METABOLIC SYNDROME AND RELATED DISORDERS

Volume XX, Number XX, 2024

 Mary Ann Liebert, Inc.
Pp. 1–10
DOI: 10.1089/met.2023.0221
Open camera or QR reader and
scan code to access this article
and other resources online.

Associations Between Obesity-Related Gene MC4R

rs17782313 Locus Polymorphism and Components
of Metabolic Syndrome:
A Systematic Review and Meta-Analysis
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Huazhao Yang, MSc, Qingzhi Huang, MSc, Hana Yu, MSc, and Zhenyu Quan, MD

Abstract
Objective: It is well established that melanocortin-4 receptor (MC4R) rs17782313 locus polymorphism is
associated with increased obesity risk and that obesity is strongly associated with an enhanced risk of all
metabolic syndrome (MS) components. Thus, in this study, we examined the association between the MC4R
rs17782313 locus polymorphism and the risk of the remaining MS components, namely, diabetes, hypertension,
low high-density lipoprotein (HDL), and hypertriglyceridemia.
Methods: We performed an extensive literature screening across six scientific databases, namely, PubMed,
Embase, Web of Science, Medline, ScienceDirect, CNKI, and WanFang employing a specific search strategy.
Eligible studies were selected for inclusion in our meta-analysis, and odds ratio (OR) values and 95% confi-
dence interval (CI) were computed through fixed- or random-effects models to examine correlation strength. In
addition, we performed subgroup analyses involving adjustment factors (unadjusted body mass index [BMI],
adjusted BMI), race (Caucasian, Asian), and source of controls (population, hospital).
Results: Twenty-two eligible studies were selected from 846 articles, involving 28,018 patients and 98,994
normal participants. Based on this meta-analysis, the MC4R rs17782313 locus polymorphism was associated
with an augmented risk of diabetes (allele contrast model T vs. C: OR = 1.05, 95% CI = 1.03–1.08; dominant
model TT vs. TC + CC: OR = 1.07, 95% CI = 1.03–1.11) and hypertension (dominant model TT vs. TC + CC:
OR = 1.16, 95% CI = 1.03–1.31) risk. However, based on this analysis, the MC4R rs17782313 locus poly-
morphism was not associated with low HDL and hypertriglyceridemia risk.
Conclusions: Based on this analysis, the MC4R rs17782313 locus polymorphism is associated with enhanced
risks of diabetes and hypertension, while the associations with low HDL and hypertriglyceridemia require
further exploration.

Keywords: MC4R, rs17782313, metabolic syndrome components, diabetes, hypertension, meta-analysis

Introduction genetic role in the occurrence and development of the

components of MS. Overweight and obesity induce hyper-

M etabolic syndrome (MS) is characterized by a dys-

regulated metabolism, and it often manifests as over-
weight and obesity, hypertension, hyperglycemia, and
dyslipidemia.1 Recent investigations have confirmed a strong
insulinemia, activation of the renin–angiotensin–aldosterone
system, stimulation of the sympathetic nervous system, ab-
normalities of adipokines such as leptin, atherosclerosis, and
insulin resistance (IR), which can ultimately contribute to

Department of Preventive Medicine, College of Medicine, Yanbian University, Yanji, Jilin, China.

