Variability in hepatic expression of organic anion transporter 7/SLC22A9, a novel pravastatin uptake transporter: impact of genetic and regulatory factors

Riedmaier, Arian Emami; Burk, Oliver; Eijck, Barbara A. C. van; Schaeffeler, Elke; Klein, Kathrin; Fehr, Sarah; Biskup, Saskia; Müller, Simon; Winter, Stefan; Zanger, Ulrich M.; Schwab, Matthias; Nies, Anne T.

doi:10.1038/tpj.2015.55

Cited by 36 publications

(41 citation statements)

References 45 publications

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“…(cell structure and proliferation; IRS: 11.11%) and BANP (migration and invasiveness; IRS: 10.73%) were all previously reported in the literature (42)(43)(44)(45)(46)(47)(48)(49)(50). This observation may suggest that highly immunogenic neoantigens are 'tolerated' preferentially if the cells gain a compensatory survival advantage from the mutation by switching off a tumor-suppressive pathway, supporting their role of propelling MSI tumor evolution ( Fig.…”

Section: Immunoselection During Msi Carcinogenesissupporting

confidence: 70%

The sharedneoantigen landscape of MSI cancers reflects immunoediting during tumor evolution

Ballhausen

Przybilla

Jendrusch

et al. 2019

Preprint

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Glossary TermMeaning ELS Epitope likelihood score GELS General epitope likelihood score IRS Immune relevance score, based on the mutation frequency (ReFrame) and the GELS M1Reading frame resulting from the deletion of one nucleotide or insertions of two nucleotides M2Reading frame resulting from the deletions of two nucleotides or insertion of one nucleotide m1, m2, m3, etc.Minus one, two, three base pair deletions p1, p2, p3, etc.Plus one, two, three base pair insertions ReFrameREgression-based FRAMEshift quantification Abbreviations B2M Beta2-microglobulin cMS Coding microsatellites CRC Colorectal cancer MMR Mismatch repair EC Endometrium cancer FSP neoantigens Frameshift peptide neoantigens HLA Human leukocyte antigen ICB Immune checkpoint blockade MSI Microsatellite instability, microsatelliteunstable NGSNext generation sequencing Abstract:The immune system can recognize and attack cancer cells, especially those with a high load of mutation-induced neoantigens. Such neoantigens are particularly abundant in DNA mismatch repair (MMR)-deficient, microsatellite-unstable (MSI) cancers. MMR deficiency leads to insertion/deletion (indel) mutations at coding microsatellites (cMS) and to neoantigen-inducing translational frameshifts. The abundance of mutational neoantigens renders MSI cancers sensitive to immune checkpoint blockade. However, the neoantigen landscape of MMR-deficient cancers has not yet been systematically mapped. In the present study, we used a novel tool to monitor neoantigen-inducing indel mutations in MSI colorectal and endometrial cancer. Our results show that MSI cancers share several highly immunogenic neoantigens that result from specific, recurrent indel mutation events.Notably, the frequency of such indel mutations was negatively correlated to the predicted immunogenicity of the resulting neoantigens. These observations suggest continuous immunoediting of emerging MMR-deficient cells during tumor evolution. Main text:DNA MMR deficiency is a major mechanism causing genomic instability in human cancer. MMR-deficient cancers accumulate an exceptionally high number of somatic mutations. These mutations encompass certain types of single nucleotide alterations, but mostly insertion/deletion (indel) mutations at repetitive sequence stretches termed microsatellites (microsatellite instability, MSI) (1, 2). About 15% of colorectal cancers (CRC), up to 30% of endometrial cancers (EC) and multiple other tumors display the MSI phenotype (3). MSI tumors can develop sporadically or in the context of Lynch syndrome, the most common inherited cancer predisposition syndrome. Due to this very specific process of genomic instability, the pathogenesis of MSI cancers can be precisely dissected (4): Indel mutations affecting coding microsatellites (cMS), predominantly coding mononucleotide repeats, in genomic regions encoding tumor suppressor genes are considered major drivers of MSI tumorigenesis (5-7). Importantly, the same indels that inactivate tumor suppressor genes simultaneously cause translational frameshi...

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Section: Immunoselection During Msi Carcinogenesissupporting

confidence: 70%

The sharedneoantigen landscape of MSI cancers reflects immunoediting during tumor evolution

Ballhausen

Przybilla

Jendrusch

et al. 2019

Preprint

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“…We found that urate transport mediated by OAT7 is inhibited by the uricosuric drugs benzbromarone and tranilast, which inhibit multiple other urate transporters [50]. Three uncommon missense variants that influence the ability of OAT7 to transport pravastatin by either causing the protein to be retained intracellularly or reducing protein levels at the plasma membrane have been reported [51], all at a frequency < 1% in East Asian. HNF4 α plays a key role in the transactivation of the SLC22A9 promoter [51], an interesting observation given that HNF4 α is also required for expression of the gene encoding the urate transportosome-stabilizing molecule PDZK1 in the liver [11], and is implicated in control of serum urate levels via the MAFTRR locus [12].…”

