Mediterranean Journal of Rheumatology

Gremlin 2, IL-6, IL-10 Gene Polymorphism and Osteoporosis

in Postmenopausal Women : A Systematic Review

Journal: Mediterranean Journal of Rheumatology

Manuscript ID Draft

Manuscript Type: Systemic Review

Postmenopausal osteoporosis, Gene polymorphism, Gene IL-6, Gene IL-

Keywords:
10, Gene Gremlin-2
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3 Gremlin-2 Gene Polymorphism
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5 No Author, Country, Subject, Gender, Menopausal Osteoporosis Site of Gene Result
6 year Age (mean ± SD) Status Diagnosis Method Examination Polymorphism OR(95%CI)
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1. Feng, China Case: 310 Postmenopausal Dual DXA BMD Hip BMD rs 11588607 T allele : 1.14 (0.90,
9 2020 F: 310 T < -2.5 Lumbar BMD 1.44) ; p 0.288
10 Age: 62.77 ± 8.42
11 Control: 339 rs 4454537 C allele 1.29 (1.01-

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12 F: 339 1.65), p 0.041
13 Age: 62.79 ± 8.30

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17 2. Kaminski, Poland Case: 333 Postmenopausal Dual DXA BMD T Lumbar BMD rs 4454537 C allele 1.08 (0.84-

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18 2018 F: 333 < -2.5 1.41), p 0.26
19 Age: NA
20 Control: 233 T allele 0.92 (0.71-
21 F: 233 1.19), p 0.27

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22 Age: NA
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3. Cheung, China Case: 417 Postmenopausal Dual DXA BMD Z Spine BMD rs 9728351 C allele 2.56 (1.33-
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2013 F: 417 ≤ -1.28 Femoral BMD 4.92), p 0.005
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28 Age:NA Hip BMD
29 Control: 359 rs 11588607 T allele 1.65 (1.14-
30 F:359 2.4), p 0.008
31 Age:NA
32 rs 4454537 T allele 1.87 (1.22-
33 2.86), p 0.004
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3 IL-10 Gene Polymorphism
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5 No Author, Country, Subject, Gender, Menopausal Osteoporosis Site of Gene Result
6 year Age (mean ± SD) Status Diagnosis Method Examination Polymorphism OR (95% CI)
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1. Suhartono, Case:50 postmenopausal Dual DXA BMD NA rs 180082 C allele 8.1(1.5-42.8),
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Indonesia F:50 T<-2.5 p 0.133
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2017 Age: NA
11 Control: 29

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12 F:29
13 Age:NA

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15 2. Kotrych, poland Case: 224 postmenopausal Dual DXA BMD Lumbar BMD Rs 1800896 G allele 0.75 (0.57-

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16 2016 F: 224 T < -2.5 Femoral BMD IL 10 -1082 0.97), p 0.029
17 Age:

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18 Control: 238 Rs 1800872 A allele 1.27 (0.93 –
19 F:238 IL 10 -592 1.73), p 0.13
20 Age:
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22 3. Tural, turkey Case: 152 postmenopausal Dual DXA BMD Hip BMD Rs 1800872 C allele 0.5043
23 2013 F: 152 T < -2.5 Lumbar BMD IL-10 -597 (0.350-0.726), p
24 Age: 63.65 ± 8.62 0.0002

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25 Control: 103
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F:103
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Age: 60.81 ± 6.97
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30 4. Chen, China Case: 43 Postmenopausal Dual DXA BMD Lumbar BMD Rs 180082 C allele 8.1(1.5-42.8),
31 2005 F: 43 T < -2.5 Femoral BMD p<0.05
32 Age: 54.34 ± 5.93
33 Control: 126
34 F:126
35 Age: 54.34 ± 5.93
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3 IL-6 Gene Polymophism
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5 No Author, Country, Subject, Gender, Menopausal Osteoporosis Site of Gene Result
6 year Age (mean ± SD) Status Diagnosis Method Examination Polymorphism OR (95%CI)
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1. Xiong, China Case: 146 NA Dual DXA BMD Thoracolumbar Rs 1800796 G allel 1.680 (1.187-
9 2022 F: 69 T < -2.5 BMD 2.376), p 0.003
10 Age: 70.98 ± 5.84
11 Control: 144

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12 F: 85
13 Age: 71.92 ± 4.21

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15 2. Ji, China Case: 758 Postmenopausal Dual DXA BMD Lumbar BMD Rs 1800796 -572 G allele 1.90 (1.29-

