GENETIC ASSOCIATION OF SOLUTE
CARRIER TRANSPORTER GENE VARIANTS
WITH METFORMIN RESPONSE
Abrahams-October Z1, Xhakaza L1, Pearce B1,*, Mandisa Masilela C1,
Benjeddou M1, Vincent Adeniyi O2, Johnson R3,4, Jebio Ongole J5
*Corresponding Author: Brendon Pearce, Ph.D., Department of Biotechnology, University of the
Western Cape, Private Bag X17, Bellville 7535, South Africa. Tel.: +2721-959-2080. Fax: +2721-959-
2648. E-mail: brendon.biff@gmail.com
page: 47
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INTRODUCTION
The prevalence of diabetes mellitus (DM) across the
world is constantly rising. It is estimated that 642 million
cases of DM will be reported by the year 2040 [1]. In the
African region alone, it was found that 15.5 million adults
were living with DM and, of these, 7.0% originate from
South Africa [2]. Diabetes mellitus is defined as a chronic
metabolic disease characterized by prolonged hyperglycemia
[3].
The prolonged hyperglycemia experienced by diabetic
patients can result in macro- and microvascular
complications that increases the risk for heart disease,
stroke, and damage to the nervous system, retina, kidneys
and other organs [4,5]. Therefore, DM treatment aims
to maintain a blood glucose level within the physiological
range [5]. Therapies implemented include dietary and
lifestyle modification and the administration of oral anti
diabetic drugs.
The preferred first line treatment in most clinical
guidelines for the management of type 2 diabetes mellitus
(T2DM), accounting for ~90.0% of all DM cases, is metformin
[6,7]. However, 38.0% of T2DM patients respond
poorly to metformin [8]. In addition to biguanides, several other classes of drugs are being prescribed to treat T2DM;
these include: sulfonylureas, meglitinides, thiazolidinediones,
α-glucosidase inhibitors, dipeptidyl peptidase-4 inhibitors,
glucagon-like peptide-1 agonist, sodium glucose
cotransporter-2 inhibitors, insulin and its analogues [9-11].
Type 2 diabetes mellitus has been linked to variability
in candidate genes that interfere with the management of
glycemic control [9]. These candidate genes are involved
in drug absorption, transportation, distribution, metabolism
and the signaling cascade of oral anti diabetic drugs [12].
Studies have shown that the T2DM patient’s response to
treatment is characterized by inter-individual variability
[13,14]. This variability in response have been linked to
genetic and environmental factors [15,16].
As metformin is the most common drug prescribed for
the treatment and management of T2DM, numerous studies
have been conducted to determine the therapeutic effects
of metformin in the presence of genetic variants. Amongst
the variants investigated, the SLC variants feature quite
often. Tzvetkov et al. [17] observed a variation in the renal
clearance of metformin in Caucasian males with genetic
polymorphisms in SLC22A1, SLC22A2 and SLC22A3.
The renal transport of metformin was associated with a
glucose lowering effect in combination with SLC47A1 and
SLC22A1 genetic variants in a Dutch cohort [18]. Chen et
al. [19] observed a very rare SLC22A1 (R206C) variant in
Asian patients diagnosed with T2DM. Patients with this
rare variant demonstrated an altered response to metformin
treatment. These studies and others like it, demonstrate the
impact that SLC variants and other genetic variants, have
on the efficacy and toxicity of prescribed drugs.
Pharmacogenomic and pharmacokinetic studies have
been conducted on the treatment response to T2DM in
various populations across the world [20-23]. However,
even though numerous studies have been conducted, limited
data is available for sub-Saharan African populations
and other African populations, regardless of the human
genomic diversity found on this continent. Genetic diversity
presented by indigenous populations across the
world, in this instance South Africa, should be explored
for improved diagnostic techniques and treatment plans
for conditions such as diabetes, cardiovascular disease and
cancer. The indigenous Nguni population of South Africa
was selected for investigation in this study. The Nguni
population is comprised of the Xhosa, Zulu, Ndebele and
Swati clades [24-26].
Loci identified in previously studied populations observed
anti diabetic drug efficacy may or may not affect
efficacy in South African populations because of ethnic
genetic differences. Seventeen single nucleotide polymorphism
(SNP) biomarkers selected for investigation in this
study, have previously been associated with T2DM in various
populations across the world [17-23,27-28]. The aim
of this study was to investigate the genetic association of
these 17 SNP biomarkers and the response to anti diabetic
treatment to determine their suitability for individualized
metformin therapy in patients diagnosed with T2DM in
the Nguni indigenous population of South Africa.
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