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Rare Genetic Variants in Nutrient Transporters: Impact on drug response and human disease

  • Author(s): Enogieru, Osatohanmwen Jessica
  • Advisor(s): Giacomini, Kathleen M
  • et al.
Abstract

Translational research, often referred to as “bench-to-bedside” science, involves converting novel biological, chemical or other scientific discoveries into clinically relevant medical treatments, devices and/or applications. Reverse translational research uses basic science tools and experimental models to investigate the biological, physiological and molecular mechanisms behind observations in human clinical data.

In this dissertation project, we use both approaches to investigate the influence of nutrient membrane transporters on clinical drug response and human disease.

Metformin is first-line treatment for Type 2 Diabetes (T2D), a metabolic disorder characterized by excessive glycemia and reduced insulin production and sensitivity. The prevalence of Type 2 Diabetes is growing both in the U.S. and globally. Therefore, a larger and increasingly diverse population of individuals will be treated with metformin. The heritability of metformin response is substantial (about 33%), but common genetic variants previously identified to associate with metformin response (SLC2A2, solute carrier family 2 member 2; ATM, ataxia telangiectasia mutated serine/threonine kinase) do not fully account for all the heritability. Our translational approach starts with conducting a metformin sequencing association study in a cohort of patients who responded very well (extreme responders) or poorly (extreme non-responders) to metformin to identify rare variants in the glucose transporter, GLUT2 (SLC2A2) that modulate metformin response. In this dissertation, I describe the study design and various data analytical approaches that will be used to discover rare variants in SLC2A2 that associate with metformin response.

In our reverse translational approach we focus on rare variants in the same gene (SLC2A2), which are causal for Fanconi-Bickel syndrome (FBS), an autosomal recessive glycogen storage disease. Mild and severe forms of FBS have been observed and reported in the clinical literature, but the question of whether residual function of mutant GLUT2 associates with disease severity has not been examined. So, I functionally characterized the impact of GLUT2 mutations causal for FBS on both transporter function and membrane expression. In the study, I identified a variant (p.Leu153_Ile154del), found in patients with a mild form of FBS that retained residual glucose transport activity, suggesting that small increases in GLUT2 activity could substantially reduce the severity of FBS symptoms.

In our final study I conducted a screen of prescription drugs as inhibitors of THTR-1 (thiamine transporter encoded by SLC19A2, solute carrier family 19 member 2). The results of that screen identified several prescription and one over-the-counter drugs that inhibit THTR-1. Using data from electronic medical records, we observed significantly reduced thiamine pyrophosphate levels in blood samples from patients exposed to two THTR-1 inhibitors (erythromycin, omeprazole) versus samples from age and sex- matched individuals not on the drugs, suggesting inhibition of THTR-1 in vivo. Both drugs are associated with megaloblastic anemia, which is also caused by genetic mutations in THTR-1. The results suggest the possibility of a novel mechanism for drug-induced megaloblastic anemia.

Our overall findings of the dissertation have important implications for understanding the role of micro- and macro- nutrient transporters in drug response and human disease. Our studies continue to examine the role of genetic variants in the glucose transporter gene, SLC2A2 and metformin response, extending the application of precision medicine to the pharmacological treatment of T2D. Importantly, our studies suggest novel treatment strategies for rare diseases caused by genetic mutations in nutrient transporter, like FBS, and novel mechanisms for drug-induced disorders, such as drug-induced megaloblastic anemia.

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