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16 2019 F: 758 T < -2.5 Femoral BMD 2.54), p 0.346
17 Age: 66.2 ± 15.6

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18 Control: 766 Rs 1800795 -174 C allele 1.12 (0.85-
19 F: 766 1.60), p 0.106
20 Age: 66.2 ± 15.6
21 Rs 2069849 T allele 2.03 (1.63-

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2.84), p 0.730
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Rs 1554606 A allele 1.04 (0.82-
26 1.53), p 0.272
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30 3. Eftekhari, iran Case: 181 Postmenopausal Dual DXA BMD T Lumbar BMD Rs 1800796 (G - C allele 0.83(0.11-
31 2018 F: 68 ± 7.21 score ≤ Femoral BMD 634C) 6.22), p 0.852
32 Age: 68.36 ± 7.21
33 Control: 116
34 F: 64 ± 5.44
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Age: 64 ± 5.44
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4 Deveci, turkey Case: 201 Postmenopausal Dual DXA BMD T Lumbar BMD IL 6 -174 G allele 0.75 (0.53-
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2012 F: 201 < -2.5 Rs 1800795 1.06), p 0.093
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Age: 57 ± 7
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Control: 155
8 F: 155
9 Age: 57 ± 6
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13 5. Czerny, Poland Case: 226 Postmenopausal Dual DXA BMD Lumbar BMD Rs 1800795 G allele 1.22 (0.82 –

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14 2010 F:226 Femoral BMD 1.81), p 0.36
15 Age: 63.3 ± 5.1

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16 Control: 224
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18 Age: 64.8 ± 6.3
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20 6. Magana, Mexico Case: 70 Premenopausal Dual DXA BMD Lumbar BMD IL-6 -174 C allele 0.47 (0.18-
21 2008 F:70 Rs 1800795 0.99), P 0.048

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Age: 74.4 ± 8.91
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Control: 70 IL-6 -572 C allele 0.89 (0.40-
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F:70 Rs1800796 2.03), p 0.798
26 Age: 34.3±10.2
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28 7. Dincel, Turkey Case:20 NA Dual DXA BMD Femoral BMD IL-6 -174 C allele 0.7, p 0.012
29 2008 F: 20 Rs 1800795
30 Age: 74.47 ± 8.91
31 Control: 17
32 F:17
33 Age: 75.47 ± 7.44
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36 8. Nordstrom, Case: 232 postmenopausal Dual DXA BMD Total body IL-6 -174 G allele 1.46(1.08-
37 Sweden F:232 BMD Rs 1800795 1.97) p = 0.01
38 2004 Age: 75 ± 0 Lumbar BMD
39 Control: 544 Hip BMD
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 Mediterranean Journal of Rheumatology Page 6 of 15

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3 ABSTRACT
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6 Background: Osteoporosis is a metabolic disease that is often found in postmenopausal
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women. Many factors predispose to osteoporosis. Genetic factors and gene polymorphisms
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9 play important role in the development of osteoporosis. Recently, there are several studies on
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11 IL-6, IL-10, and gremlin 2 gene polymorphisms and their association with osteoporosis in
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13 postmenopausal women; however, the results are not consistent. Therefore, we conducted this
14 study to systematically evaluate the association.
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17 Materials and Methods: A total of 16 studies with 5488 osteoporosis patients and 3314
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controls were included in this literature review. Systematic literature review was conducted
20 based on PRISMA guideline. We searched related studies in Pubmed. Odds ratio (OR) and
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22 95% confidence interval (CI) were calculated to evaluate the association between IL-6, IL-10,
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24 and Gremlin 2 gene polymorphisms and the risk of osteoporosis.
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26 Results: The IL-6 gene polymorphism rs 1800796, were not significantly associated with
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28 susceptibility to osteoporosis, but the IL-6 gene polymorphism rs 1800795 tended to reduce
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the risk of osteoporosis. The IL-10 gene polymorphisms reduced the risk of osteoporosis.
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34 Conclusion: Our study suggests the association between gene polymorphism and
35 postmenopausal osteoporosis based on specific site of gene polymorphism. Further studies in
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37 large population and multiple ethnics are needed to draw a definite conclusion on the causal
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39 relationship.
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42 Key Words: Postmenopausal osteoporosis, Gene polymorphism, Gene IL-6, Gene IL-10,
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44 Gene Gremlin-2
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3 INTRODUCTION
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5 Osteoporosis is the commonest metabolic bone disease worldwide, characterized by
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7 decreased in bone mineral density, resulting in fracture susceptibility(1)(2). Osteoporosis
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9 causes more than 8.9 million fractures annually. It is estimated that 1 in 3 women and 1 in 5
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men aged over 50 experience osteoporosis fracture.(3) Risk factors for osteoporosis are age,
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12 gender, race (Caucasians especially), genetic, reproductive status, low calcium intake, daily
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14 life style(4)(5).
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16 Genetic factors play an essential role in postmenopausal osteoporosis, including the
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18 Gremlin-2 (GREM 2) as an antagonist of bone morphogenetic protein (BMP), a class of
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20 proteins that are important for bone formation, body patterning, morphogenesis(6). BMP
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activity changes within fully developed bone are linked to decrease bone fracture healing
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23 capacity, osteoarthritis, and osteoporosis(5). Another candidate gene that may affect bone
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25 mineral density is Interleukin 10 (IL-10). IL-10is a powerful anti-inflammatory potent T helper

