Meta Gene 28 (2021) 100868

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Meta Gene
journal homepage: www.elsevier.com/locate/mgene

Association of GOLPH2 gene polymorphisms (rs10868366 and rs7019241)

with the risk of Alzheimer’s disease: Evidence from a meta-analysis
Md. Abdul Barek 1, Md. Abdul Aziz 1, Sarah Jafrin, Mohammad Safiqul Islam *
Department of Pharmacy, Faculty of Science, Noakhali Science and Technology University, Noakhali 3814, Bangladesh

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Alzheimer’s disease (AD) is an irreversible and leading neurodegenerative disorder throughout the
Alzheimer’s disease world. Several studies have investigated the association between the GOLPH2 gene polymorphisms and AD, but
GOLPH2 the results were controversial.
Polymorphism
Objective: We performed a meta-analysis to provide a more precise outcome on the correlation of the GOLPH2
rs10868366
rs7019241
gene polymorphisms (rs10868366 & rs7019241) and AD risk.
Meta-analysis Methods: A comprehensive literature search in PubMed, ScienceDirect, BMC, Wiley, MDPI, SAGE, Cochrane,
Google Scholar, and Springer was performed to collect all relevant data. Meta-analysis was conducted using
Review Manager 5.4 software. Heterogeneity was analyzed by I2, whereas publication bias was assessed by
Egger’s test and Begg-Mazumdar’s rank correlation.
Results: Four studies were included comprising a total of 9557 subjects that contains 4916 cases (2420 for
rs10868366 & 2496 for rs7019241) and 4641 controls (2289 for rs10868366 & 2352 for rs7019241). The results
revealed that a statistically significantly lower risk for AD was correlated with four genetic models of rs10868366
polymorphism (T vs. G: OR = 0.76, 95%CI = 0.61–0.96, p = 0.022; TT vs. GG: OR = 0.59, 95%CI = 0.39–0.88, p
= 0.009; TT vs. TG: OR = 0.67, 95%CI = 0.46–0.97, p = 0.033; TT vs. TG + GG: OR = 0.63, 95%CI = 0.44–0.90,
p = 0.010), whereas the other genetic models showed a lower risk but not statistically significant results. In the
case of rs7019241 polymorphism, no significant association was observed for AD risk with any of the genetic
models.
Conclusions: The present analysis suggests that SNP rs10868366 of the GOLPH2 gene may be associated with a
lower risk of AD, but SNP rs7019241 is not associated with AD susceptibility.

1. Introduction (Kumar et al., 2020).

Alzheimer’s disease (AD) is one of the main complex neurodegen­
erative disorders and is the primary leading cause of dementia (Bekris
et al., 2010). Elder people (age > 60–65 years) are mainly affected by
this incurable disease (95%) and 5% is early-onset (age < 60–65 years)
(Harman, 2006). More than 50 million patients currently exist with AD,
and this number is projected to surpass 100 million by 2050 (Cummings
et al., 2019). To the present world, AD is one of the greatest medical care
challenges, and the World Health Organization (WHO) has suspected
that the disorder will overtake cancer to become the second leading
cause of death following cardiovascular disease (Gammon, 2014). AD is
currently ranked as the sixth leading cause of death, and about 1 in every
4 people in the United States have been diagnosed with this disease
To date, no effective therapeutic option has been developed by the
healthcare providers to combat the progression of AD or clinical treat­
ment of it. AD is characterized by the production of amyloid plaques,
intraneuronal neurofibrillary tangles, and amyloid angiopathy, which
are associated with the loss of neuronal function and neuronal cell death
(DeTure and Dickson, 2019). The factors responsible for the pathogen­
esis and the development of AD include causative factors (oxidative
damage, abnormal protein deposition); environmental factors (family
history, low income, education, dietary habits, smoking, physical ac­
tivity); genetic factors (such as genetic abnormities and mutations); and
others (atherosclerosis, diabetes, neuro-inflammation). However, large-
scale genome-wide association studies (GWASs) have shown that this
complex polygenic disease is associated with several genes like

* Corresponding author.
E-mail address: research_safiq@nstu.edu.bd (M.S. Islam).
1
Contributed equally.