1
 2 YANG ET AL.
hyperlipidemia, hypertension, and diabetes.2–5 Therefore,
obesity-related genes might be potential candidates for trig-
gering diabetes, hypertension, and dyslipidemia.
The melanocortin-4 receptor (MC4R) is a hypothalamic G
protein-coupled receptor,6 and it is associated with nutrient
absorption, lipid metabolism, energy expenditure, insulin se-
cretion, food intake, and so on.7 In 2008, based on a report by
the Genome-Wide Association Study, the rs17782313 single
nucleotide polymorphism (SNP) at 188 kb, downstream of the
MC4R gene, is associated with the enhanced body mass index
(BMI) and obesity risk.8 In a previous meta-analysis, different
model results showed an association between MC4R
rs17782313 locus polymorphism and obesity (allele contrast
model odds ratio [OR] = 1.325, 95% confidence interval (CI):
1.219–1.439; dominant model OR = 1.320, 95% CI: 1.184–
1.472).9 However, the results of correlation evaluations be-
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tween MC4R rs17782313 and other MS components remain
inconsistent. Sull et al.10 and Hammad et al.11 demonstrated
that the MC4R rs17782313 locus polymorphism is markedly
associated with an augmented risk of diabetes and hyperten-
sion. However, both Han et al.12 and Szkup et al.13 reported
the opposite conclusion in their studies.
Therefore, in this study, we conducted an extensive review
and meta-analysis of the association of MC4R rs17782313
locus polymorphism with diabetes, hypertension, and dysli-
pidemia, and assessed the risk for each MS component.
Methods
Literature search
We performed an extensive screening of scientific online
databases, such as PubMed, Embase, Web of Science, Med-
line, ScienceDirect, CNKI, and WanFang, to search for articles
published in English and Chinese on the association between
MC4R rs17782313 locus polymorphism and the risk of MS
components. We screened for articles from the establishment
of each database until August 2, 2023.
The search strategy was as follows, diabetes: ‘‘MC4R
rs17782313’’ OR ‘‘melanocortin 4 receptor rs17782313’’ AND
‘‘polymorphism’’ OR ‘‘variant’’ OR ‘‘genotype’’ AND
‘‘T2DM’’ OR ‘‘diabetes’’ OR ‘‘diabetes mellitus’’ OR ‘‘dia-
betic.’’ Hypertension: ‘‘MC4R rs17782313’’ OR ‘‘melano-
cortin 4 receptor rs17782313’’ AND ‘‘polymorphism’’ OR
‘‘variant’’ OR ‘‘genotype’’ AND ‘‘hypertension’’ OR ‘‘hyper-
tensions’’ OR ‘‘hypertensive’’. Low high-density lipoprotein
(HDL): ‘‘MC4R rs17782313’’ OR ‘‘melanocortin 4 receptor
rs17782313’’ AND ‘‘polymorphism’’ OR ‘‘variant’’ OR ‘‘ge-
notype’’ AND ‘‘HDL-C’’ OR ‘‘high-density lipoprotein.’’
Hypertriglyceridemia: ‘‘MC4R rs17782313’’ OR ‘‘melano-
cortin 4 receptor rs17782313’’ AND ‘‘polymorphism’’ OR
‘‘variant’’ OR ‘‘genotype’’ AND ‘‘High triglyceridemia’’ OR
‘‘triglyceridemia’’ OR ‘‘TG’’ OR ‘‘triglyceride.’’
In addition, we manually searched the references of the
literature included in the meta-analysis to identify additional
potentially eligible studies. When multiple studies used the
same or overlapping datasets, the study with the larger
sample size was selected. The present research was con-
ducted, based on the Preferred Reporting Items for Sys-
tematic Reviews and Meta-Analyses (PRISMA statement).
The protocol for the review was registered on the Interna-
tional Prospective Register of Systematic Reviews (PROS-
PERO) database under the number CRD42021292062.
Inclusion and exclusion criteria
Two authors separately reviewed the literature for study
eligibility. Our inclusion criteria were as follows: (1) as-
sessment of the MC4R rs17782313 locus polymorphism and
its associated risk for each MS component; (2) provision of
OR with 95% CI, under allele contrast model, dominant
model, or availability of sufficient data to calculate OR; (3)
the total number of subjects and cases were reported. The
exclusion criteria were used as follows: (1) meta-analysis or
review; (2) duplicate material; (3) animal research; and (4)
missing relevant data.
Data extraction
We retrieved the following information from each se-
lected article: (1) first author; (2) year of publication; (3)
race; (4) source of controls; (5) number of cases and con-
trols; (6) Hardy–Weinberg; (7) adjustment factors; (8)
genotyping methods; (9) OR values and corresponding 95%
CIs for the association strength of MC4R rs17782313 locus
polymorphism with each MS component. Data were ex-
tracted separately by two authors, and any disagreements
were settled through discussion.
Quality assessment of the studies
To assess study quality, two independent authors assessed
each article according to the Newcastle–Ottawa Scale. Any
disagreement was resolved through discussion. Ultimately,
we included studies with scores of 6 and above.9
Statistical analyses
All data analyses employed STATA software version
17.0 (StataCorp LP, College Station, TX, USA). In the case
of multiple ORs in a single study, estimates of multivariate-
adjusted risk were preferentially pooled. We employed
meta-regression analysis, Cochrane’s Q test, and I2 statistics
to evaluate heterogeneity among studies. The heterogeneity
source was analyzed through the random-effects model, and
I2 > 50% and/or P value <0.05 was deemed significant.
Otherwise, a fixed model was used.14 The subgroup analyses
of the MC4R rs17782313 locus polymorphism and diabetes-
related data were performed based on the following char-
acteristics: adjustment factors (unadjusted BMI, adjusted
BMI), race (Caucasian, Asian), and source of controls
(population, hospital). Our data stability was assessed based
on a sensitivity analysis, which removed one study at a time.
Lastly, funnel plots, as well as the Begg’s and Egger’s tests
were employed to evaluate potential publication bias.15
When the results from Begg’s and Egger’s tests contradict
each other, the results from Egger’s tests prevail.16
Results
Characteristics and quality assessment
of the eligible studies
Overall, 844 eligible articles were identified through
screening of various databases, and 2 articles were obtained
through other means. After screening, 22 qualified articles
were selected for our meta-analysis, which were published
between 2008 and 2020. The entire process of article se-
lection is illustrated in Fig. 1. The study by Cauchi et al.17
 RS17782313 ON COMPONENTS OF METABOLIC SYNDROME
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covered data from two different populations in Morocco and
Tunisia. In the subsequent analysis of the data, these two
groups were considered independent studies.
In terms of race, 12 studies were conducted among
Caucasians and 11 among Asians. The genotyping methods
included TaqMan, MALDI-TOF-MS, sequences retrieval,
iPLEX, MassARRAY technology, SNPlex technology,
and OpenArray SNP Genotyping System. In terms of the
source of control subjects, 12 studies included controls from
the general population and 11 included controls from the
hospital itself. All studies exhibited quality assessment
scores of 6 and above, with a maximum score of 8. The
characteristics of our eligible studies are summarized in
Table 1.
Association between the MC4R rs17782313 locus
polymorphism and the risk of diabetes
Based on fixed-effects model, the MC4R rs17782313 lo-
cus polymorphism was associated with diabetes risk (allele
contrast model: OR = 1.05, 95% CI = 1.03–1.08, P < 0.001;
dominant model: OR = 1.07, 95% CI = 1.03–1.11,
P < 0.001). In terms of the sensitivity analysis, eliminating
single studies did not significantly influence the pooled ORs
(Fig. 2).
Based on the subgroup analyses, our results revealed that
the overall OR for the allele contrast model was 1.05 (95%
CI = 1.03–1.08). Upon further stratification analyses, the
association persisted when grouped by adjustment factors,
3
FIG. 1. A schematic of the
publication screening pro-
cess. HDL, high-density li-
poprotein.
race, and source of controls (all P < 0.05). For the dominant
model, the overall OR was 1.07 (95% CI = 1.03–1.11).
Upon further stratification analyses, it was found that the
MC4R rs17782313 locus polymorphism was associated
with the risk of diabetes when unadjusted for BMI, but this
association disappeared when adjusted for BMI. When
controls originated from hospitals, the MC4R rs17782313
locus polymorphism was associated with diabetes risk, but
this association disappeared when controls originated from
the population. The specific data are summarized in
Table 2.
Association between the MC4R rs17782313 locus
polymorphism and the risk of hypertension
Based on fixed-effects model, the MC4R rs17782313 lo-
cus polymorphism was associated with hypertension risk
(dominant model: OR = 1.16, 95% CI = 1.03–1.31,
P = 0.014). In terms of the sensitivity analysis, eliminating
single studies did not significantly influence the pooled ORs
(Fig. 3).
Association between the MC4R rs17782313 locus
polymorphism and the risk of low HDL
Based on fixed-effects model, the MC4R rs17782313 lo-
cus polymorphism was not associated with low HDL risk
(dominant model: OR = 0.95, 95% CI = 0.70–1.29,
P = 0.757) (Supplemetnary Fig. S1).
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Table 1. Characteristics of the Eligible Studies

