Browsing by Subject "SNPs"

Now showing 1 - 5 of 5
  • Thumbnail Image
    Item
    Genetic variation affecting exon skipping contributes to brain structural atrophy in Alzheimer's disease
    (American Medical Informatics Association, 2018-05-18) Lee, Younghee; Han, Seonggyun; Kim, Dongwook; Kim, Dokyoon; Horgousluoglu, Emrin; Risacher, Shannon L.; Saykin, Andrew J.; Nho, Kwangsik; Alzheimer’s Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of Medicine
    Genetic variation in cis-regulatory elements related to splicing machinery and splicing regulatory elements (SREs) results in exon skipping and undesired protein products. We developed a splicing decision model to identify actionable loci among common SNPs for gene regulation. The splicing decision model identified SNPs affecting exon skipping by analyzing sequence-driven alternative splicing (AS) models and by scanning the genome for the regions with putative SRE motifs. We used non-Hispanic Caucasians with neuroimaging, and fluid biomarkers for Alzheimer's disease (AD) and identified 17,088 common exonic SNPs affecting exon skipping. GWAS identified one SNP (rs1140317) in HLA-DQB1 as significantly associated with entorhinal cortical thickness, AD neuroimaging biomarker, after controlling for multiple testing. Further analysis revealed that rs1140317 was significantly associated with brain amyloid-f deposition (PET and CSF). HLA-DQB1 is an essential immune gene and may regulate AS, thereby contributing to AD pathology. SRE may hold potential as novel therapeutic targets for AD.
  • Thumbnail Image
    Item
    Medical genetics and epigenetics of telomerase
    (Wiley, 2011-03) Koziel, Jillian E.; Fox, Melanie J.; Steding, Catherine E.; Sprouse, Alyssa A.; Herbert, Brittney-Shea; Department of Medical & Molecular Genetics, IU School of Medicine
    Telomerase is a specialized reverse transcriptase that extends and maintains the terminal ends of chromosomes, or telomeres. Since its discovery in 1985 by Nobel Laureates Elizabeth Blackburn and Carol Greider, thousands of articles have emerged detailing its significance in telomere function and cell survival. This review provides a current assessment on the importance of telomerase regulation and relates it in terms of medical genetics. In this review, we discuss the recent findings on telomerase regulation, focusing on epigenetics and non-coding RNAs regulation of telomerase, such as microRNAs and the recently discovered telomeric-repeat containing RNA transcripts. Human genetic disorders that develop due to mutations in telomerase subunits, the role of single nucleotide polymorphisms in genes encoding telomerase components and diseases as a result of telomerase regulation going awry are also discussed. Continual investigation of the complex regulation of telomerase will further our insight into the use of controlling telomerase activity in medicine.
  • Thumbnail Image
    Item
    Micro-RNA regulation of hepatic drug metabolism : age-related changes in micro-RNA expression and genetic variants in micro-RNA target sites
    (2017-08-31) Burgess, Kimberly Sherrelle; Skaar, Todd C.; Arrizabalaga, Gustavo; Cummins, Theodore; Desta, Zeruesenay; Nass, Richard; Zhang, Jian-Tian
    Developmental changes in the liver significantly impact drug disposition. Due to the emergence of microRNAs as important regulators of drug disposition, we hypothesize that age-dependent change in microRNA expression and genetic variants in microRNA target sites contribute to variability in drug disposition. In human liver tissues, expression of 533 microRNAs and over 14,000 genes were measured. In all, 114 microRNAs were upregulated and 72 downregulated from fetal to pediatric, and 2 and 3, respectively, from pediatric to adult. Among these microRNAs, 99 microRNA-mRNA interactions were predicted or have previously been validated to target drug disposition genes and over 1,000 significant negative correlations were observed between miRNA-mRNA pairs. We validated these interactions using various cell culture models. Genetic variants in the promoter and coding regions of drug disposition genes have also been shown to alter enzyme expression and/or activity. However, these variants do not account for all variability in enzyme activity. Emerging evidence has shown that variants in the 3’UTR may explain variable drug response by altering microRNA regulation. Five 3’UTR variants were associated with significantly altered CYP2B6 activity in healthy human volunteers. The rs70950385 (AG>CA) variant was associated with decreased CYP2B6 activity among normal metabolizers. In vitro luciferase assays confirmed that the CA allele altered miR 1275 targeting of CYP2B6 mRNA. Due to the large number of 3’UTR variants predicted to alter microRNA regulation, a high-throughput method, PASSPORT-seq, was developed to test over 100 3’UTR variants simultaneously in different cell lines. Thirty-eight variants resulted in FDR-significant altered expression between wild-type and variant sequences. Our data suggest a mechanism for the marked changes in hepatic gene expression between the fetal and pediatric developmental periods, support a role for these age dependent microRNAs in regulating drug disposition, and provide strong evidence that 3’UTR variants are also an important source of variability in drug disposition.