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27 (TH)2 cell cytokines. It is produced by various cells, such as TH2 cells, eosinophils and
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lymphoid cells, and their role involved in inhibiting macrophage/monocyte replication and T-
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30 cell lymphocytes and inflammatory secretion cytokines(7). In the opposite, Interleukin 6 (IL-
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32 6), an inflammatory cytokine, can potentially regulate Receptor Activator of Nuclear Faktor
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Kappa-B Ligand (RANKL) expression in osteoblasts, related with bone destruction(8). Several
35 studies have been conducted to evaluate the relationship between those gene polymorphism
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37 and osteoporosis; nevertheless, the results are varied.

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39 Therefore, we performed a systematic review to analyze the association between
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GREM 2, IL-6, IL-10 gene polymorphism and postmenopausal osteoporosis.
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44 METHODS
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46 Search Strategy
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49 Systematic review was conducted according to the PRISMA guideline (see PRISMA
50 checklist). To identify articles, we searched several databases: PubMed, Web of Science,
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52 Google Scholar (up to August 31th 2022). The following search term were applied:
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54 (Interleukin-6 or IL-6) and (variant or variation or polymorphism) and (osteoporosis) or
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(postmenopausal osteoporosis) or (senile osteoporosis), (Interleukin-10 or IL-10) and (variant
57 or variation or polymorphism) and (osteoporosis) or (postmenopausal osteoporosis) or (senile
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59 osteoporosis), (Gremlin-2 or GREM2) and (variant or variation or polymorphism) and
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3 (osteoporosis) or (postmenopausal osteoporosis) or (senile osteoporosis). Additional manual
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5 search was performed to look for additional relevant studies.
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10 Eligibility Criteria
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12 Inclusion criteria were: (1) observational case control study, (2) case subjects:
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14 menopausal women for at least for one year, not receiving hormonal replacement therapy, not
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16 receiving drugs effecting bone mass having osteoporosis based on BMD (3) having control
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subjects: menopausal women having normal BMD result. (4) having the data of either IL-6,
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19 IL-10, or GREM 2 polymorphism gene in both groups, (5) having adjusted odds ratio (OR)
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21 with 95% confidence interval (CI) for osteoporosis risk by comparing Bone Mineral Density
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23 (BMD) between the osteoporosis group and non osteoporosis group. Exclusion criteria were:
24 Subject with a history of bone disease, kidney disease, cancer, metabolic or endocrine disorders
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26 (hyperthyroidism, hyperparathyroidism, diabetes mellitus, liver disease, renal disease),
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28 hematologic disease, autoimmune, and malabsorption syndrome were excluded from this
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study. Any review, commentaries, abstracts, case report were not included in our study. Two
31 reviewers separately searched for potentially eligible studies. Any disagreements about study
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33 inclusion resolved by consensus.
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35 Data Extraction
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38 Data were extracted independently by 2 authors from original studies as follows:
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author’s name, publication year, origin country; participant characteristic (total number, gender
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41 and age), postmenopausal status; osteoporosis diagnosis method, site of examination; gene
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43 polymorphism; incidence or prevalence of osteoporosis, adjusted OR with 95% CI.
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50 RESULTS
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Our initial search yielded 73 studies. After the final screening, there were 16 studies that met
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54 the inclusion criteria.(Figure 1) Four studies about IL-10 gene, 9 studies about IL-6 gene, and
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56 3 studies about GREM 2 gene. The total number of subjects were 8,802, consisted of 5,488
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58 osteoporosis patients and 3,314 healthy controls.
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3 Study Characteristics
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6 The studies were published between 2013 and 2021 from various countries, including China
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(n=5)(5)(6)(8)(16)(17), Poland (n=3)(10)(14)(21), Turkey (n=3)(15)(20)(23), Indonesia
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9 (n=1)(12), Iran (n=1)(18), Mexico (n=1)(22), Sweden (n=1)(24). Characteristics of the
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11 included studies are summarized in Table 1.
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16 73 Studies identified in literature search
Identification

