A PILOT STUDY OF ANXA2, MED12, CALM1 AND MAPK1 GENE VARIANTS IN PRIMARY HYPERPARATHYROIDISM
Chorti A#1, Achilla C#2, Siasiaridis A2, Aristeidis I1, Cheva A3, Theodosios Papavramidis T##1, Chatzikyriakidou A##*2,4
*Corresponding Author: *Corresponding Author: Anthoula Chatzikyriakidou, Laboratory of Medical Biology - Genetics, Faculty of Medicine, School of Health Sciences, Aristotle University, 54124, Thessaloniki, Greece. Tel: +30 2310999013, Email: chatzikyra@auth.gr
page: 33
|
|
DISCUSSION
PHPT is a prevalent endocrine disorder characterized
by the excessive functioning of the parathyroid glands [3].
The genetic basis of PHPT is only partially understood, and
genetic variants have emerged as potential contributors to
the development and progression of the disease affecting
the genes’ expression. This comprehensive study aimed
to investigate the association between specific variants of
ANXA2, MED12, CALM1, and MAPK1 genes with PHPT.
The genes investigated in this study have been im-
plicated in tumorigenesis and have shown associations
with various types of cancer and parathyroid malignan-
cies. ANXA2 is involved in tumor progression, invasion,
and metastasis and its upregulation has been reported in
parathyroid adenomas and several types of cancer [7, 8].
MED12 variants were frequently observed in various
cancer types, while overexpression has been related to
parathyroid adenomas [11, 20]. CALM1 was reported to
participate in calcium signaling [12], making it a potential
candidate for association with PHPT. Moreover, CALM1
has been related to an inhibitory effect on PTH secretion
in parathyroid adenoma [13]. Finally, MAPK1/ERK2 has
been described as a key component of signaling pathways
regulated by PTH secretion and has been related to cell
proliferation, differentiation, and survival [15].
In previous studies, the minor alleles of ANXA2
rs7170178, rs17191344, and rs11633032 gene variants
have been reported to reduce ANXA2 gene expression and
to down regulate ANXA2 signaling [21, 22]. Specifically,
the minor alleles create repressor-binding protein sites for
transcription factors that contribute to reduced ANXA2
gene expression [21, 22]. The variants rs17191344 and
rs11633032 have been associated with coronary disease
risk in Caucasians through increasing low-density lipopro-
tein cholesterol levels, while rs7170178 has been associ-
ated with osteonecrosis in sickle cell disease in Latin and
Indian patients [21–23]. Moreover, MED12 rs1057519912
and MAPK1 rs1057519911 have been identified as hotspots
in cancer [24]. In addition, rs12885713 in the promoter
region of the CALM1 gene has been reported to affect the
transcription of the gene [25]. This variant has been stud-
ied for its association with osteoarthritis, but the results
were contradictory [26, 27]. The meta-analysis including
studies stratification by ethnicity in the analyses revealed
that the rs12885713 variant increases the risk of osteoar-
thritis among Asians [26]. Furthermore, rs12885713 has
also been associated with double curve and lumbar curve
adolescent idiopathic scoliosis in Chinese patients [28, 29].
In a previous study, we have reported that ANXA2,
MED12, and MAPK1 proteins have positive staining in
the immunohistochemical study of sporadic parathyroid
adenomas in varying intensity and allocation percentages
[30]. Due to technical issues in protocol establishment
the protein CALM1 has not been included in that study.
In the present pilot genetic association study, a total of
50 unrelated PHPT patients and an equal number of
healthy controls were genotyped for ANXA2 (rs7170178,
rs17191344 and rs11633032), MED12 (rs1057519912),
CALM1 (rs12885713) and MAPK1 (rs1057519911) ge-
netic variants. The variants rs17191344 and rs11633032
of the ANXA2 gene and the rs1057519911 of the MAPK1
gene were found to be monomorphic which is in accord-
ance with the very low frequency of their minor alleles
reported in the NCBI database for Caucasians. However,
these variants were initially selected to be studied based on their reported positive association with transcription levels
of ANXA2 gene and as a cancer variant hotspot of MAPK1
gene [21, 22, 24]. Regarding the variants rs7170178
ANXA2, rs1057519912 MED12, and rs12885713 CALM1
no significant association was observed in genotypes or
alleles distributions between PHPT patients and controls.
Due to the reported female preponderance of PHPT
adenoma [19], the study group mainly included female
PHPT patients. The present study is a pilot one and sets the
initial step in exploring a novel intervention. Pilot results
can inform about the feasibility and identify modifica-
tions needed in the design of a larger study testing the
same hypothesis [31, 32]. It is worth mentioning that it
was reported that power analyses should not be presented
in an application in case of a pilot study which does not
propose inferential tests. Instead, a pilot sample size is
based on the pragmatics of recruitment and the necessity
for examining the feasibility [31, 32].
The lack of significant associations between the stu
died genetic variants and PHPT of our study may be attri
buted to several factors, including the genetic heterogene-
ity of PHPT [33]. PHPT is a complex disorder influenced
by both genetic and environmental factors, and multiple
genetic variants likely contribute to its development. It is
estimated that 60% of the variation in PTH concentration is
genetically determined [34], and therefore several genetic
variants have thus far been associated with PHPT patho-
genesis causing among others disturbances in calcium
regulation or cell signaling [35–38]. The sample size of
our study is small, but it follows the suggested standards
for pilot studies, which try to find preliminary evidence
and tendencies of the studied variants’ associations [18].
