Genetic Association of Solute Carrier Transporter Gene Variants with Metformin Response

Z Abrahams-October; L Xhakaza; B Pearce; C Mandisa Masilela; M Benjeddou; O Vincent Adeniyi; R Johnson; J Jebio Ongole

doi:10.2478/bjmg-2021-0004

Genetic Association of Solute Carrier Transporter Gene Variants with Metformin Response

Balkan J Med Genet. 2021 Jul 27;24(1):47-56. doi: 10.2478/bjmg-2021-0004. eCollection 2021 Jun.

Authors

Z Abrahams-October¹, L Xhakaza¹, B Pearce¹, C Mandisa Masilela¹, M Benjeddou¹, O Vincent Adeniyi², R Johnson^{3

4}, J Jebio Ongole⁵

Affiliations

¹ Precision Medicine Unit, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, South Africa.
² Department of Family Medicine, Walter Sisulu University, East London, South Africa.
³ South African Medical Research Council, Parow, Cape Town, South Africa.
⁴ Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.
⁵ Department of Family Medicine, Piet Retief Hospital, Mkhondo, Mpumalanga, South Africa.

Abstract

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by elevated blood glucose levels and is influenced by both genetic and environmental factors. It is treated with various classes of oral antidiabetic drugs, however, response to treatment is highly variable with patients failing to achieve adequate glycemic control. Treatment response variability has been associated with single nucleotide polymorphisms (SNPs) which influence the pharma-cokinetics and pharmacodynamics of drug(s). The aim of this study was to evaluate the genetic association of 17 SNPs and the response to metformin therapy in patients diagnosed with diabetes from the indigenous Nguni population of South Africa. One hundred and forty indigenous African patients diagnosed with T2DM were recruited and genotyped using the MassARRAY® system. Therapeutic response of patients was ascertained by a change in Hb A^1c. Two SNPs (rs1801282 and rs6265) were monomorphic. All other variants were within the Hardy-Weinberg equilibrium (HWE). The T allele of the SLC variant rs316009 [odds ratio (OR) = 0.25, 95% confidence interval (95% CI) = 0.01-0.09, p value = 0.044] and the CT genotype of the PCK1 variant rs4810083 (OR = 2.80, 95% CI = 1.01-7.79, p value = 0.049) were associated with an improved response to treatment after adjustment. No association was observed with post Bonferroni correction. Moreover, this study provides important additional data regarding possible associations between genetic variants and metformin therapy outcomes. In addition, this is one of the first studies providing genetic data from the understudied indigenous sub-Saharan African populations.

Keywords: SLC variants; Single nucleotide polymorphisms (SNPs); South African cohort; Treatment response; Type 2 diabetes mellitus (T2DM).

Grants and funding

The study reported herein was made possible through funding by the South African Medical Research Council through its Division of Research Capacity Development under funding received from the South African National Treasury (Cape Town, Western Cape, South Africa). In addition, partial funding from the National Research Foundation of South African and the University of the Western Cape was used for this study.