Association of the IL-6 -174G &gt; C (rs1800795) Polymorphism with Adolescent Idiopathic Scoliosis: Evidence from a Case-Control Study and Meta-Analysis

Sobhan, Mohammad Reza; Mahdinezhad-Yazdi, Masoud; Dastgheib, Seyed Alireza; Ahrar, Hossein; Aghili, Kazem; Neamatzadeh, Hossein

doi:10.1055/s-0039-1700813

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Review Articles • Rev. bras. ortop. 55 (01) • Jan-Feb 2020 • https://doi.org/10.1055/s-0039-1700813 copy

Association of the IL-6 -174G > C (rs1800795) Polymorphism with Adolescent Idiopathic Scoliosis: Evidence from a Case-Control Study and Meta-Analysis

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Recent epidemiological studies have identified that the -174G > C (rs1800795) polymorphism in the promoter region of the interleukin-6 (IL-6) gene is associated with the risk of developing adolescent idiopathic scoliosis (AIS), but they presented inconsistent and controversial results. Thus, we performed a case-control study and meta-analysis to derive a more precise estimation of the relationship between the IL-6 -174G > C polymorphism and the risk of developing AIS. A total of 80 patients with AIS and 80 matched healthy control subjects were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. In addition, all eligible studies published up to June 2018 were identified through a search in the PubMed, EMBASE, Google Scholar, and China National Knowledge Infrastructure (CNKI) databases. We calculated the odds ratios (ORs) and 95% confidence intervals (95%CIs) to assess the association. A total of 10 eligible studies comprising 1,695 AIS cases and 2,097 healthy controls were included in the meta-analysis. The pooled data suggested a significant association between the IL-6 -174G > C polymorphism and the susceptibility to develop AIS, which was demonstrated under 4 genetic models, that is, the allelic (C versus G; OR = 0.671; 95%CI: 0.457-0.985; p = 0.042), heterozygous (CG versus GG; OR = 0.734; 95%CI: 0.554-0.973; p = 0.032), dominant (CC + CG versus GG; OR = 0.660; 95%CI: 0.440-0.990; p = 0.044) and recessive models (CC versus CG + GG; OR = 0.506; 95%CI: 0.264-0.970; p = 0.040). The stratification analysis by ethnicity revealed an increased risk of developing AIS in Caucasians, but not in Asians. The present meta-analysis, which is inconsistent with the previous meta-analysis, suggests that the IL-6 -174G > C polymorphism may increase the individual susceptibility to develop AIS, especially in Caucasians, and it could serve as a biomarker to predict the population at high risk of developing AIS.

Keywords
idiopathic scoliosis; interleukin-6; polymorphism; association; meta-analysis

	Cases (n = 80)	Controls (n = 80)	OR (95%CI)	p -value
IL-6 -174 G > C
Genotypes
GG	74 (92.50)	76 (95.0)	Reference
CG	5 (6.25)	4 (5.0)	1.267(0.327-4.900)	0.732
CC	1 (1.25)	0 (0.00)	3.038(0.122-75.693)	0.498
Allele
G	153 (95.62)	156 (97.50)	Reference
C	7 (4.38)	4 (2.50)	1.784(0.512-6.219)	0.363
Genetic models
Dominant (CC + CG versus GG)			1.541(0.418-5.681)	0.516
Recessive (CC versus CG + GG)			3.038(0.122-75.693)	0.498