Sample size
Publication Source of P value Quality
No. Study year Race controls Cases Controls for HWE Adjustment factors Genotyping methods scores
Diabetes
1 Qi et al.18 2008 Caucasian Population 1533 4191 >0.05 Age, BMI, waist circumference, OpenArray SNP 8
smoking, alcohol consumption, Genotyping System
physical activity, and menopausal
status
2 Zobel et al.19 2009 Caucasian Hospital 3903 4918 >0.05 Age, sex, and BMI TaqMan 7
3 Renstrom et al.20 2009 Caucasian Population 1038 3885 >0.01 Age, sex, and BMI TaqMan 8
4 Cauchi et al.21 2009 Caucasian Population 307 2351 >0.05 Age, sex, and BMI TaqMan 8
5 Wen et al.22 2010 Asian Hospital 1165 1136 >0.05 Age, sex, and BMI IPLEX 7
6 Huang et al.23 2011 Asian Hospital 591 1200 >0.05 Not adjusted Sequences retrieval 7
7 Tang et al.24 2012 Asian Population 1177 1113 0.189 Not adjusted MassARRAY technology 7
8 Cauchi et al.(M)17 2012 Caucasian Population 1193 1055 ‡0.01 Age and sex SNPlex technology 7
9 Cauchi et al.(T)17 2012 Caucasian Hospital 1446 942 ‡0.01 Age and sex TaqMan 7
10 Ortega-Azorı́n et al.25 2012 Caucasian Hospital 3430 3622 0.637 Age, sex, center, total energy TaqMan 7
intake, physical activity, and
BMI
11 Janipalli et al.26 2012 Asian Population 1712 1392 >0.05 Age, sex, location, and BMI MassARRAY technology 8
12 Thomsen et al.27 2012 Caucasian Population 3467 61,345 >0.05 Not adjusted TaqMan 7
13 Han et al.12 2013 Asian Hospital 2806 1113 >0.05 Age, sex, and BMI IPLEX 7