  • Thumbnail Image
    Item
    Pharmacogenomics of Novel Direct Oral Anticoagulants: Newly Identified Genes and Genetic Variants
    (MDPI, 2019-01-17) Kanuri, Sri H.; Kreutz, Rolf P.; Pharmacology and Toxicology, School of Medicine
    Direct oral anticoagulants (DOAC) have shown an upward prescribing trend in recent years due to favorable pharmacokinetics and pharmacodynamics without requirement for routine coagulation monitoring. However, recent studies have documented inter-individual variability in plasma drug levels of DOACs. Pharmacogenomics of DOACs is a relatively new area of research. There is a need to understand the role of pharmacogenomics in the interpatient variability of the four most commonly prescribed DOACs, namely dabigatran, rivaroxaban, apixaban, and edoxaban. We performed an extensive search of recently published research articles including clinical trials and in-vitro studies in PubMed, particularly those focusing on genetic loci, single nucleotide polymorphisms (SNPs), and DNA polymorphisms, and their effect on inter-individual variation of DOACs. Additionally, we also focused on commonly associated drug-drug interactions of DOACs. CES1 and ABCB1 SNPs are the most common documented genetic variants that contribute to alteration in peak and trough levels of dabigatran with demonstrated clinical impact. ABCB1 SNPs are implicated in alteration of plasma drug levels of rivaroxaban and apixaban. Studies conducted with factor Xa, ABCB1, SLCOB1, CYP2C9, and VKORC1 genetic variants did not reveal any significant association with plasma drug levels of edoxaban. Pharmacokinetic drug-drug interactions of dabigatran are mainly mediated by p-glycoprotein. Strong inhibitors and inducers of CYP3A4 and p-glycoprotein should be avoided in patients treated with rivaroxaban, apixaban, and edoxaban. We conclude that some of the inter-individual variability of DOACs can be attributed to alteration of genetic variants of gene loci and drug-drug interactions. Future research should be focused on exploring new genetic variants, their effect, and molecular mechanisms that contribute to alteration of plasma levels of DOACs.
  • Thumbnail Image
    Item
    Polycyclic Aromatic Hydrocarbons and Pancreatic Cancer: An Analysis of the Blood Biomarker, r-1,t-2,3,c-4-Tetrahydroxy-1,2,3,4-tetrahydrophenanthrene and Selected Metabolism Gene SNPs
    (MDPI, 2024-02-28) Nguyen, Sierra; Carlson, Heather; Yoder, Andrea; Bamlet, William R.; Oberg, Ann L.; Petersen, Gloria M.; Carmella, Steven G.; Hecht, Stephen S.; Jansen, Rick J.; Richard M. Fairbanks School of Public Health
    Exposure to polycyclic aromatic hydrocarbons (PAHs), byproducts of incomplete combustion, and their effects on the development of cancer are still being evaluated. Recent studies have analyzed the relationship between PAHs and tobacco or dietary intake in the form of processed foods and smoked/well-done meats. This study aims to assess the association of a blood biomarker and metabolite of PAHs, r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT), dietary intake, selected metabolism SNPs, and pancreatic cancer. Demographics, food-frequency data, SNPs, treatment history, and levels of PheT in plasma were determined from 400 participants (202 cases and 198 controls) and evaluated based on pancreatic adenocarcinoma diagnosis. Demographic and dietary variables were selected based on previously published literature indicating association with pancreatic cancer. A multiple regression model combined the significant demographic and food items with SNPs. Final multivariate logistic regression significant factors (p-value < 0.05) associated with pancreatic cancer included: Type 2 Diabetes [OR = 6.26 (95% CI = 2.83, 14.46)], PheT [1.03 (1.02, 1.05)], very well-done red meat [0.90 (0.83, 0.96)], fruit/vegetable servings [1.35 (1.06, 1.73)], recessive (rs12203582) [4.11 (1.77, 9.91)], recessive (rs56679) [0.2 (0.06, 0.85)], overdominant (rs3784605) [3.14 (1.69, 6.01)], and overdominant (rs721430) [0.39 (0.19, 0.76)]. Of note, by design, the level of smoking did not differ between our cases and controls. This study does not provide strong evidence that PheT is a biomarker of pancreatic cancer susceptibility independent of dietary intake and select metabolism SNPs among a nonsmoking population.