https://doi.org/10.1016/j.mgene.2021.100868
Received 15 November 2020; Received in revised form 14 January 2021; Accepted 7 February 2021
Available online 18 February 2021
2214-5400/© 2021 Elsevier B.V. All rights reserved.
Md.A. Barek et al.
β-amyloid precursor protein (APP), presenilin 1 (PSEN1), presenilin 2
(PSEN2), apolipoprotein E ε4 (APOE-ε4), death-associated protein ki­
nase 1 (DAPK1), bridging integrator 1 (BIN1), complement receptor 1
(CR1), clusterin (CLU), phosphatidylinositol binding clathrin assembly
protein (PICALM), CD2-associated protein (CD2AP), siglec-3 (CD33),
ephrin type-A receptor 1 (EPHA1), ATP binding cassette subfamily A
member 7 (ABCA7), and so on (Giri et al., 2016).
The GOLPH2 gene (Golgi phosphoprotein 2), also known as GOLM1,
GP73 or HEL46, has become a type II transmembrane protein that codes
for a 73 kDa protein located in the cis and medial-Golgi cisternae
engaged in Golgi transmembrane trafficking and also has a short cyto­
plasmic tail which is essential for Golgi localization (Zhou et al., 2011).
The intra-lumenal portion is the core part of 366 amino acid protein
containing a membrane-near furin cleavage site and soluble GOLPH2 or
sGOLPH2 released by photolytic cleavage (Liu et al., 2019). Soluble
GOLPH2, a very stable protein, can be measured in supernatants of
cultured cells, urine, serum and other body fluids (Liu et al., 2019).
GOLPH2 protein has diverse functions, including modulating cellular
responses to infections (Zhang et al., 2017a, 2017b). Overexpression of
the GOLPH2 gene has been observed in certain cancers, like hepato­
cellular carcinoma (Marrero et al., 2005), prostate cancer (Kristiansen
et al., 2008), gastric cancer (Liu et al., 2014), lung cancer (Zhang et al.,
2010), glioblastoma (Ding et al., 2019), and melanoma (Donizy et al.,
2016). GOLPH2 is also involved in mediating several signaling path­
ways, including epidermal growth factor receptor (EGFR)/receptor
tyrosine kinase (RTK) pathway (Ye et al., 2016), platelet-derived growth
factor receptors (PDGFR) pathway (Xu et al., 2017), phosphoinositide 3-
kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin
(mTOR) pathway (Chen et al., 2015), mitogen-activated protein kinase
(MEK)/extracellular signal-regulated kinase (ERK) pathway (Yang et al.,
2019, and toll-like receptor (TLR)/retinoic acid-inducible gene 1 (RIG-
1) pathway (Zhang et al., 2017a, 2017b).
GOLPH2 gene is located on chromosome 9 (9q21.33), and this
chromosomal region was previously linked to AD (Blacker et al., 2003;
Holmans et al., 2005). There are almost 11 exons and two splicing
variants in the GOLPH2 genomic sequence (Kim et al., 2012). This gene
is usually expressed in many human tissues, including some areas of the
brain. The GOLPH2 rs10868366 marker has been identified to be asso­
ciated with a regional decrease in grey matter volume in patients with
AD (Rao et al., 2008). The GOLPH2 gene is also overexpressed in human
and mouse brain neurons in the hippocampal formation and temporal
cortex subfields (Su et al., 2004). However, the rs10868366 and
rs7019241 SNPs located in the GOLPH2 gene intron do not appear to be
associated with established functional roles like splicing or transcrip­
tional regulation (Kladney et al., 2000), can affect the expression of
GOLPH2 and involve the risk of AD.
Multiple studies have shown that the incidence of the diseases in
different regions of the world is different due to the high degree of
geographic and ethnic variation in recent years (Prohaska et al., 2019;
Lu et al., 2014). Even two different studies may sometimes show
different results in the same ethnicity (Huang et al., 2015). In view of the
facts, studies are needed to identify risk factors of AD in vulnerable
populations for early detection and prompt management and summarize
the published evidence. Since there is no previous systematic review or
meta-analysis has been carried out to determine the link between the
GOLPH2 gene polymorphisms with AD, we completed this study to
assess the potential correlation of rs10868366 and rs7019241 of the
GOLPH2 gene with AD that will help to identify the risk factors.
2. Methodology
2.1. Literature search strategy
The relevant studies were comprehensively searched in PubMed,
ScienceDirect, BMC, Wiley, SAGE, Cochrane, Google Scholar, and
Springer. The literature acquisition was updated on up to 10 October
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Meta Gene 28 (2021) 100868
2020, and the keywords of the search strategy are the following terms-
rs10868366 polymorphism, rs7019241 polymorphism, GOLPH2 poly­
morphism, and Alzheimer’s disease. There were no limitations on lan­
guage or country, and the search was restricted to humans. The
additional literature was obtained from cited references also reviewed.
2.2. Study eligibility
2.2.1. Inclusion criteria
1) Patient’s outcome must be AD; 2) studies on the correlation be­
tween GOLPH2 gene (rs7019241 and rs10868366) polymorphism and
AD; 3) case-control studies with at least 100 cases and 100 controls; 4)
studies that have data on genotypic and allelic frequencies in cases and
controls; 5) providing an odds ratio for estimation with a 95% confi­
dence interval and p-value.
2.2.2. Exclusion criteria
1) Reviews, case reports, and commentaries; 2) studies on the animal
model; 3) multiple publications; 4) not studied GOLPH2 genotype fre­
quency and distribution; 5) studies without a control group; 6) irrelevant
or insufficient information for data extraction.
2.3. Data extraction
Two investigators (MAB and MAA) independently and systematically
searched the relevant publications online and extracted the data. SF and
MSI settled disagreements of the studies. For the selection of studies,
Rayyan QCRI, a structural analysis web application, was used (Ouzzani
et al., 2016). For observational cohort studies, the Newcastle Ottawa
Scale (NOS) Guidelines were followed to assess the validity of the
