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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DISCUSSION
In this study the genetic association of 17 pharmacogenomic
biomarkers and response to metformin treatment
in the indigenous Nguni population of South Africa was
determined. Previously, the MATE2K variant, rs12943590
and the variant rs12752688, had been suggested for inclusion
in pharmacogenomic profiling of the Nguni population
[24]. This study will provide additional pharmacogenomic
biomarker information about possible associations
between genetic variants and response to metformin
therapy in the Nguni population.
All SNPs, besides rs1801282 and rs6265 (which were
shown to be monomorphic), were within HWE and showed
p values ranged between 0.145-0.932 in the study population
(Table 2). The two monomorphic SNPs (i.e. rs1801282
and rs6265) are rare variants, however, they were included
in the study because of the important roles they play in
the development and progression of the diabetes disease.
The PPARG variant, rs1801282, is important in the
development of obesity as well as adipose and muscle
tissue metabolism [33]. This variant has recently been
investigated in the development of early visual impairment
in T2DM Chinese Han population [33] and been associated
with obstructive sleep apnea in Chinese Han and
Indian subjects diagnosed with T2DM [34,35]. Obesity is
a known comorbid disease of diabetes and sleep apnea has
also been associated with diabetes, therefore, this variant
was included for investigation.
The BDNF gene theoretically plays a significant role
on the well-being and health of individuals, as it has diverse
roles throughout the body and brain [36]. The BDNF variant,
rs6265, has been linked to obesity and T2DM in Chinese
populations [36,37] and BMI in Korean [38] and British
populations [39]. Because this variant could affect T2DM,
comorbid diseases related to diabetes and other physical
indicators of the progression of diabetes, it was selected
for the study, regardless of its rarity in African populations.
Genotype and allele distribution of the 17 SNPs were
determined in all the study participants (Tables 3 and 4).
Among the SNPs analyzed, 13 of the SNPs selected for
this study showed no statistically significant association
between treatment response and the SNP variant (Table
3). The remaining four variants however, i.e. rs316009
(genotype p value 0.023; allele p value 0.027), rs316019
(genotype p value 0.026), rs4810083 (genotype p value
0.021) and rs578427 (genotype p value 0.022), showed
a significant association between variant and treatment
response prior to adjustment (Table 4). This study showed
an increased treatment response to metformin for T2DM
patients with SNP variants rs316009, rs316019 and
rs4810083. In contrast, rs578427 demonstrated a decrease
in response to treatment. However, post adjustment, only
the T allele of rs316009 (p value 0.044) and the CT genotype
of rs4810083 (p value 0.049) were associated with
treatment response. Post Bonferroni correction rs316009 (p
value 0.088) and rs4810083 (p value 0.098), demonstrated
a lack of association. However, this can be attributed to
the small sample size of the study cohort.
The rs316009 variant is located in a transcription factor
binding motif and is in linkage disequilibrium with the
non synonymous variant rs316019 [21,40-47]. In previous
studies, the TT genotype of rs316009 showed an increase
response to metformin in comparison to the CC and CT genotypes
[41]. Unfortunately, the homozygous TT genotype
was not observed in this study population. From the data
available, the CT genotype demonstrated a better response
to treatment in comparison to the CC genotype (Table 4).
The rs316019 is the most common variant of SLC22A2 in
many populations and has displayed contradictory results,
linked to both decreased and increased renal clearance of
metformin in healthy subjects [5,40,42-45].
The interaction of metformin and other drugs in the
presence of rs316019 was determined in silico by Sajib et al.
[43]. Based upon the in silico data generated by Sajib et al. [43], all substrates bind to the same pocket of SLC22A2 and
substrates fit better to the binding site of the C allele [43]. The
rs316019 results in a protein change that clears metformin
from circulation much more slowly than the wild-type [43].
The AA genotype, especially in females, has been linked to
hyperlactacidemia within clinical doses of metformin [43].
Thus, dose adjustments based on the rs316019 variant may
be beneficial to maximize treatment response.
Prior to correction, the A allele was significantly associated
with an improved response to treatment. This is in
contradiction to studies conducted by Song et al. [44] and
Wang et al. [42], as well as the in silico data generated by
Sajib et al. [43]. This data is however in agreement with
studies conducted by Chen et al. [40]. Other studies also
indicated no association between this variant and response
to metformin treatment [17,21].
The SNP variant rs4810083 T allele is not associated
with a response to metformin treatment in T2DM patients
[46]. The results obtained in this study, however, may
suggest that the T allele is most likely to be associated
with a decrease in response to diabetic treatment as more
patients in the uncontrolled category carry the T allele in
comparison to the controlled category. This study group
also shows the CT genotype to be associated with an improved
response to treatment (Table 4). To enable further
clarity with regard to the significance of this SNP variant,
more data is required from other population groups as
well as a bigger sample cohort for the current study group.
In the case of the SNP rs578427, the TT genotype
has been associated with an increased renal clearance and
secretion clearance of metformin in comparison to the CC
genotype in a healthy population [47]. As the accumulation
of metformin in the body can result in the development of
lactic acidosis, the TT genotype can thus be associated with
an improved response to treatment. These results are in
concordance with the data generated for this study population
as the CC genotype was shown to be significantly associated
with a decreased response to treatment (Table 4).
Contradictory, as well as inconclusive, results may
have arisen for a number of reasons. The most relevant being
sample size as well as SNP selection and the approach
used to analyze individual SNPs. Because SNPs do not
occur in isolation of each other, but rather as combinations
forming defined haplotypes, the phenotypic effect of individual
SNPs is not always consistent with functional effects.
Thus, genotyping single or a few individual SNPs may fail
to reflect the true functionality of genetic variants [48].
Therefore, it should be recommended that future studies
evaluate haplotypes to establish the functional effects that
a collection of SNPs may have on response to treatment.
Conclusions. In this study, two SNP variants
(rs316009 and rs4810083) were significantly associated
with improved response to diabetic treatment prior to Bonferroni
correction. The greatest limitation of this study
was the sample size and this has inadvertently affected
the relevance of significantly associated SNP variants.
Regardless of this, this study provides additional important
data regarding possible associations between genetic
variants and metformin therapy outcomes. In, addition,
this study is one of the first studies providing genetic data
from the understudied indigenous sub-Saharan African
populations.
Acknowledgments. The authors would like to thank
the study participants, Cecilia Makiwane Hospital and the
Department of Health Eastern Cape (Mdantsane, Eastern
Cape, South Africa). The content hereof is the sole responsibility
of the authors and do not necessarily represent
the official views of the South African Medical Research
Council or the funders.
Declaration of Interest. The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of this article.
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.
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