Section: Discussionmentioning

confidence: 99%

Genomic dissection of 43 serum urate-associated loci provides multiple insights into molecular mechanisms of urate control

Boocock

Leask

Okada

et al. 2019

Preprint

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69Serum urate is the end-product of purine metabolism. Elevated serum urate is causal of 70 gout and a predictor of renal disease, cardiovascular disease and other metabolic 71 conditions. Genome-wide association studies (GWAS) have reported dozens of loci 72 associated with serum urate control, however there has been little progress in 73 understanding the molecular basis of the associated loci. Here we employed trans-74 ancestral meta-analysis using data from European and East Asian populations to 75 identify ten new loci for serum urate levels. Genome-wide colocalization with cis-76 expression quantitative trait loci (eQTL) identified a further five new loci. By cis-and 77 trans-eQTL colocalization analysis we identified 24 and 20 genes respectively where 78 the causal eQTL variant has a high likelihood that it is shared with the serum urate-79 associated locus. One new locus identified was SLC22A9 that encodes organic anion 80 transporter 7 (OAT7). We demonstrate that OAT7 is a very weak urate-butyrate 81 exchanger. Newly implicated genes identified in the eQTL analysis include those 82 encoding proteins that make up the dystrophin complex, a scaffold for signaling 83 proteins and transporters at the cell membrane; MLXIP that, with the previously 84 identified MLXIPL, is a transcription factor that may regulate serum urate via the 85 pentose-phosphate pathway; and MRPS7 and IDH2 that encode proteins necessary for 86 mitochondrial function. Trans-ancestral functional fine-mapping identified six loci 87 (RREB1, INHBC, HLF, UBE2Q2, SFMBT1, HNF4G) with colocalized eQTL that 88 contained putative causal SNPs (posterior probability of causality > 0.8). This 89 systematic analysis of serum urate GWAS loci has identified candidate causal genes at 90 19 loci and a network of previously unidentified genes likely involved in control of 91 serum urate levels, further illuminating the molecular mechanisms of urate control. 92 93 Author Summary 94 High serum urate is a prerequisite for gout and a risk factor for metabolic disease. 95Previous GWAS have identified numerous loci that are associated with serum urate 96 control, however, only a small handful of these loci have known molecular 97 consequences. The majority of loci are within the non-coding regions of the genome 98 and therefore it is difficult to ascertain how these variants might influence serum urate 99 levels without tangible links to gene expression and / or protein function. We have 100 applied a novel bioinformatic pipeline where we combined population-specific GWAS 101 4 data with gene expression and genome connectivity information to identify putative 102 causal genes for serum urate associated loci. Overall, we identified 15 novel serum 103 urate loci and show that these loci along with previously identified loci are linked to 104 the expression of 44 genes. We show that some of the variants within these loci have 105 strong predicted regulatory function which can be further tested in functional analyses. 106 This study expands on previous GWAS by ident...

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“…NGS was conducted at the Center for Genomics and Transcriptomics (CeGaT GmbH, Tübingen, Germany) as previously described. 39 Details are provided in the supplementary methods.…”

Section: Methodsmentioning

confidence: 99%

Polymorphic Variation in TPMT Is the Principal Determinant of TPMT Phenotype: A Meta‐Analysis of Three Genome‐Wide Association Studies

Tamm

Mägi

Tremmel

et al. 2017

Clin Pharma and Therapeutics

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Thiopurine-related hematotoxicity in paediatric acute lymphoblastic leukemia (ALL) and inflammatory bowel diseases has been linked to genetically defined variability in thiopurine S-methyltransferase (TPMT) activity. While gene testing of TPMT is being clinically implemented, it is unclear if additional genetic variation influences TPMT activity with consequences for thiopurine-related toxicity. To examine this possibility, we performed a genome-wide association study (GWAS) of red blood cell TPMT activity in 844 Estonian individuals and 245 paediatric ALL-cases. Additionally, we correlated genome-wide genotypes to human hepatic TPMT activity in 123 samples. Only genetic variants mapping to chromosome 6, including TPMT gene region, were significantly associated with TPMT activity (P<5.0×10−8) in each of the three GWAS and a joint meta-analysis of 1212 cases (top hit P=1.2×10−72). This finding is consistent with TPMT genotype being the primary determinant of TPMT activity, reinforcing the rationale for genetic testing of TPMT alleles in routine clinical practice to individualize MP dosage.

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Variability in hepatic expression of organic anion transporter 7/SLC22A9, a novel pravastatin uptake transporter: impact of genetic and regulatory factors

Cited by 36 publications

References 45 publications

The sharedneoantigen landscape of MSI cancers reflects immunoediting during tumor evolution

The sharedneoantigen landscape of MSI cancers reflects immunoediting during tumor evolution

Genomic dissection of 43 serum urate-associated loci provides multiple insights into molecular mechanisms of urate control

Polymorphic Variation in TPMT Is the Principal Determinant of TPMT Phenotype: A Meta‐Analysis of Three Genome‐Wide Association Studies

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