STUDY OF THREE SINGLE NUCLEOTIDE
POLYMORPHISMS IN THE SLC6A14 GENE
IN ASSOCIATION WITH MALE INFERTILITY
Noveski P1, Mircevska M1, Plaseski T2, Peterlin B3, Plaseska-Karanfilska D1,*
*Corresponding Author: Dijana Plaseska-Karanfilska, M.D., Ph.D., Research Centre for Genetic Engineering
and Biotechnology “Georgi D. Efremov,” Macedonian Academy of Sciences and Arts, Krste Misirkov 2, 1000
Skopje, Republic of Macedonia. Tel. +389-2-3235-410. Fax: +389-2-3115-434. E-mail: dijana@manu.edu.mk
page: 61
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DISCUSSION
We previously showed that rs5911500 SNP, located
in the Xq24 region, is associated with male
infertility [7]. In close proximity to this SNP is the
SLC6A14 gene that has previously been found in
association with obesity [9] and cystic fibrosis [12],
both of which have been implicated in male infertility.
Because men are hemizygous for this gene, any
positive or negative effect of a given allele would
be expressed directly. For these reasons, we conducted
this study to investigate the possible involvement
of this gene in male infertilty/subfertility. In
order to account for variation in SNP genotype and
haplotype frequencies in different populations due
to a physical separation and genetic drift, we have
matched patients and controls in a population-based
(Macedonian and Slovenian) manner from a fixed
geographic area.
Of the three studied SNPs, only the rs2011162
differed in allele distribution between infertile and
fertile men, and only in the Macedonian population.
The alternative G allele for rs2011162 was present
with a lower frequency in infertile Macedonian men
(54.0%) in comparison to the fertile controls (66.0%).
This allele was also a part of a rs2312054(A)-
rs2071877(C)-rs2011162(G) haplotype that was present
at significantly lower frequencies in infertile than
in fertile Macedonian men. For comparison, data
from 1000 Genomes showed that the rs2011162(G)
allele varies in frequency from 27.0% in Africans to
66.0% in the American population. This means that
in some populations, an alternative rs2011162(G)
allele could be under selection and more favorable
than the ancestral rs2011162 (C) allele. In our study,
the alternative G allele was more prevalent in both the
Macedonian and the Slovenian populations compared
to the ancestral C allele. Based on results of significant
association of the rs2011162(G) allele with male
fertility, we further investigated the possible influence
that this SNP could exhibit on SLC6A14 gene expression.
It is localized in the 3’UTR (3’ untranslated
region) of the SLC6A14 gene and is not a part of the
coding and translated sequence of mRNA. However,
the 3’UTR is important because it contains regulatory
regions with roles in transcript cleavage, stability and
polyadenylation, translation and mRNA localization
[19]. Mutations that change the secondary structure
of the 3’UTR may result in disruption of expression
[19-22]. Our assessment of the possible influence
of rs2011162 alleles on secondary structure of the
3’UTR showed a significant (p = 0.0783) structural
effect in Mode 1 of analysis and indicated that the
SLC 6A14 mRNA with a rs2011162(G) allele might
be expressed more efficiently than the mRNA with
the rs2011162(C) allele.
In conclusion, an alternative rs2011162(G) allele
and the SLC6A14 rs2312054(A)-rs2071877(C)-
rs2011162(G) haplotype might exhibit some kind of
protective effect on the spermatogenesis. SLC6A14
could be a population-specific, low-penetrance locus
that confers susceptibility to male infertility/subfertility.
To the best of our knowledge, this is the first study
addressing the possible association of SLC6A14 with
male infertility. More rigorous follow-up studies,
involving larger number of infertile men from different
populations and eventually, testicular expression
studies, are needed in order to confirm this finding.
Conflict of Interest. This study was supported
by grant CRP/MAC09-01 from ICGEB-Trieste (to D.
Plaseska-Karanfilska). The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of this article.
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