Additionally, the lack of significant genetic associations
in this study is restricted to the studied genetic variants
and does not reject the possible association between other
variants of ANXA2, MED12, CALM1, and MAPK1 genes
with PHPT predisposition.
However, the publication of negative findings is as
important as publishing statistically significant findings to
overcome the issue of publication bias, which results from
the preferential publication of positive associations and
the reduced likelihood of negative findings being reported
[39–41]. Even though the reported associations between
gene variants and disease could have tremendous impor-
tance for the prevention, prediction, and treatment of dis-
eases, commonly there is an irreproducibility of the results,
and the majority of these associations are not robust [42].
Preliminary studies based on random small sample groups
have been proved of great importance as many times the
results of genome-wide association studies have limited
clinical predictive value and other limitations [43,44]. Con-
sequently, the negative associations, as these of the present
study, offer to decide if it is advantageous to investigate the
above-mentioned variants as risk factors in disease predis-
position especially in complex disorders such as PHPT [34].
It is worth mentioning that given the small sample size, the
study may be underpowered to detect subtle associations.
However, there are many reasons for the significance of
pilot studies’ results in the scientific community such as
assessing the feasibility of a survey, assessing whether the
research protocol is realistic and workable, and developing
a research question and research plan [45].
Undoubtedly, understanding the genetic basis of
PHPT can provide valuable insights into disease mecha-
nisms and potentially guide the development to persona
lized treatment strategies. Genetic association studies of
both positive and negative results can be proven a valuable
resource in the struggle to understand and treat diseases
since the conclusions should not be drawn from a single
report. Positive and negative associations of other similar
studies add to the pool of genetic data for their future
meta-analyses concluding with more accuracy.
Declaration of Interest: The authors report no con-
flicts of interest.
|
|
|
|
 |
Number 27
VOL. 27 (2), 2024 |
Number 27
VOL. 27 (1), 2024 |
Number 26
Number 26 VOL. 26(2), 2023 All in one |
Number 26
VOL. 26(2), 2023 |
Number 26
VOL. 26, 2023 Supplement |
Number 26
VOL. 26(1), 2023 |
Number 25
VOL. 25(2), 2022 |
Number 25
VOL. 25 (1), 2022 |
Number 24
VOL. 24(2), 2021 |
Number 24
VOL. 24(1), 2021 |
Number 23
VOL. 23(2), 2020 |
Number 22
VOL. 22(2), 2019 |
Number 22
VOL. 22(1), 2019 |
Number 22
VOL. 22, 2019 Supplement |
Number 21
VOL. 21(2), 2018 |
Number 21
VOL. 21 (1), 2018 |
Number 21
VOL. 21, 2018 Supplement |
Number 20
VOL. 20 (2), 2017 |
Number 20
VOL. 20 (1), 2017 |
Number 19
VOL. 19 (2), 2016 |
Number 19
VOL. 19 (1), 2016 |
Number 18
VOL. 18 (2), 2015 |
Number 18
VOL. 18 (1), 2015 |
Number 17
VOL. 17 (2), 2014 |
Number 17
VOL. 17 (1), 2014 |
Number 16
VOL. 16 (2), 2013 |
Number 16
VOL. 16 (1), 2013 |
Number 15
VOL. 15 (2), 2012 |
Number 15
VOL. 15, 2012 Supplement |
Number 15
Vol. 15 (1), 2012 |
Number 14
14 - Vol. 14 (2), 2011 |
Number 14
The 9th Balkan Congress of Medical Genetics |
Number 14
14 - Vol. 14 (1), 2011 |
Number 13
Vol. 13 (2), 2010 |
Number 13
Vol.13 (1), 2010 |
Number 12
Vol.12 (2), 2009 |
Number 12
Vol.12 (1), 2009 |
Number 11
Vol.11 (2),2008 |
Number 11
Vol.11 (1),2008 |
Number 10
Vol.10 (2), 2007 |
Number 10
10 (1),2007 |
Number 9
1&2, 2006 |
Number 9
3&4, 2006 |
Number 8
1&2, 2005 |
Number 8
3&4, 2004 |
Number 7
1&2, 2004 |
Number 6
3&4, 2003 |
Number 6
1&2, 2003 |
Number 5
3&4, 2002 |
Number 5
1&2, 2002 |
Number 4
Vol.3 (4), 2000 |
Number 4
Vol.2 (4), 1999 |
Number 4
Vol.1 (4), 1998 |
Number 4
3&4, 2001 |
Number 4
1&2, 2001 |
Number 3
Vol.3 (3), 2000 |
Number 3
Vol.2 (3), 1999 |
Number 3
Vol.1 (3), 1998 |
Number 2
Vol.3(2), 2000 |
Number 2
Vol.1 (2), 1998 |
Number 2
Vol.2 (2), 1999 |
Number 1
Vol.3 (1), 2000 |
Number 1
Vol.2 (1), 1999 |
Number 1
Vol.1 (1), 1998 |
|
|