included studies, as stated elsewhere (Wells et al., 1999).
2.4. Statistical analysis
This meta-analysis was conducted by Review Manager 5.4 (RevMan
5.4). To evaluate the strength of the association between rs7019241 and
rs10868366 polymorphisms and the risk of AD, odds ratios (ORs), p-
values, and 95% confidence intervals (CIs) were determined. Seven
genetic models (co-dominant-1, 2, & 3, dominant, recessive, over­
dominant, and allele models) are used to determine ORs and the asso­
ciation between AD with polymorphism. p < 0.05 was marked as
statistically significant.
2.5. Heterogeneity and publication bias
Using both the Cochrane chi-square Q-test and I2 statistics, hetero­
geneity in the forest plot was assessed. If p < 0.1 or I2 > 50%, there was
statistically significant heterogeneity. If significant heterogeneity was
found, the random-effect model was used to calculate the pooled ORs
values. In any other way, the fixed-effects model was applied. The
pooled OR’s significance was calculated by Z-test and considered to be
statistically significant at p < 0.05. Sensitivity analyzes were carried out
to determine the findings’ stability and reliability by omitting each case-
control study to reflect the effect of the individual data set on the pooled
OR. Publication bias was analyzed by Egger’s test and Begg-Mazumdar’s
rank correlation and the level of significance of publication bias was p <
0.05.
3. Results
3.1. Literature retrieval and study characteristics
According to the initial search strategy, 89 studies about the asso­
ciation of GOLPH2 rs10868366 and rs7019241 polymorphisms with AD
risk were retrieved. A total of 49 records were deleted because of
duplication, and further 16 articles were omitted after reviewing the
Md.A. Barek et al.
title and abstract. Based on the inclusion criteria, at last, 4 articles (Yuan
et al., 2012; Antúnez et al., 2009; Li et al., 2008; Lin et al., 2010) were
eligible in the meta-analysis. Among these, three studies with four ethnic
groups were associated with rs10868366 polymorphism (2420 cases/
2289 controls), and four studies with 5 ethnic groups were associated
with rs7019241 polymorphism (2496 cases/2352 controls). Li et al.
included genetic data of two ethnic groups (Canadian and English) (Li
et al., 2008). The whole process of selecting studies is defined in Fig. 1.
Table 1 summarizes the characteristics, genotype frequency, allelic
frequency, and HWE p-value of selected studies. As shown in Supple­
mentary Table S1, most of the included studies’ quality was of high
quality (scores ranging from 6 to 8) as assessed by the Newcastle Ottawa
(NOS) scale.
3.2. Meta-analysis
3.2.1. Association of rs10868366 polymorphism with AD
Table 2 and Fig. 2 show the findings of the association between
rs10868366 polymorphism and AD. For the meta-analysis of
rs10868366 polymorphism, three studies from 4 ethnic groups were
pooled together. The studies reported statistically significant but lower
risk association of rs10868366 polymorphism with AD under four ge­
netic models including allele model (T vs. G: OR = 0.76, 95%CI =
0.61–0.96, p = 0.022), co-dominant model 2 & 3 (TT vs. GG: OR = 0.59,
95%CI = 0.39–0.88, p = 0.009; TT vs. TG: OR = 0.67, 95%CI =
0.46–0.97, p = 0.033), and recessive model (TT vs. TG + GG: OR = 0.63,
95%CI = 0.44–0.90, p = 0.010). However, no statistically significant
association of SNP rs10868366 with AD risk was found for co-dominant
model 1, dominant model, and overdominant model (TG vs. GG: OR =
0.81, 95%CI = 0.62–1.06, p = 0.122; TT + TG vs. GG: OR = 0.76, 95%CI
= 0.58–1.00, p = 0.052; and TG vs. TT + GG: OR = 0.87, 95%CI =
0.67–1.15, p = 0.328, respectively).
3.2.2. Association of rs7019241 polymorphism with AD
To measure the association of rs7019241 polymorphism with AD, we
pooled four studies from 5 ethnic groups and the findings are
Fig. 1. Flow diagram of the study selection process for the meta-analysis.
3
Meta Gene 28 (2021) 100868
summarized in Table 2 and Fig. 3. It was observed that there were no
statistically significant risk association between rs7019241 poly­
morphism and AD under any genetic models (allele: T vs. C: OR = 0.87,
95%CI = 0.67–1.12, p = 0.275; co-dominant model 1: TC vs. CC: OR =
0.89, 95%CI = 0.67–1.19, p = 0.438; co-dominant model 2: TT vs. CC:
OR = 0.84, 95%CI = 0.43–1.64, p = 0.610; co-dominant model 3: TT vs.
TC: OR = 0.91, 95%CI = 0.69–1.20, p = 0.491; dominant model: TT +
TC vs. CC: OR = 0.87, 95%CI = 0.64–1.19, p = 0.383; recessive model:
TT vs. TC + CC: OR = 0.88, 95%CI = 0.56–1.39, p = 0.587; over­
dominant model: TC vs. TT + CC: OR = 0.92, 95%CI = 0.74–1.15, p =
0.479).
3.3. Heterogeneity analysis
We carried out heterogeneity test of rs10868366 polymorphism and
significant heterogeneity (I2 > 50) existed in four genetic models
including allele (T vs. G: p = 0.022, I2 = 69%), co-dominant model 1 (TG
vs. GG: p = 0.039, I2 = 64%), dominant model (TT + TG vs. GG: p =
0.027, I2 = 67%), and overdominant model (TG vs. TT + GG: p = 0.023,
I2 = 68%). In case of rs7019241 polymorphism, six genetic models
including allele (T vs. C: p = 0.001, I2 = 79%), co-dominant model 1 (TC
vs. CC: p = 0.012, I2 = 69%), co-dominant model 2 (TT vs. CC: p = 0.014,
I2 = 68%), dominant model (TT + TC vs. CC: p = 0.002, I2 = 76%),
recessive model (TT vs. TC + CC: p = 0.087, I2 = 51%), and over­
dominant model (TC vs. TT + CC: p = 0.057, I2 = 56%) showed signif­
icant heterogeneity in case of AD. Detailed results are described in
Table 2.
3.4. Publication bias and sensitivity analyses
The publication bias was evaluated using the Egger’s test and the
rank correlation of Begg-Mazumdar (Table 2 and Figs. 4 & 5). The funnel
plots’ patterns appeared symmetrical, indicating the absence of publi­
cation bias in the studies. In addition, Egger’s test and Begg-Mazumdar’s
rank correlation showed the publication bias only in the allele contrast
(T vs. G) of rs10868366 polymorphism (Table 2). Using sensitivity
Md.A. Barek et al. Meta Gene 28 (2021) 100868