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21 Studies excluded after screening titles and
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Screening

26 Potentially relevant studies for further

27 evaluation
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(n=29)
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31 Full-text studies excluded
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(n=10)
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36 Potentially relevant studies met
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inclusion criteria
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45 Studies included in the meta-analysis
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(n=16)
Included

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 IL-10 (n= 4)
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50  IL-6 (n= 8)
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54 Figure 1. flow chart of study selection process
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3 Gremlin 2 gene polymorphism
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6 Three studies with a total of 2,070 subjects evaluated grem polymorphism. The polymorphism
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of 972831 reported in study by Cheung was significantly increased the risk of osteoporosis.
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9 Other polymorphisms (rs 4454537 and rs 11588607) had a tendency to increase the risk of
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11 osteoporosis. Overall 3 studies reported Gremlin 2 gene polymorphism associated with
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13 increased risk of osteoporosis based on lumbar and hip BMD
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15 IL-10 gene polymorphism
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The result of four studies evaluating the association of IL-10 polymorphism and osteoporosis
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19 were varied. Rs 180082 significantly increased the risk of osteoporosis , Rs 1800896 IL 10 -
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21 1082 significantly decreased the risk of osteoporosis. The association of Rs 1800872 with osteoporosis
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IL-6 gene polymorphism
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27 The 3870 women of 8 studies evaluating The association between IL-6 polymorphism and
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29 osteoporosis were varied. The result of rs 1800796 was depend on the allele, polymorphism
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in G allele was significantly increased the risk of osteoporosis but in C allele has the opposite
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32 result. C allele was significantly decreased the risk of osteoporosis. The polymorphism of rs
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34 1800795 also depend on the allele. Polymorphism in G allele had a tendency to increase the
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36 risk of osteoporosis, but C allele had a tendency to decreased the risk of osteoporosis. Other
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polymorphism (rs 2069849 and rs 1554606) increased the risk of osteoporosis with no
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7 Discussion
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9 Osteoporosis is a disease that appears worldwide and affects many people, especially
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11 older adults and postmenopausal women. Decreased bone mineral density (BMD) and bone
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strength is a sign of osteoporosis which can lead to bone fragility. From various related studies,
14 the BMP-2 pathway plays an important role in bone homeostasis, morphogenesis and body
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16 patterning.(6) (9) One of the antagonists of BMP is GREM 2. Therefore, GREM 2 competes
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18 with BMP receptors to regulate the activity of BMP ligands.(28) These changes in activity may
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be associated with osteoporosis. In addition, GREM 2 is also involved in osteoblast
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21 differentiation and osteogenesis.(5)
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23 In our systematic review, we found that GREM 2 gene polymorphism from 3 promoter
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region associated with increased risk of osteoporosis.(5)(6)(10) Our finding is in line with
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26 previous studies showing gremlin-2 as BMP antagonist, therefore GREM 2 inhibits excessive
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28 BMP activity during osteogenesis. However, increasing in GREM 2 result in decrease BMP
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30 activity so that osteogenesis is disrupted. Disruption of osteogenesis might further increase the
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risk of osteoporosis (26)
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34 Interleukin-10 (IL-10) is a potent anti-inflammatory cytokine that has important
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36 immunoregulatory functions. (25) The genotype polymorphism of the anti-inflammatory IL-
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37 10 gene could affect the activity and expression of the protein, so it can disrupt the balance of
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39 bone formation and resorption. Disruption of this balance can increase the risk of osteoporosis.
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In animal studies, it was shown that the lack of expression of the IL-10 gene can inhibit bone
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resorption, increase bone fragility and also reduce femoral BMD.(11)
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45 Our study demonstrated that IL-10 gene polymorphism tends to increase the risk of
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47 osteoporosis. Two studies about IL-10 -726 gene polymorphism have shown that
48 postmenopausal women with genotype C/C have an 8.1 times greater risk of developing
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50 osteoporosis.(12)(13) while the other studies at rs 1800896 decreased the risk of osteoporosis
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52 and rs 1800872 the results was inconclusive. (14)(15)
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54 Other gene that may affect bone mineral density is IL-6. IL-6 is a multifunctional
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56 cytokine that functions to stimulate bone formation and resorption. Several studies have shown
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58 that the IL-6 gene and other inflammatory cytokines have the potential to regulate RANKL in
59 osteoblasts, accelerating RANKL signal transduction, thereby directly causing bone
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3 destruction. (8) We obtained 8 studies evaluating the association between IL-6 polymorphisms
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5 and osteoporosis in postmenopausal women.. The promoter region that studied were rs
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7 1800796, rs 1800795, rs 2069849, and rs 1554606. The result of IL-6 gene polymorphism at rs
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1800796 was depends on the allele. The c Allele significantly decreased the risk of osteoporosis
10 and the G allele significantly increased the risk of osteoporosis. At the 4 sites studied, the most
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12 common SNP found in the Asian population was rs 1800796. rs 1800796 is a 572 cytocytic
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14 mutation to guanine, which functions to promote transcription of the IL-6 promoter resulting
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in an abnormally elevated IL-6 level. (27) the other promoter region, rs 1800795 also depend
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17 on the allele, the C allele had a tendency to decreased the risk of osteoporosis and the G allele
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19 had a tendency to increased the risk of osteoporosis. Based on previous studies, the bones of
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21 women with CC genotype have lower resorption capacity and lower bone mass loss.
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23 Our study is the first study evaluating Grem 2 and IL-10 gene polymorphism in
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postmenopausal women. Other strength was the study conducted in multiple ethnics.
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27 However there are some limitation. First, some study have a small population.
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29 Secondly, the writer’s lack of language skills so that only study using English can be evaluated.
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Thirdly, we only evaluated the relationship between the individual gene polymorphism of IL-
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32 6, IL-10, and Grem 2 in postmenopausal osteoporosis. Therefore it has not fully elucidated the
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34 pathogenesis of osteoporosis.
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39 Conclusion
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41 Our study suggests the association between gene polymorphism and postmenopausal
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43 osteoporosis based on specific site of gene polymorphism. Further studies in large population
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3 DAFTAR PUSTAKA
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12 3. Epidemiology of osteoporosis and fragility fractures | International Osteoporosis
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17 4. Gallagher, Christopher; Tella S. Prevention and Treatment of Post Menopausal
18 Osteoporosis. 2015;155–70.
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20 5. Feng Y, Zhu L, Gu Y, Wang LJ, Niu BJ, Cai F, et al. Association of Gremlin-2 gene
21 polymorphisms with osteoporosis risk in Chinese postmenopausal women. Biosci Rep.
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22 2020 Apr 1;40(4).

