Biology subjects

Nioi, P.

Publications and source records attributed to Nioi, P..

4 recordsLinked to original sources

bioRxiv2020

Genome-wide association study of circulating liver enzymes reveals an expanded role for manganese transporter SLC30A10 in liver health

To investigate mechanisms of hepatocellular damage, we performed genome-wide association studies (GWAS) on alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum activities across 411,048 subjects from four ancestry groups in the UK Biobank, and found 100 loci associating with both enzymes. The rare missense variant SLC30A10 Thr95Ile (rs188273166) associates with a larger elevation in ALT and AST than any other variant tested and this association also replicates in the DiscovEHR study. SLC30A10 excretes manganese from the liver to the bile duct, and rare homozygous loss of function causes the syndrome hypermanganesemia with dystonia-1 (HMNDYT1) which involves cirrhosis. Consistent with hematological symptoms of hypermanganesemia, SLC30A10 Thr95Ile carriers have increased hematocrit and risk of iron deficiency anemia. Carriers also have increased risk of extrahepatic bile duct cancer. These associations suggest that genetic variation in SLC30A10 adversely affects more individuals than patients with diagnosed HMNDYT1.

genetics↗

bioRxiv2019

Transthyretin-stabilizing mutation T119M is not associated with protection against vascular disease or death in the UK Biobank

BackgroundDestabilized transthyretin (TTR) can result in the progressive, fatal disease transthyretin-mediated (ATTR) amyloidosis. A stabilizing TTR mutation, T119M, is the basis for a therapeutic strategy to reduce destabilized TTR. Recently, T119M was associated with extended lifespan and lower risk of cerebrovascular disease in a Danish cohort. We aimed to determine whether this finding could be replicated in the UK Biobank.\n\nMethodsTTR T119M carriers were identified in the UK Biobank, a large prospective cohort of [~]500,000 individuals. Association between T119M genotype and inpatient diagnosis of vascular disease, cardiovascular disease, cerebrovascular disease, and mortality was analyzed.\n\nResultsFrequency of T119M within the white UK Biobank population (n=337,148) was 0.4%. Logistic regression comparing T119M carriers to non-carriers found no association between T119M and vascular disease (odds ratio [OR]=1.08; p=.27), cardiovascular disease (OR=1.08; p=.31), cerebrovascular disease (OR=1.1; p=.42), or death (OR=1.2; p=.06). Cox proportional hazards regression showed similar results (hazard ratio>1, p>.05). Age at death and vascular disease diagnosis were similar between T119M carriers and non-carriers (p=.12 and p=.38, respectively).\n\nConclusionsThere was no association between the TTR T119M genotype and risk of vascular disease or death in a large prospective cohort study, indicating that TTR tetramer stabilization through T119M is not protective in this setting.

genetics↗

bioRxiv2019

Deep phenotyping of a healthy human HAO1 knockout informs therapeutic development for primary hyperoxaluria type 1.

Primary Hyperoxaluria Type 1 (PH1) is a rare autosomal recessive metabolic disorder of oxalate metabolism leading to kidney failure as well as multi-organ damage. Overproduction of oxalate occurs in the liver due to an inherited genetic defect in the enzyme alanine-glyoxylate aminotransferase (AGXT), causing pathology due to the insolubility of calcium oxalate crystals in body fluids. The main current therapy is dual liver-kidney transplant, which incurs high morbidity and has poor availability in some health systems where PH1 is more prevalent. One approach currently in active clinical investigation targets HAO1 (hydroxyacid oxidase 1), encoding glycolate oxidase, to reduce substrate levels for oxalate production. To inform drug development, we sought individuals with reduced HAO1 function due to naturally occurring genetic variation.\n\nAnalysis of loss of function variants in 141,456 sequenced individuals suggested individuals with complete HAO1 knockout would only be observed in 1 in 30 million outbred people. However in a large sequencing and health records program (Genes & Health), in populations with substantial autozygosity, we identified a healthy adult individual predicted to have complete knockout of HAO1 due to an ultra rare homozygous frameshift variant (rs1186715161, ENSP00000368066.3:p.Leu333SerfsTer4). Primary care and hospital health records confirmed no apparently related clinical phenotype. At recall, urine and plasma oxalate levels were normal, however plasma glycolate levels (171 nmol/mL) were 12 times the upper limit of normal in healthy, reference individuals (mean+2sd=14 nmol/mL, n=67) while her urinary glycolate levels were 6 times the upper limit of normal. Comparison with preclinical and phase 1 clinical trial data of an RNAi therapeutic targeting HAO1 (lumasiran) suggests the individual likely retains <2% residual glycolate oxidase activity.\n\nThese results provide important data to support the safety of HAO1 inhibition as a potential chronic therapy for a devastating metabolic disease (PH1). We also suggest that the effect of glycolate oxidase suppression in any potential other roles in humans beyond glycolate oxidation do not lead to clinical phenotypes, at least in this specific individual. This demonstrates the value of studying the lifelong complete knockdown of a target protein in a living human to aid development of a potential therapeutic, both in de-risking the approach and providing potential hypotheses to optimize its development. Furthermore, therapy for PH1 is likely to be required lifelong, in contrast to data from chronicity studies in non-human species or relatively short-term therapeutic studies in people. Our approach demonstrates the potential for improved drug discovery through unlocking relevant evidence hiding in the diversity of human genetic variation.

genetics↗

bioRxiv2018

Phenotypes associated with genes encoding drug targets are predictive of clinical trial side effects

Biomedical scientists face major challenges in developing novel drugs for unmet medical needs. Only a small fraction of early drug programs progress to the market, due to safety and efficacy failures, despite extensive efforts to predict drug and target safety as early as possible using a variety of assays in vitro and in preclinical species. In principle, characterizing the effect of natural variation in the genes encoding drug targets should present a powerful alternate approach to predict not only whether a protein will be an effective drug target, but also whether a protein will be an inherently safe drug target, while avoiding the challenges of translating biology from experiments in non-human species. We have embarked on a retrospective analysis, demonstrating for the first time a statistical link between the organ systems involved in genetic syndromes of drug target genes and the organ systems in which side effects are observed clinically. Across 1,819 drugs and 21 organ system phenotype categories analyzed, drug side effects are more likely to occur in organ systems where there is genetic evidence of a link between the drug target and a phenotype involving that organ system, compared to when there is no such genetic evidence (30.0% vs 19.2%; OR = 1.80). Conversely, we find that having genetic evidence of a Mendelian syndrome involving a drug target in which a certain organ system is unaffected decreases the likelihood that side effects will manifest in that organ system, relative to having no informative syndrome (18.5% vs 20.2%; OR = 0.89). We find a relationship between genetics and side effects even when controlling for known confounders such as drug delivery route and indication. We highlight examples where genetics of drug targets could have anticipated side effects observed during clinical trials. This result suggests that human genetic data should be routinely used to predict potential safety issues associated with novel drug targets. This may lead to selection of better targets, appropriate monitoring of putative side effects early in development, reduction of the use of preclinical animal experiments, and ultimately increased success of molecules. Furthermore, deeply phenotyping human knockouts will be critically important to understand the full spectrum of effects that a new drug may elicit.

genetics↗