Table 1
Characteristics, genotype frequency, allelic frequency, and HWE p-value of selected studies.
Study Country Ethnicity Source of Mean age (y) Case/ rs10868366 HWE p-
control (case/ control value
Cases Controls
control)
TT TG GG T G TT TG GG T G

Antúnez Spain Caucasian Population 78.8/49.9 1131/ 14 237 880 265 1997 25 235 926 285 2087 0.031
et al., 1186
2009
Li et al., Canada Hispanic & Hospital 77.8/73.4 692/ 7 113 572 127 1257 5 147 536 157 1219 0.136
2008 others 688
Li et al., UK Caucasian Population 81.6/76.5 406/ 0 68 338 68 744 6 56 173 68 402 0.569
2008 235
Yuan et al., China Asian Hospital 73.1/74.3 191/ 44 94 53 182 200 59 83 38 201 159 0.383
2012 180
Total 2420/ 65 512 1843 642 4198 95 521 1673 711 3867
2289

Study Country Ethnicity Source of Mean age Case/ rs7019241 HWE

control (case/ control p-value
Cases Controls
control)
TT TC CC T C TT TC CC T C

Antúnez Spain Caucasian Population 78.8/49.9 1068/ 15 219 834 249 1887 12 221 918 245 2057 0.748
et al., 1151
2009
Li et al., Canada Hispanic & Hospital 77.8/73.4 602/ 4 102 496 110 1094 6 138 468 150 1074 0.230
2008 others 612
Li et al., UK Caucasian Population 81.6/76.5 353/ 0 63 290 63 643 3 44 138 50 320 0.812
2008 185
Lin et al., China Asian Population 79.5/76.1 282/ 103 131 48 337 227 74 97 53 245 203 0.059
2010 224
Yuan et al., China Asian Hospital 73.1/74.3 191/ 47 94 50 188 194 61 86 33 208 152 0.781
2012 180
Total 2496/ 169 609 1718 947 4045 156 586 1610 898 3806
2352

Table 2
Association of rs10868366 and rs7019241 polymorphism with AD.
rs10868366

Model Test of association Test of heterogeneity Publication bias (p-value)