Autor/Ano	Author (year)	Country (ethnicity)	Genotyping technique	Case/Control	Cases					Controls					MAFs	HWE
					Genotypes			Allele		Genotypes			Allele
					GG	CG	CC	G	C	GG	CG	CC	G	C
Aulisa et al ¹⁴14 Aulisa L, Papaleo P, Pola E, et al. Association between IL-6 and MMP-3 gene polymorphisms and adolescent idiopathic scoliosis: a case-control study. Spine 2007;32(24):2700–2702 (2007)	Aulisa et al ¹⁴14 Aulisa L, Papaleo P, Pola E, et al. Association between IL-6 and MMP-3 gene polymorphisms and adolescent idiopathic scoliosis: a case-control study. Spine 2007;32(24):2700–2702 (2007)	Italy (Caucasian)	PCR-RFLP	53/206	28	22	3	78	28	54	90	62	198	214	0.519	0.073
Lee et al ¹⁶16 Lee JS, Suh KT, Eun IS. Polymorphism in interleukin-6 gene is associated with bone mineral density in patients with adolescent idiopathic scoliosis. J Bone Joint Surg Br 2010;92(08):1118–1122 (2010)	Lee et al ¹⁶16 Lee JS, Suh KT, Eun IS. Polymorphism in interleukin-6 gene is associated with bone mineral density in patients with adolescent idiopathic scoliosis. J Bone Joint Surg Br 2010;92(08):1118–1122 (2010)	Korea (Asian)	TaqMan	198/120	197	1	0	395	1	119	1	0	239	1	0.004	0.963
Liu et al ¹⁷17 Liu Z, Tang NL, Cao XB, et al. Lack of association between the promoter polymorphisms of MMP-3 and IL-6 genes and adolescent idiopathic scoliosis: a case-control study in a Chinese Han population. Spine 2010;35(18):1701–1705 (2010)	Liu et al ¹⁷17 Liu Z, Tang NL, Cao XB, et al. Lack of association between the promoter polymorphisms of MMP-3 and IL-6 genes and adolescent idiopathic scoliosis: a case-control study in a Chinese Han population. Spine 2010;35(18):1701–1705 (2010)	China (Asian)	PCR-RFLP	487/494	487	0	0	974	0	494	0	0	988	0	0.000	NA
Mórocz et al ¹⁸18 Mórocz M, Czibula A, Grózer ZB, et al. Association study of BMP4, IL6, Leptin, MMP3, and MTNR1B gene promoter polymorphisms and adolescent idiopathic scoliosis. Spine 2011;36(02):E123–E130 (2011)	Mórocz et al ¹⁸18 Mórocz M, Czibula A, Grózer ZB, et al. Association study of BMP4, IL6, Leptin, MMP3, and MTNR1B gene promoter polymorphisms and adolescent idiopathic scoliosis. Spine 2011;36(02):E123–E130 (2011)	Hungary (Caucasian)	PCR-RFLP	126/197	34	67	25	135	117	64	97	36	225	169	0.428	0.943
Nikolova et al ¹⁹19 Nikolova S, Dikova M, Dikov D, et al. Role of the IL-6 gene in the etiopathogenesis of idiopathic scoliosis. Anal Cell Pathol (Amst) 2015;2015:621893 (2015)	Nikolova et al ¹⁹19 Nikolova S, Dikova M, Dikov D, et al. Role of the IL-6 gene in the etiopathogenesis of idiopathic scoliosis. Anal Cell Pathol (Amst) 2015;2015:621893 (2015)	Bulgaria (Caucasian)	PCR-RFLP	80/160	42	29	9	113	47	56	62	42	174	146	0.456	0.005
Nikolova et al ²⁰20 Nikolova ST, Yablanski VT, Vlaev EN, et al. Association Between IL- 6 and MMP3 Common Genetic Polymorphisms and Idiopathic Scoliosis in Bulgarian Patients: A Case-control Study. Spine 2016; 41(09):785–791 (2016)	Nikolova et al ²⁰20 Nikolova ST, Yablanski VT, Vlaev EN, et al. Association Between IL- 6 and MMP3 Common Genetic Polymorphisms and Idiopathic Scoliosis in Bulgarian Patients: A Case-control Study. Spine 2016; 41(09):785–791 (2016)	Bulgaria (Caucasian)	PCR-RFLP	105/210	54	40	11	148	62	63	94	53	220	200	0.476	0.136
Sui et al ²¹21 SuiW, Yang J, Huang Z,Wang Q, Fan H, Deng Y. Polymorphisms in promoter regions of MMP-3 and IL-6 genes are not associated to adolescent idiopathic scoliosis (AIS) gender bias. J Back Musculoskeletal Rehabil 2017;30(03):559–563 (2017)	Sui et al ²¹21 SuiW, Yang J, Huang Z,Wang Q, Fan H, Deng Y. Polymorphisms in promoter regions of MMP-3 and IL-6 genes are not associated to adolescent idiopathic scoliosis (AIS) gender bias. J Back Musculoskeletal Rehabil 2017;30(03):559–563 (2017)	China (Asian)	PCR-RFLP	200/200	195	5	0	395	5	196	4	0	396	4	0.010	0.886
Lee et al ²²22 Lee JS, Shin JK, Goh TS. Interleukin 6 gene polymorphism in patients with degenerative lumbar scoliosis: a cohort study. Eur Spine J 2018;27(03):607–612 (2018)	Lee et al ²²22 Lee JS, Shin JK, Goh TS. Interleukin 6 gene polymorphism in patients with degenerative lumbar scoliosis: a cohort study. Eur Spine J 2018;27(03):607–612 (2018)	China (Asian)	DS	184/220	183	1	0	367	1	218	2	0	438	2	0.004	0.946
Gao et al ²³23 Gao J, Zhang L, Liu Z, Yao S, Gao S. [Correlation analysis between interleukin 6 polymorphism and adolescent idiopathic scoliosis susceptibility and bracing effectiveness]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2018;32(06):678–684 (2018)	Gao et al ²³23 Gao J, Zhang L, Liu Z, Yao S, Gao S. [Correlation analysis between interleukin 6 polymorphism and adolescent idiopathic scoliosis susceptibility and bracing effectiveness]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2018;32(06):678–684 (2018)	China (Asian)	PCR-RFLP	182/210	128	44	10	298	64	136	60	14	332	88	0.209	0.046
P	Present study	Iran (Asian)	PCR-RFLP	80/80	74	5	1	153	7	76	4	0	156	4	0.025	0.818

