trial for postmenopausal pts with hormone receptor-positive, HER2 negative, MBC progressing on prior NSAI, treated with EXE-EVE. Blood samples were obtained from all pts, and 12 SNPs in key genes involved in EXE pharmacokinetics (ABCB1, CYP2C8, CYP3A4, CYP3A5) and pharmacodynamics (AKT1, AKT2, FGFR4, PHLPP2, PIK3R1, RAPTOR) were genotyped. EVE pharmacokinetics data was available for a subset of 37 pts. The association between the SNPs and EVE pharmacokinetic parameters were analyzed using U-Mann-Whitney test. A selection of clinically relevant toxicities (non-infectious pneumonitis (NIP), mucositis, hyperglycemia and hematological) was analyzed using binary logistic regression. Cox regression was used to analyze the association of SNPs with time to treatment modifications (reduction or interruption) due to toxicity, PFS and OS. Results: 90 patients with median age of 62 yrs were included. At data cut off, a total of 77 pts had discontinued treatment. Major reasons for discontinuation were: disease progression (80%), adverse events (17%) and death (2%). Number of prior chemotherapy lines: 0; 50%, 1;18%, 2;10%, ≥3; 22%. 76% of pts experienced at least one adverse event related to EVE. CYP3A4 rs35599367 (CYP3A4*22 allele) heterozygous pts had higher EVE concentration in blood compared to wild type pts (P=0.019), in agreement with previous data. Regarding EVE toxicities, ABCB1 SNP rs1045642 showed a higher risk of mucositis (HR=2.3, 95%CI=1.1-4.8, P=0.031; multivariable analysis), and PIK3R1 rs10515074 variant was inversely associated with hyperglycemia (HR=0.24, 95%CI=0.1-0.8, P=0.016; multivariable analysis). RAPTOR rs9906827 protected for NIP (HR=0.38, 95%CI=0.2-0.9, P=0.024; multivariable analysis). When analyzing the time to treatment modification due to any toxicity, we observed a trend for FGFR4 rs351855 and RAPTOR rs9906827 (HR=0.59, 95%CI=0.3-1.0, P=0.06 and HR=0.71, 95%CI=0.5-1.1, P=0.12; respectively, in multivariable analysis). Regarding activity, RAPTOR rs9906827 was also associated with longer PFS (dominant model HR=0.48, 95%CI=0.3-0.8, P=0.006; multivariable analysis). No SNP was significantly associated with OS. Conclusions: We found altered EVE pharmacokinetics for CYP3A4*22 carriers and protection for NIP and longer PFS for RAPTOR rs9906827. This study supports prospective trials for genetic testing prior to EXE-EVE therapy to stratify patients according to toxicity and efficacy risk profiles. Citation Format: Pascual-Martínez T, Apellániz-Ruiz M, Pernaut C, Cueto-Felgueroso C, Villalba P, Alvarez C, Manso L, Rodriguez-Antona C, Ciruelos EM. Pharmacogenetic study of exemestane and everolimus in metastatic breast cancer patients progressing on prior non-steroidal aromatase inhibitors. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-40.

Association between single-nucleotide polymorphisms of key genes in T regulatory cells signaling pathways and the efficacy of allergic rhinitis immune therapy

To investigate the genetic association pattern between single-nucleotide polymorphisms (SNP) of key genes in T regulatory cells signaling pathways and the efficacy of allergic rhinitis (AR) specific immune therapy(SIT). A population of 102 AR patients(Beijing Tongren hospital, from January to Decemeber 2012) caused by simple dust mite received standardized specific immune therapy, who lived in Beijing region was recruited. In immunotherapy before and after 1 years of treatment, the study objects were scored by nasal symptoms score, nasal signs score and total score of daily life distress three indicators to assess the efficacy. A total of 43 reprehensive marker SNP which were in FOXP3, IL-2, TGF-βand EBI3 gene regions and the upstream and downstream 1 000 kb were selected according to the Beijing people database from Hapmap website. The individual genotyping was performed by MassARRAY platform.Plink software was used for statistic analysis. Subgroup analysis for the efficacy evaluation of three indicators displayed that IL-2_rs77468365, FOXP3(rs2280883, rs2232365 and rs3761548) were associated with the improvement of sneezing in nasal symptoms. IL-2_rs77468365, FOXP3(rs2280883, rs2232365 and rs3761548) were associated with the improvement of runny nose in nasal symptoms. TGF-β(rs747857, rs6508975, rs2241715, rs12462166, rs12983775, rs1800470 and rs2317130)and FOXP3(rs2280883, rs2232365 and rs3761548)were associated with the improvement of nasal obstruction in nasal symptoms. FOXP3(rs2280883, rs2232365 and rs3761548)were associated with the improvement of nasal itching in nasal symptoms. IL-2_rs77468365 and FOXP3(rs2280883, rs2232365 and rs3761548) were associated with the overall improvement in nasal symptoms. EBI3_rs670188 and FOXP3(rs2280883, rs2232365, rs3761549, rs3761548 and rs3761547) were associated with the improvement of inferior turbinate mucosa swelling in nasal signs. IL-2_rs77468365, EBI3_rs393581, TGF-β(rs11466359 and rs11466345), FOXP3(rs2280883, rs17847095, rs2232365 and rs3761548)were associated with the improvement of inferior turbinate mucosa color in nasal signs. EBI3(rs393581, rs4740 and rs353702), FOXP3(rs2280883, rs2232365 and rs3761548)were associated with the improvement of water discharge in nasal signs. IL-2_rs77468365, EBI3(rs393581, rs4740 and rs353702), FOXP3( rs2280883, rs2232365 and rs3761548)were associated with the overall improvement in nasal signs. TGF-β(rs12461895, rs2241717 and rs7258445), FOXP3(rs2280883, rs2232365, rs3761549, rs3761548 and rs3761547)were associated with the improvement of life puzzle. The genetic polymorphism (SNPs) of four important functional candidate genes( FOXP3, IL-2, TGF-βand EBI3) in T regulatory cells signaling pathways were detected in significant correlation with the efficacy of allergic rhinitis specific immune therapy.