4
14 Dwivedi et al.28 2013 Asian Population 2049 2028 >0.05 Age and sex IPLEX 8
15 Mutombo et al.29 2014 Asian Population 155 1095 Not reported Not adjusted TaqMan 7
16 Bazzi et al.30 2014 Asian Hospital 90 95 0.375 Not adjusted TaqMan 7
17 Rotter et al.31 2016 Caucasian Hospital 50 222 >0.05 Not adjusted PCR 7
18 Hammad et al.11 2020 Caucasian Population 122 160 >0.05 Age and sex TaqMan 8
19 Sull et al.10 2020 Asian Hospital 379 3880 Not reported Age, sex, and BMI TaqMan 7
Hypertension
1 Xi et al.32 2013 Asian Population 619 2458 >0.05 Age, sex, and BMI TaqMan 8
2 Qiu et al.2 2014 Asian Hospital 440 328 Cases: 0.335 Sex, overweight or obese, high MALDI-TOF-MS 7
Controls: 0.226 triglyceridemia,
hypercholesteremia, and high-
and low-density lipoproteinemia
3 Fernandes et al.7 2015 Caucasian Hospital 78 308 >0.05 Age, gender, and Z-BMI TaqMan 7
4 Rotter et al.31 2016 Caucasian Hospital 150 122 >0.05 Not adjusted PCR 7
5 Szkup et al.13 2017 Caucasian Population 268 157 Not reported Not adjusted TaqMan 6
6 Hamma et al.11 2020 Caucasian Population 87 195 >0.05 Age and sex TaqMan 7
Low HDL
1 Fernandes et al.7 2015 Caucasian Hospital 230 166 >0.05 Age, gender, and Z-BMI TaqMan 7
2 Szkup et al.13 2017 Caucasian Population 322 103 Not reported Not adjusted TaqMan 6
Hypertriglyceridemia
1 Fernandes et al.7 2015 Caucasian Hospital 139 254 >0.05 Age, gender, and Z-BMI TaqMan 7
2 Szkup et al.13 2017 Caucasian Population 110 315 Not reported Not adjusted TaqMan 6
BMI, body mass index; HWE, Hardy–Weinberg equilibrium; Low HDL, low high-density lipoprotein; MALDI-TOF-MS, Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass
Spectrometry; SNP, single nucleotide polymorphism.
 RS17782313 ON COMPONENTS OF METABOLIC SYNDROME 5