2
OR 95% CI p-value Model p-value I Egger’s test Begg –Mazumdar’s

Co-dominant 1 (TG vs. GG) 0.81 0.62–1.06 0.122 Random 0.039 0.64 0.315 0.497
Co-dominant 2 (TT vs. GG) 0.59 0.39–0.88 0.009 Fixed 0.148 0.44 0.617 1.00
Co-dominant 3 (TT vs. TG) 0.67 0.46–0.97 0.033 Fixed 0.131 0.47 0.783 0.497
Dominant model (TT + TG vs. GG) 0.76 0.58–1.00 0.052 Random 0.027 0.67 0.157 0.497
Recessive model (TT vs. TG + GG) 0.63 0.44–0.90 0.010 Fixed 0.157 0.42 0.652 0.497
Overdominant (TG vs. TT + GG) 0.87 0.67–1.15 0.328 Random 0.023 0.68 0.582 1.00
Allele contrast (T vs. G) 0.76 0.61–0.96 0.022 Random 0.022 0.69 0.006 0.042

rs7019241

Model Test of association Test of heterogeneity Publication bias (p-value)

OR 95% CI p-value Model p-value I2 p-value (Egger’s test) Begg –Mazumdar’s

Co-dominant 1 (TC vs. CC) 0.89 0.67–1.19 0.438 Random 0.012 0.69 0.694 1.00
Co-dominant 2 (TT vs. CC) 0.84 0.43–1.64 0.610 Random 0.014 0.68 0.347 0.327
Co-dominant 3 (TT vs. TC) 0.91 0.69–1.20 0.491 Fixed 0.376 0.05 0.449 0.327
Dominant model (TT + TC vs. CC) 0.87 0.64–1.19 0.383 Random 0.002 0.76 0.564 1.00
Recessive model (TT vs. TC + CC) 0.88 0.56–1.39 0.587 Random 0.087 0.51 0.400 0.327
Overdominant (TC vs. TT + CC) 0.92 0.74–1.15 0.479 Random 0.057 0.56 0.603 0.327
Allele contrast (T vs. C) 0.87 0.67–1.12 0.275 Random 0.001 0.79 0.159 0.327

analysis, we found that the results of meta-analysis remained mostly
unchanged (Figs. S1 & S2) in different genetic models using the exclu­
sion of studies one-by-one.
4. Discussion
AD is the most common neurodegenerative disorder that causes
aging-associated dementia in people, accounting for approximately 60
to 70% of all neurodegenerative cases (Moya-Alvarado et al., 2016).
Since the end of the last century, researchers worldwide have begun to
focus on the genetic susceptibility of AD between different races and
ethnicities. So far, different investigations have resulted in conflicting
outcomes in the case of AD genetic variability. However, a meta-analysis
that gathers published data from single small research is a powerful tool
in identifying the association of the disease with genes. Our present
meta-analysis explicated the precise association of the GOLPH2 gene

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Md.A. Barek et al. Meta Gene 28 (2021) 100868

Fig. 2. Forest plot showing the association between rs10868366 polymorphism and Alzheimer’s disease in the study population under the following models: A. (TG
vs. GG), B. (TT vs. GG), C. (TT vs. TG), D. Dominant model (TT + TG vs. GG), E. Recessive model (TT vs. TG + GG), F. Over dominant (TG vs. TT + GG), and Allele
contrast (T vs. G).

5
Md.A. Barek et al. Meta Gene 28 (2021) 100868

Fig. 3. Forest plot showing the association between rs7019241 polymorphism and Alzheimer’s disease in the study population under the following models: A. (TC vs.
CC), B. (TT vs. CC), C. (TT vs. TC), D. Dominant model (TT + TC vs. CC), E. Recessive model (TT vs. TC + CC), F. Over dominant (TC vs. TT + CC), and Allele contrast
(T vs. C).

6
Md.A. Barek et al. Meta Gene 28 (2021) 100868

Fig. 4. Funnel plots for the association between rs10868366 polymorphism and Alzheimer’s disease in the study population under the following models:: A. (TG vs.
GG), B. (TT vs. GG), C. TT vs. TG, D. Dominant model (TT + TG vs. GG), E. Recessive model (TT vs. TG + GG), F. Over dominant (TG vs. TT + GG), and Allele contrast
(T vs. G).

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Md.A. Barek et al. Meta Gene 28 (2021) 100868

Fig. 5. Funnel plots for the association between rs7019241polymorphism and Alzheimer’s disease in the study population under the following models: A. (TC vs.
CC), B. (TT vs. CC), C. (TT vs. TC), D. Dominant model (TT + TC vs. CC), E. Recessive model (TT vs. TC + CC), F. Over dominant (TC vs. TT + CC), and Allele contrast
(T vs. C).

