The role of <scp>ITPA</scp> and ribavirin transporter genes polymorphisms in prediction of ribavirin‐induced anaemia in chronic hepatitis C Egyptian patients

Desoky, Ehab S El; Abdelhafez, Alaa T; Cusato, Jessica; Kamel, Sherif; Nicolò, Amedeo De; Perri, Giovanni Di; D’Avolio, Antonio

doi:10.1111/1440-1681.12786

Cited by 4 publications

(3 citation statements)

References 19 publications

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“…Table S1 summarises the collection of exonic variants that are more confidently dominance fine-mapped. The non-additive signal in the ITPA locus associated with red blood cell distribution width was fine-mapped to rs1127354, a non-synonymous single nucleotide variant which is known to predict drug induced anaemia among chronic HCV patients (39)(40)(41)(42)(43). The genome-wide significant non-additive association with hearing difficulty/problems was fine-mapped to rs2877561, a synonymous change in ILDR1 associated with age-related hearing impairment (44) but which did not reach genome-wide significance in that study.…”

Section: Application: Fine-mapping Dominance Locimentioning

confidence: 99%

Analysis of genetic dominance in the UK Biobank

Palmer

Zhou

Abbott

et al. 2021

Preprint

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In classical statistical genetic theory, a dominance effect is defined as the deviation from a purely additive genetic effect for a biallelic variant. Dominance effects are well documented in model organisms. However, evidence in humans is limited to a handful of traits, particularly those with strong single locus effects such as hair color. We carried out the largest systematic evaluation of dominance effects on phenotypic variance in the UK Biobank. We curated and tested over 1,000 phenotypes for dominance effects through GWAS scans, identifying 175 loci at genome-wide significance correcting for multiple testing (P < 4.7 × 10-11). Power to detect non-additive loci is much lower than power to detect additive effects for complex traits: based on the relative effect sizes at genome-wide significant additive loci, we estimate a factor of 20-30 increase in sample size will be necessary to capture clear evidence of dominance similar to those currently observed for additive effects. However, these localised dominance hits do not extend to a significant aggregate contribution to phenotypic variance genome-wide. By deriving a version of LD-score regression to detect dominance effects tagged by common variation genome-wide (minor allele frequency > 0.05), we found no strong evidence of a contribution to phenotypic variance when accounting for multiple testing. Across the 267 continuous and 793 binary traits the median contribution was 5.73 × 10-4, with unbiased point estimates ranging from -0.261 to 0.131. Finally, we introduce dominance fine-mapping to explore whether the more rapid decay of dominance LD can be leveraged to find causal variants. These results provide the most comprehensive assessment of dominance trait variation in humans to date.

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Section: Application: Fine-mapping Dominance Locimentioning

confidence: 99%

Analysis of genetic dominance in the UK Biobank

Palmer

Zhou

Abbott

et al. 2021

Preprint

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“…Recently ribavirin triphosphate (RTP) has been reported to be dephosphorylated intracellularly to ribavirin monophosphate (RMP) by ITPase [35]. As ribavirin and RMP, but not RTP, can be transported across the plasma membrane through specific transporter proteins (ENT1, ENT2, CNT2, MRP4 and MRP5) [23,[36][37][38][39], it is not surprising that reduced ITPase activity is associated both with higher intracellular RTP levels [35] and lower plasma ribavirin concentrations (Figure 1) [32].…”

Section: Impact Of Inosine Triphosphate Pyrophosphatase On Ribavirinmentioning

confidence: 99%

Ribavirin: Pharmacology, Multiple Modes of Action and Possible Future Perspectives

et al. 2019

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Ribavirin is a unique guanosine analog with broad-spectrum activity against many RNA and DNA viruses. In addition to its mutational properties, ribavirin exerts extensive perturbation of cellular and viral gene expression. Furthermore, recent advances indicate that the impact of ribavirin on divergent cellular and viral pathways may be concentration dependent. This review aims at providing an overview of the pharmacology and multiple modes of action of ribavirin as well as pointing to possible novel future uses.

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“…Table S4 summarizes the collection of exonic variants that are more confidently dominance fine-mapped. The nonadditive signal in the ITPA locus that is associated with red blood cell distribution width was fine-mapped to rs1127354, a nonsynonymous single-nucleotide variant that predicts druginduced anemia among patients with chronic hepatitis C virus infection (71)(72)(73)(74)(75). The genomewide significant nonadditive association (P = 5.79 × 10 −13 ; fig.…”

Section: Fine-mapping Dominance Locimentioning

confidence: 99%

Analysis of genetic dominance in the UK Biobank

Palmer

Zhou

Abbott

et al. 2023

Science

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Classical statistical genetics theory defines dominance as any deviation from a purely additive, or dosage, effect of a genotype on a trait, which is known as the dominance deviation. Dominance is well documented in plant and animal breeding. Outside of rare monogenic traits, however, evidence in humans is limited. We systematically examined common genetic variation across 1060 traits in a large population cohort (UK Biobank, N = 361,194 samples analyzed) for evidence of dominance effects. We then developed a computationally efficient method to rapidly assess the aggregate contribution of dominance deviations to heritability. Lastly, observing that dominance associations are inherently less correlated between sites at a genomic locus than their additive counterparts, we explored whether they may be leveraged to identify causal variants more confidently.

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The role of ITPA and ribavirin transporter genes polymorphisms in prediction of ribavirin‐induced anaemia in chronic hepatitis C Egyptian patients

Cited by 4 publications

References 19 publications

Analysis of genetic dominance in the UK Biobank

Analysis of genetic dominance in the UK Biobank

Ribavirin: Pharmacology, Multiple Modes of Action and Possible Future Perspectives

Analysis of genetic dominance in the UK Biobank

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