Subgroup	Genetic model	Type of model	Heterogeneity (H)		Odds Ratio				Publication Bias
Subgroup	Genetic model	Type of model	I² (%)	p _H	OR	95%CI	Z test	p _OR	p _Begg	p _Egger
Overall	C versus G	Random	73.65	≤ 0.001	0.671	0.457-0.985	−2.035	0.042	0.754	0.909
	CC versus GG	Random	77.57	≤ 0.001	0.439	0.439-0.192	−1.951	0.051	1.000	0.792
	CG versus GG	Fixed	22.24	0.245	0.734	0.554-0.973	−2.150	0.032	0.754	0.834
	CC + CG versus GG	Random	61.46	0.008	0.660	0.440-0.990	−2.010	0.044	1.000	0.786
	CC versus CG + GG	Random	67.97	0.008	0.506	0.264-0.970	−2.052	0.040	1.000	0.727
By ethnicity
Asian	C versus G	Fixed	0.00	0.816	0.865	0.624-1.201	−0.866	0.386	1.000	0.552
	CC versus GG	Fixed	0.00	0.409	0.831	0.366-1.885	−0.443	0.658	NA	NA
	CG versus GG	Fixed	0.00	0.915	0.840	0.562-1.256	−0.851	0.395	0.806	0.642
	CC + CG versus GG	Fixed	0.00	0.873	0.845	0.578-1.234	−0.872	0.383	1.000	0.571
	CC versus CG + GG	Fixed	0.00	0.437	0.885	0.394-1.989	−0.296	0.767	NA	NA
Caucasian	C versus G	Random	88.10	≤0.001	0.552	0.318-0.959	−2.110	0.035	0.308	0.173
	CC versus GG	Random	84.71	≤0.001	0.329	0.114-0.951	−2.053	0.040	0.308	0.204
	CG versus GG	Random	65.43	0.034	0.670	0.413-1.086	−1.626	0.104	1.000	0.519
	CC + CG versus GG	Random	81.71	0.001	0.541	0.290-1.008	−1.935	0.053	0.734	0.490
	CC versus CG + GG	Random	77.97	0.003	0.408	0.180-0.925	−2.146	0.032	0.308	0.114
Asian (Chinese)	C versus G	Fixed	0.00	0.790	0.824	0.585-1.160	−1.109	0.267	1.000	0.799
	CC versus GG	Fixed	0.00	1.000	0.759	0.325-1.770	−0.639	0.523	NA	NA
	CG versus GG	Fixed	0.00	0.775	0.811	0.530-1.243	−0.961	0.337	1.000	0.797
	CC + CG versus GG	Fixed	0.00	0.771	0.804	0.539-1.199	−1.069	0.285	1.000	0.780
	CC versus CG + GG	Fixed	0.00	1.000	0.814	0.352-1.880	−0.482	0.630	NA	NA

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[1] Address for correspondence Dr. Seyed Alireza Dastgheib, Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran (e-mail: dastgheibsa@gmail.com).