8
Md.A. Barek et al.
polymorphisms (rs10868366 G > T and rs7019241 C > T) with AD.
Multiple genetic studies have reported various functions of the
GOLPH2 gene to date that cover its role in infection (Zhang et al., 2017a,
2017b), several cancers (Marrero et al., 2005; Kristiansen et al., 2008;
Liu et al., 2014; Zhang et al., 2010; Ding et al., 2019; Donizy et al.,
2016), and others. Most importantly, GOLPH2 has been found to be
associated with the development of AD in different ethnicity, including
Chinese (Yuan et al., 2012; Lin et al., 2010), Spanish (Antúnez et al.,
2009), Canadian (Li et al., 2008) and British (Li et al., 2008) population.
However, these results were inconstant that motivated us to conduct the
present meta-analysis for a more precise outcome.
By meta-analysis of the 3 studies with 4 ethnic groups (2420 cases/
2289 controls) of rs10868366 polymorphism, we obtained that four
genetic models- allele model (T vs. G: OR = 0.76, 95%CI = 0.61–0.96),
co-dominant model 2 & 3 (TT vs. GG: OR = 0.59, 95%CI = 0.39–0.88; TT
vs. TG: OR = 0.67, 95%CI = 0.46–0.97), and recessive model (TT vs. TG
+ GG: OR = 0.63, 95%CI = 0.44–0.90) showed statistically significant
association (p < 0.05) with lower AD susceptibility. The other three
genetic models of this SNP, including co-dominant model 1 (TG vs. GG:
OR = 0.81, 95%CI = 0.62–1.06), dominant model (TT + TG vs. GG: OR
= 0.76, 95%CI = 0.58–1.00), and overdominant model (TG vs. TT + GG:
OR = 0.87, 95%CI = 0.67–1.15) showed statistically not a significant
risk for the development of AD. Our results also showed that four genetic
models (allele model, co-dominant model 1, dominant model, and
overdominant model) showed a significant genetic heterogeneity (I2 >
50%) in the case of rs10868366 variant with AD development.
To establish the correlation of rs7019241 polymorphism with AD
risk, we investigated four studies with five ethnic groups based on the
genotype data of 4848 samples (2496 cases/2352 controls) in seven
genetic models. In our meta-analysis, we found that there are no sta­
tistical significant associations between rs7019241 polymorphism with
AD risk in any genetic models- allele model (T vs. C: OR = 0.87, 95%CI
= 0.67–1.12), co-dominant model 1 (TC vs. CC: OR = 0.89, 95%CI =
0.67–1.19), co-dominant model 2 (TT vs. CC: OR = 0.84, 95%CI =
0.43–1.64), co-dominant model 3 (TT vs. TC: OR = 0.91, 95%CI =
0.69–1.20), dominant model (TT + TC vs. CC: OR = 0.87, 95%CI =
0.64–1.19), recessive model (TT vs. TC + CC: OR = 0.88, 95%CI =
0.56–1.39), overdominant model (TC vs. TT + CC: OR = 0.92, 95%CI =
0.74–1.15). But in the case of heterogeneity analysis, we have observed
significant heterogeneity (I2 < 50%) in six genetic models (allele model,
co-dominant model 1, co-dominant model 2, dominant model, recessive
model, and overdominant model). The reliability of our outcomes was
shown by the consistent results among the seven genetic models. The
results of the publication bias and the consistent sensitivity analysis both
demonstrated that our outcomes were accurate.
This is by far the first meta-analysis with the GOLPH2 gene poly­
morphisms (rs10868366 & rs7019241) and the risk of AD. We carried
out the heterogeneity, sensitivity, and publication bias analyses that are
the strengths of this meta-analysis. However, in our meta-analysis,
certain limitations should be taken into account. Firstly, as no other
related studies have been identified, the number of studies is small.
Secondly, the number of cases and controls included in the studies was
relatively low. Thirdly, in some studies, the controls were not univer­
sally identified as age and gender-matched. Without these limitations,
the quality of the literature used in this research is high, the analysis is
rigorous, and the findings drawn from the study are highly credible, and
the conclusions drawn by the study are incredibly reliable.
5. Conclusions
Our present study indicates that rs10868366 genetic polymorphism
in GOLPH2 is significantly correlated with a lower risk of AD, whereas
rs7019241 polymorphism is not associated with AD susceptibility.
9
Meta Gene 28 (2021) 100868