Association between the Interaction of Key Genes Involved in Effector T-Cell Pathways and Susceptibility to Develop allergic Rhinitis: A Population-Based Case-Control Association Study.

BackgroundEvidence suggests that interaction between key genes mediating signaling and transcriptional networks involving effector T-cell responses may influence an individual’s susceptibility to develop allergic rhinitis(AR).ObjectiveThe aim of this study was todetermine whether specific interactions between key genes involved in effector T-cell pathways are associated with an individual’s susceptibility to develop AR in Han Chinese subjects.MethodA cohort of 489 patients with AR and 421 healthy controls was enrolled from the Han Chinese population in Beijing, China. AR was established by questionnaire and clinical examination, and peripheral blood was drawn from all subjects for DNA extraction. A total of 96 single nucleotide polymorphisms (SNPs) in 26 reprehensive candidate genes involved in T helper 1 (Th1), Th2, Th17, Th9 and T regulatory cell pathways were selected from the International Haplotype Mappingdatabase for Han Chinese in Beijing (CHB) population, and IlluminaGoldenGate assay was conducted for SNP genotyping. The PLINK software package was used to perform statistical analyses.ResultsSimple SNP-phenotype association analysis using logistic regression showed SNP rs8193036 in IL17A gene, rs2569254 in IL-12 and rs1898413 in RORα weresignificantlyassociatedwith AR.Simple SNP-phenotype association analysis with genetic models demonstrated thatrs2569254 in IL-12, rs1031508 in STAT4, and rs3741809 in IL-26 were likely to be recessive, rs8193036 in IL17A allelic, rs897200in STAT4 genotypic, and rs1898413 in RORα dominant. Epistasis analyses exhibited that 83 SNPs in 23 genes were significantly interactive; of which 59 interactions/SNP pairs demonstrated OR values higher than 2 or lower than 0.5, and 12 interactions/SNP pairs OR values higher than 4 or lower than 0.25. STAT3, RORα and IL-26, involved in Th17 pathway,were the mostfrequentlyinteractive genes.ConclusionThis study suggests that interactions between several SNPs in key genes involved in effector T-cell pathways are likely to influence an individual’s susceptibility to develop AR.

Dopamine receptor D1 and postsynaptic density gene variants associate with opiate abuse and striatal expression levels

Opioid drugs are highly addictive and their abuse has a strong genetic load. Dopamine-glutamate interactions are hypothesized to be important for regulating neural systems central for addiction vulnerability. Balanced dopamine-glutamate interaction is mediated through several functional associations, including a physical link between discs, large homolog 4 (Drosophila) (DLG4, PSD-95) and dopamine receptor 1 (DRD1) within the postsynaptic density to regulate DRD1 trafficking. To address whether genetic associations with heroin abuse exist in relation to dopamine and glutamate and their potential interactions, we evaluated single-nucleotide polymorphisms of key genes within these systems in three populations of opiate abusers and controls, totaling 489 individuals from Europe and the United States. Despite significant differences in racial makeup of the separate samples, polymorphisms of DRD1 and DLG4 were found to be associated with opiate abuse. In addition, a strong gene-gene interaction between homer 1 homolog (Drosophila) (HOMER1) and DRD1 was predicted to occur in Caucasian subjects. This interaction was further analyzed by evaluating DRD1 genotype in relation to HOMER1b/c protein expression in postmortem tissue from a subset of Caucasian subjects. DRD1 rs265973 genotype correlated with HOMER1b/c levels in the striatum, but not cortex or amygdala; the correlation was inversed in opiate abusers as compared with controls. Cumulatively, these results support the hypothesis that there may be significant, genetically influenced interactions between glutamatergic and dopaminergic pathways in opiate abusers.

Performance of an Adipokine Pathway-Based Multilocus Genetic Risk Score for Prostate Cancer Risk Prediction

Few biomarkers are available to predict prostate cancer risk. Single nucleotide polymorphisms (SNPs) tend to have weak individual effects but, in combination, they have stronger predictive value. Adipokine pathways have been implicated in the pathogenesis. We used a candidate pathway approach to investigate 29 functional SNPs in key genes from relevant adipokine pathways in a sample of 1006 men eligible for prostate biopsy. We used stepwise multivariate logistic regression and bootstrapping to develop a multilocus genetic risk score by weighting each risk SNP empirically based on its association with disease. Seven common functional polymorphisms were associated with overall and high-grade prostate cancer (Gleason≥7), whereas three variants were associated with high metastatic-risk prostate cancer (PSA≥20 ng/mL and/or Gleason≥8). The addition of genetic variants to age and PSA improved the predictive accuracy for overall and high-grade prostate cancer, using either the area under the receiver-operating characteristics curves (P<0.02), the net reclassification improvement (P<0.001) and integrated discrimination improvement (P<0.001) measures. These results suggest that functional polymorphisms in adipokine pathways may act individually and cumulatively to affect risk and severity of prostate cancer, supporting the influence of adipokine pathways in the pathogenesis of prostate cancer. Use of such adipokine multilocus genetic risk score can enhance the predictive value of PSA and age in estimating absolute risk, which supports further evaluation of its clinical significance.