Table 2. Subgroup Analysis of the MC4R Variant rs17782313 and Diabetes

Characteristic Studies number Q test P value I2 Model selected OR (95% CI)
T vs. C
Overall 15 0.036 43.7 Fixed 1.05 (1.03–1.08)
Adjustment factors
Unadjusted BMI 9 0.097 40.5 Fixed 1.04 (1.01–1.08)
Adjusting for BMI 6 0.058 53.2 Random 1.08 (1.01–1.16)
Race
Caucasian 5 0.446 0.0 Fixed 1.04 (1.00–1.08)
Asian 10 0.023 53.4 Random 1.07 (1.01–1.15)
Source of controls
Population 9 0.065 45.6 Fixed 1.06 (1.02–1.10)
Hospital 6 0.082 48.9 Fixed 1.04 (1.00–1.09)
TT vs. TC + CC
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Overall 13 0.132 31.4 Fixed 1.07 (1.03–1.11)

Adjustment factors
Unadjusted BMI 9 0.203 25.3 Fixed 1.07 (1.03–1.12)
Adjusting for BMI 2 0.045 75.1 Random 1.12 (0.88–1.42)
Race
Caucasian 6 0.268 22.1 Fixed 1.06 (1.02–1.11)
Asian 7 0.095 44.4 Fixed 1.09 (1.01–1.17)
Source of controls
Population 5 0.347 10.3 Fixed 1.04 (0.99–1.10)
Hospital 8 0.122 38.6 Fixed 1.10 (1.04–1.16)
CI, confidence interval; OR, odds ratio.

Association between the MC4R rs17782313 locus
polymorphism and the risk of hypertriglyceridemia
Based on random-effects model, the MC4R rs17782313
locus polymorphism was not associated with hyper-
triglyceridemia risk (dominant model: OR = 1.53, 95%
CI = 0.91–2.57, P = 0.107) (Supplementary Fig. S2).
Evaluation of heterogeneity, publication bias
The meta-regression analysis indicated that the P values
were all >0.05, and the differences were not statistically
significant (Table 3). Our initial observations through funnel
plots (Fig. 4) showed a symmetrical distribution within the
region, which enhanced the confidence in our results. The
Begg’s and Egger’s tests were employed for the purpose of
examining publication bias. The results suggested no publi-
cation bias in terms of the association between the MC4R
variant rs17782313 and diabetes (allele contrast model: Eg-
ger’s test: P = 0.357, Begg’s test: P = 0.621; dominant model
Egger’s test: P = 0.101, Begg’s test: P = 0.044) and hyper-
tension (Egger’s test: P = 0.378, Begg’s test: P = 0.707).
Discussion
With the rapid rise in MS incidences worldwide, it is now
a global disease that seriously affects human health, par-
ticularly, due to its association with cardiovascular disease.
Early studies revealed that MS is associated with a 2-fold
increase in the risk of cardiovascular disease, cardiovascular
disease mortality, myocardial infarction, and stroke, as well
as a 1.5-fold increase in all-cause mortality.33 Due to the
complexity of its pathogenesis, MS has been the focus of
numerous scientific reports over the past few years. Factors,
such as IR constitute the main pathophysiological pillar of
MS pathogenesis,34 and any 3 of its components may
manifest as IR.35 Among them, obesity is one of the typical
diseases that plays an important role in MS prevalence,36
and it is closely related to other components.
Much research has recently focused on genetic obesity,
with the association between the MC4R gene and obesity
prevalence being one of the most common cases.37 MC4R is
ubiquitously expressed in the hypothalamus,38 and it is in-
volved in the modulation of food selection, food intake, and
energy expenditure. One study indicated that 44% of the
variance in meal frequency and 65% of the variance in meal
size is genetically determined.39 MC4R gene mutations often
diminish the ability of MC4R to interact with the a-
melanocyte-stimulating hormone or/and agouti-related pep-
tide, which can have detrimental energy intake outcomes.40
The C allele carrying MC4R rs17782313 is correlated with
uncontrolled eating, elevated energy intake, and binge eating
behavior in adults,41,42 which, in turn, contributes to obesity
and other related diseases.10 In addition, a study showed that
the polymorphism of rs17782313 is associated with MS
prevalence in postmenopausal women.43 However, the as-
sociation between MC4R rs17782313 locus polymorphism
and other MS components remains unclear and controversial.
This study found that the MC4R rs17782313 locus poly-
morphism was associated with enhanced diabetes risk.
Further subgroup analysis showed that in the allele contrast
model, there was a marked association between the MC4R
rs17782313 locus polymorphism and diabetes in all groups.
In the dominant model, the MC4R rs17782313 locus poly-
morphism was found to be associated with the risk of dia-
betes when unadjusted for BMI, but this association
disappeared after adjustment for BMI. This may imply that
the association of the MC4R rs17782313 locus polymor-
phism with diabetes risk is actually realized through its in-
fluence on BMI.19 It may also be because the relevant
literature is more limited, containing only 2 articles
 6 YANG ET AL.
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FIG. 2. Forest plot and sensitivity analysis for MC4R variant rs17782313 and diabetes. (A) Forest plot of the relationship
between the MC4R variant rs17782313 and diabetes based on the allele contrast model (T vs. C). (B) Sensitivity analysis of
the relationship between the MC4R variant rs17782313 and diabetes based on the allele contrast model. (C) Forest plot of
the relationship between the MC4R variant rs17782313 and diabetes based on the dominant model (TT vs. TC + CC).
(D) Sensitivity analysis of the relationship between the MC4R variant rs17782313 and diabetes based on the dominant
model. CI, confidence interval; OR, odds ratio.