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24 6. Cheung CL, Lau KS, Sham PC, Tan KCB, Kung AWC. Genetic variants in grem2 are
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26 Endocrinol Metab. 2013;98(9):1557–61.
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28 7. Byung LP, In KH, Ho SL, Lyoung HK, Sa JK, Shin JS, et al. Association of
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women. J Biochem Mol Biol. 2004;37(6):691–9.
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32 8. Chen B, Li HZ. Association of IL-6 174G/C (rs1800795) and 572C/G (rs1800796)

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Disord. 2020;21(1):1–12.
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51 12. Indonesia U, Indonesia U, Indonesia U. Journal of International Dental and Medical
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55 13. Chen HY, Chen WC, Hsu CM, Tsai FJ, Tsai CH. Tumor necrosis factor α, CYP 17,
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al. TNF-α and IL10 gene polymorphisms in women with postmenopausal osteoporosis.
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9 15. Tural S, Alayli G, Kara N, Tander B, Bilgici A, Kuru O. Association between
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11 postmenopausal women. Hum Immunol [Internet]. 2013;74(9):1179–83. Available
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14 16. Xiong Y, He Y, Peng Y, Geng Y. Association of IL-6 and TGF- β Gene
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16 Fractures. 2022;(February):351–8.
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18 17. Ji Y, Jiang X, Li W, Ge X. Impact of interleukin-6 gene polymorphisms and its
19 interaction with obesity on osteoporosis risk in Chinese postmenopausal women.
20 2019;1–6.
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