Ethics approval and consent to participate
No ethical approval is required, as it is a meta-analysis. However,
before performing the individual studies, the respective authors
received ethical approval from the proper authorities and consent from
the participants for all the studies included in this meta-analysis.
Consent for publication
All the authors read the final version of the manuscript, and they
agreed to submit the manuscript.
Availability of data and materials
Data supporting the findings of this study were included in the
manuscript.
Competing interests
The authors announce that they do not have a conflict of interest.
Funding
No research-funding organization has supported this work.
Authors contributions
Authors MAB, MAA, SF, MSI equally participated in the conduction
of the review. MAB and MAA did the initial literature search. MAB, MAA
and SF participated in preparing the manuscript. MSI designed the
concept, analyzed the data, and revised the manuscript. All authors read
the final manuscript and accepted it.
Acknowledgements
The authors are thankful to the Review Manager (RevMan) devel­
oper because this meta-analysis was performed by using this software.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.mgene.2021.100868.
References
Antúnez, C., Boada, M., López-Arrieta, J., Ramirez-Lorca, R., Hernández, I., Marín, J.,
et al., 2009. GOLPH2 gene markers are not associated with Alzheimer’s disease in a
sample of the Spanish population. J. Alzheimers Dis. 18, 751–754.
Bekris, L.M., Yu, C.E., Bird, T.D., Tsuang, D.W., 2010. Genetics of Alzheimer disease.
J. Geriatr. Psychiatry Neurol. 23 (4), 213–227.
Blacker, D., Bertram, L., Saunders, A.J., Moscarillo, T.J., Albert, M.S., Wiener, H., et al.,
2003. NIMH genetics initiative Alzheimer’s disease study group. Results of a high-
resolution genome screen of 437 Alzheimer’s disease families. Hum. Mol. Genet. 12,
23–32.
Chen, X., Wang, Y., Tao, J., Shi, Y., Gai, X., Huang, F., et al., 2015. mTORC1 up-regulates
GP73 to promote proliferation and migration of hepatocellular carcinoma cells and
growth of xenograft tumors in mice. Gastroenterology 149, 741–752 (e14.
Cummings, J.L., Tong, G., Ballard, C., 2019. Treatment combinations for Alzheimer’s
disease: current and future pharmacotherapy options. J. Alzheimers Dis. 67,
779–794.
DeTure, M.A., Dickson, D.W., 2019. The neuropathological diagnosis of Alzheimer’s
disease. Mol. Neurodegener. 14 (32–32).
Ding, X., Deng, G., Liu, J., Liu, B., Yuan, Fe, Yang, X., Chen, Q., 2019. GOLM1 silencing
inhibits the proliferation and motility of human glioblastoma cells via the Wnt/
β-catenin signaling pathway. Brain Res. 1717, 117–126.
Donizy, P., Kaczorowski, M., Biecek, P., Halon, A., Szkudlarek, T., Matkowski, R., 2016.
Golgi-related proteins GOLPH2 (GP73/GOLM1) and GOLPH3 (GOPP1/MIDAS) in
cutaneous melanoma: patterns of expression and prognostic significance. Int. J. Mol.
Sci. 17, 1619.
Gammon, K., 2014. Neurodegenerative disease: brain windfall. Nature. 515, 299–300.
Giri, M., Zhang, M., Lü, Y., 2016. Genes associated with Alzheimer’s disease: an overview
and current status. Clin. Interv. Aging 11, 665–681.
Md.A. Barek et al.
Harman, D., 2006. Alzheimer’s disease pathogenesis: role of aging. Ann. N. Y. Acad. Sci.
1067, 454–460.
Holmans, P., Hamshere, M., Hollingworth, P., Rice, F., Tunstall, N., Jones, S., et al.,
2005. Genome screen for loci influencing age at onset and rate of decline in late
onset Alzheimer’s disease. Am. J. Med. Genet. B Neuropsychiatr. Genet. 135B,
24–32.
Huang, T., Shu, Y., Cai, Y.D., 2015. Genetic differences among ethnic groups. BMC
Genomics 16, 1093.
Kim, H.J., Lv, D., Zhang, Y., Peng, T., Ma, X., 2012. Golgi phosphoprotein 2 in physiology
and in diseases. Cell Biosci. 2, 31.
Kladney, R.D., Bulla, G.A., Guo, L., Mason, A.L., Tollefson, A.E., Simon, D.J., et al., 2000.
GP73, a novel Golgi-localized protein upregulated by viral infection. Gene. 249,
53–65.
Kristiansen, G., Fritzsche, F.R., Wassermann, K., Jäger, C., Tölls, A., Lein, M., et al., 2008.
GOLPH2 protein expression as a novel tissue biomarker for prostate cancer:
implications for tissue-based diagnostics. Br. J. Cancer 99, 939–948.