involving BMI adjustment, and the statistical efficacy is
insufficient, and further studies are needed to complement it.
When the source of the control group was different
(hospitals or populations), the findings showed differences,
so further research is needed to validate this association by
considering the effects of factors such as study design,
sample size, and setting.44 There are significant differences
in the prevalence of diabetes across geographic regions and
races. In the United States, for example, the prevalence of
diabetes is higher among people of African descent, at 14%,
compared with 9% among the white population of European
ancestry.45 Despite different genetic backgrounds among the
Caucasian and Asian populations, we observed no hetero-
geneity within the overall population. Moreover, we dem-
onstrated associations between the MC4R rs17782313 locus
polymorphism and diabetes risk, with effect sizes compa-
rable between the Caucasian and Asian populations.
The MC4R gene may cause diabetes through obesity.
Numerous studies suggested that obesity increases diabetes
risk.46 Obese patients often exhibit increased plasma renin
activity and plasma angiotensin II concentrations, as well as
augmented catecholamine-induced lipolysis. The resulting
rise in serum-free fatty acid levels can, in turn, enhance the
risk of developing type 2 diabetes mellitus (T2DM).47 In
addition, MC4R modulates glucose metabolism through
sympathetic nerve regulation.48 Some studies suggested that
the correlations between the MC4R rs17782313 polymor-
phisms and T2DM and obesity are partially dependent on
dietary intake. This indicates that both T2DM and obesity
have a common genetic etiology.25 Finally, Chambers
et al.49 demonstrated that MC4R polymorphisms are also
correlated with IR, which is a major pathophysiological
factor that leads to diabetes.
In this study, the MC4R rs17782313 locus polymorphism
was associated with an increased risk of hypertension.
Studies show that 60%–70% of primary hypertension is
attributed to obesity and the prevalence of hypertension
increases by 20%–30% as the weight increases by 5%.50
The MC4R gene may indirectly cause hypertension through
an obesity-related pathway. Obese conditions generally
 RS17782313 ON COMPONENTS OF METABOLIC SYNDROME 7

FIG. 3. Forest plot and sensitiv-

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ity analysis of the relationship be-

tween the MC4R variant
rs17782313 and hypertension.
(A) Forest plot. (B) A sensitivity
analysis.

reduce levels of vasodilators, such as lipocalin and nitric
oxide, while increasing vasoconstrictors such as resistin and
endolipin. This, in turn, induces a rise in blood pressure.47
Greenfield et al.51 used both genetic and pharmacological
investigations to demonstrate that MC4R is associated with
hypertension. They revealed that MC4R modulates hyper-
tension development through a central melanocortin signaling
pathway, an effect achieved independent of obesity-induced
hyperinsulinemia.
In addition, the product of the MC4R gene, melanocortin
receptor-4, exerts bidirectional regulation of the sympathetic
and parasympathetic preganglionic neurons, which, in turn,
affects alterations in insulin levels and blood pressure.52 Lastly,
the rs17782313 locus has the potential to indirectly promote
hypertension by accelerating atherosclerosis and vascular re-
modeling through changes in serum total cholesterol.2
In this study, the MC4R rs17782313 locus polymorphism
was not associated with the risk of low HDL and

Table 3. The Meta-Regression Analysis of the Association Between

the MC4R Variant rs17782313 and Diabetes Risk
Models Factors Exp (b) 95% CI P value of regression
Allele contrast model Year 0.982 0.951–1.013 0.212
Adjustment factors 1.030 0.910–1.165 0.598
Race 0.990 0.836–1.171 0.892
Source of controls 0.981 0.864–1.114 0.736
Genotyping methods 1.001 0.940–1.067 0.963
HWE 0.920 0.724–1.168 0.442
Dominant model Year 1.054 0.992–1.119 0.078
Adjustment factors 0.807 0.617–1.056 0.099
Race 1.058 0.890–1.259 0.454
Source of controls 1.191 0.988–1.435 0.062
Genotyping methods 1.005 0.942–1.072 0.860
HWE 1.149 0.727–1.816 0.485
 8 YANG ET AL.
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FIG. 4. The funnel plots of the relationship between the MC4R variant rs17782313 and diabetes and hypertension risks.
(A) Diabetes (allele contrast model). (B) Diabetes (dominant model). (C) Hypertension (dominant model).

hypertriglyceridemia. On the contrary, the research of Fer-
nandes et al.7 found that the MC4R rs17782313 locus
polymorphism was associated with hypertriglyceridemia
risk. Therefore, more high-quality studies are needed to
verify this association.
We encountered the following limitations in this article.
First, our study searched restricted databases, and there may
exist articles that meet our inclusion criteria, which were not
included. Second, in terms of obtaining multivariate-adjusted
ORs where possible, some ORs were acquired without ad-
justment, which may potentially affect the accuracy of our
results. Third, the impact of intergenic and gene–environment
interactions on the accuracy of the current results was not
evaluated in our study.
In summary, this meta-analysis supports the association
between the MC4R rs17782313 polymorphism and diabetes
and hypertension risk within the study population. Individuals
with the MC4R rs17782313 TC/CC genotype were more
susceptible to diabetes and hypertension. In contrast, associ-
ations with hypertriglyceridemia and low HDL risk remained
unknown, and require more high-quality studies to confirm
the relationship. Further research is recommended to clarify
the association and potential mechanism between the MC4R
rs17782313 locus polymorphism and MS components.
Authors’ Contributions
H.Y.: Conceptualization, data curation, formal analysis,
investigation, methodology, software, validation, writing––
original draft, and writing––review and editing. Q.H.:
Conceptualization, data curation, formal analysis, investi-
gation, methodology, validation, and writing––review and
editing. H.Y.: Methodology, investigation, and validation.
Z.Q.: Conceptualization, validation, and writing––review
and editing. All authors contributed to the study design and
article preparation.
Author Disclosure Statement
The authors declare no conflicts of interest.
Funding Information
This work was supported by the National Natural Science
Foundation of China (Grant No. 81660562).
 RS17782313 ON COMPONENTS OF METABOLIC SYNDROME
Supplementary Material
Supplementary Figure S1
Supplementary Figure S2
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Address correspondence to:
Zhenyu Quan, MD
Department of Preventive Medicine
College of Medicine
Yanbian University
977 Gongyuan Street
Yanji, Jilin 133002
China
E-mail: zyquan@ybu.edu.cn