Kumar, A., Sidhu, J., Goyal, A., Tsao, J.W., 2020. Alzheimer disease. In: StatPearls
[Internet]. StatPearls Publishing, Treasure Island (FL).
Li, H., Wetten, S., Li, L., St Jean, P.L., Upmanyu, R., Surh, L., et al., 2008. Candidate
single-nucleotide polymorphisms from a genomewide association study of Alzheimer
disease. Arch. Neurol. 65, 45–53.
Lin, K., Tang, M., Han, H., Guo, Y., Lin, Y., Ma, C., 2010. Association between the
polymorphisms of CALHM1 and GOLPH2 genes and Alzheimer’s disease. Psychiatr.
Genet. 20, 190.
Liu, G., Zhang, Y., He, F., Li, J., Wei, X., Li, Y., et al., 2014. Expression of GOLPH2 is
associated with the progression of and poor prognosis in gastric cancer. Oncol. Rep.
32, 2077–2085.
Liu, Y., Liewen, H., Markuly, N., Stenner, F., 2019. A review of GOLPH2, an oncogenic
protein and novel therapeutic options for GOLPH2 driven tumours. J. Transl. Sci. 6,
1–4.
Lu, Y.F., Goldstein, D.B., Angrist, M., Cavalleri, G., 2014. Personalized medicine and
human genetic diversity. Cold Spring Harb. Perspect. Med. 4, a008581.
Marrero, J.A., Romano, P.R., Nikolaeva, O., Steel, L., Mehta, A., Fimmel, C.J., et al.,
2005. GP73, a resident Golgi glycoprotein, is a novel serum marker for
hepatocellular carcinoma. J. Hepatol. 43, 1007–1012.
Moya-Alvarado, G., Gershoni-Emek, N., Perlson, E., Bronfman, F.C., 2016.
Neurodegeneration and Alzheimer’s disease (AD). What can proteomics tell us about
the Alzheimer’s brain? Mol. Cell. Proteomics 15, 409–425.
10
Meta Gene 28 (2021) 100868
Ouzzani, M., Hammady, H., Fedorowicz, Z., Elmagarmid, A., 2016. Rayyan-a web and
mobile app for systematic reviews. Syst. Rev. 5, 210.
Prohaska, A., Racimo, F., Schork, A.J., Sikora, M., Stern, A.J., Ilardo, M., et al., 2019.
Human disease variation in the light of population genomics. Cell. 177, 115–131.
Rao, A., Filippini, N., Wetten, S., Gibson, R., Inkster, B., Borrie, M., et al., 2008. P3-254:
effect of APOE-e 4 load and GOLPH2 genotype on regional grey matter volumes in
subjects with Alzheimer’s disease. Alzheimers Dement. 4, T596. https://doi.org/
10.1016/j.jalz.2008.05.1822.
Su, A.I., Wiltshire, T., Batalov, S., Lapp, H., Ching, K.A., Block, D., et al., 2004. A gene
atlas of the mouse and human protein-encoding transcriptomes. Proc. Natl. Acad.
Sci. U. S. A. 101, 6062–6067.
Wells, G.A., Shea, B., O’Connell, D., Peterson, J., Welch, V., Losos, M., Tugwell, P., 1999.
The Newcastle-Ottawa Scale for Assessing the Quality of Nonrandomized Studies in
Meta-Analyses. Available at: http://www.ohri.ca/programs/clinical_epidemiology/o
xford.asp.
Xu, R., Ji, J., Zhang, X., Han, M., Zhang, C., Xu, Y., et al., 2017. PDGFA/PDGFRα-
regulated GOLM1 promotes human glioma progression through activation of AKT.
J. Exp. Clin. Cancer Res. 36 (1), 193.
Yang, X., Wei, C., Liu, N., Wu, F., Chen, J., Wang, C., et al., 2019. GP73, a novel TGF-β
target gene, provides selective regulation on Smad and non-Smad signaling
pathways. Biochim. Biophys. Acta, Mol. Cell Res. 1866, 588–597.
Ye, Q.H., Zhu, W.W., Zhang, J.B., Qin, Y., Lu, M., Lin, G.L., et al., 2016. GOLM1
modulates EGFR/RTK cell-surface recycling to drive hepatocellular carcinoma
metastasis. Cancer Cell 30, 444–458.
Yuan, Q., Chu, C., Jia, J., 2012. Association studies of 19 candidate SNPs with sporadic
Alzheimer’s disease in the north Chinese Han population. Neurol. Sci. 33,
1021–1028.
Zhang, F., Gu, Y., Li, X., Wang, W., He, J., Peng, T., 2010. Up-regulated Golgi
phosphoprotein 2 (GOLPH2) expression in lung adenocarcinoma tissue. Clin.
Biochem. 43, 983–991.
Zhang, X., Zhu, C., Wang, T., Jiang, H., Ren, Y., Zhang, Q., Wu, K., Liu, F., Liu, Y., Wu, J.,
2017a. GP73 represses host innate immune response to promote virus replication by
facilitating MAVS and TRAF6 degradation. PLoS Pathog. 13 (4), e1006321.
Zhang, X., Zhu, C., Wang, T., Jiang, H., Ren, Y., Zhang, Q., et al., 2017b. GP73 represses
host innate immune response to promote virus replication by facilitating MAVS and
TRAF6 degradation. PLoS Pathog. 13, e1006321.
Zhou, Y., Li, L., Hu, L., Peng, T., 2011. Golgi phosphoprotein 2 (GOLPH2/GP73/GOLM1)
interacts with secretory clusterin. Mol. Biol. Rep. 38, 1457–1462.