External Apical Root Resorption and IL-1A, IL-1RN Gene Polymorphisms: A Systematic Review and Meta-Analysis of Prospective Studies

Nowrin, Shifat A.; Jaafar, Saidi; Rahman, Norma Ab; Shahid, Fazal; Basri, Rehana; Alam, Mohammad Khursheed

doi:10.1590/pboci.2021.065

Shifat A. Nowrin

Orthodontic Unit, School of Dental Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.

http://orcid.org/0000-0001-7730-4481

Saidi Jaafar

Craniofacial Biology Research Group, School of Dental Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.

http://orcid.org/0000-0002-1470-8806

Norma Ab Rahman

Orthodontic Unit, School of Dental Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.

http://orcid.org/0000-0002-9299-8554

Fazal Shahid

Orthodontic Unit, School of Dental Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.

http://orcid.org/0000-0002-2097-1926

Rehana Basri

Department of Medicine, College of Medicine, Jouf University, Sakaka, Kingdom of Saudi Arabia.

http://orcid.org/0000-0002-7025-0414

Mohammad Khursheed Alam

Orthodontic Unit, College of Dentistry, Jouf University, Sakaka, Kingdom of Saudi Arabia.

http://orcid.org/0000-0001-7131-1752

Correspondence: Dr. Saidi Jaafar, School of Dental Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia. E-mail:saidijaafar@usm.my

Authors’ Contributions

SAN https://orcid.org/0000-0001-7730-4481 Conceptualization, Methodology, Formal Analysis, Investigation, Data Curation, Writing - Original Draft and Writing - Review and Editing.

SJ https://orcid.org/0000-0002-1470-8806 Conceptualization, Methodology, Investigation, Data Curation, Writing - Original Draft and Writing - Review and Editing.

NAR https://orcid.org/0000-0002-9299-8554 Conceptualization, Investigation, Writing - Original Draft and Writing - Review and Editing.

FS https://orcid.org/0000-0002-2097-1926 Conceptualization, Formal Analysis, Investigation, Resources, Data Curation, Writing - Original Draft and Writing - Review and Editing.

RB https://orcid.org/0000-0002-7025-0414 Conceptualization, Methodology, Writing - Original Draft and Writing - Review and Editing.

MKA https://orcid.org/0000-0001-7131-1752 Conceptualization, Writing - Original Draft, Writing - Review and Editing and Supervision.

All authors declare that they contributed to critical review of intellectual content and approval of the final version to be published.

Conflict of Interest

The authors declare no conflicts of interest.

Gene	Author	Country	Ethnicity	Sample Size	Radiographs Used	Genotype Method	Biological Marker	Outcome
IL-1A	Al-Qawasmi et al. [¹[1] Al-Qawasmi RA, Hartsfield JK Jr., Everett ET, Flury L, Liu L, Foroud TM, et al. Genetic predisposition to external apical root resorption. Am J Orthod Dentofacial Orthop 2003; 123(3):242-52. https://doi.org/10.1067/mod.2003.42 https://doi.org/10.1067/mod.2003.42... ]	USA	Caucasian	118 subjects from 35 families	Lateral Cephalogram and OPG	Ncoi and TaqI	IL-1A and IL-1B	IL-1B gene, known to decrease the production of IL-1 cytokine in vivo, significantly increases the risk of EARR.
	Iglesias-Linares et al. [²[2] Iglesias-Linares A, Yanez-Vico R, Ballesta-Mudarra S, Ortiz-Ariza E, Ortega-Rivera H, Mendoza-Mendoza A, et al. Postorthodontic external root resorption is associated with IL1 receptor antagonist gene variations. Oral Dis 2012; 18(2):198-205. https://doi.org/10.1111/j.1601-0825.2011.01865.x https://doi.org/10.1111/j.1601-0825.2011... ]	Spain	White	54	Lateral Cephalogram and OPG	HotStar Taq polymerase	IL-1A, IL-1B and IL-1RN	Not only in the IL-1B gene are determinants of a predisposition to postorthodontic EARR.
	Linhartova et al. [³[3] Linhartova P, Cernochova P, Holla LI. IL1 gene polymorphisms in relation to external apical root resorption concurrent with orthodontia. Oral Dis 2013; 19(3):262-70. https://doi.org/10.1111/j.1601-0825.2012.01973.x https://doi.org/10.1111/j.1601-0825.2012... ]	Czech Republic	Not Mentioned	106	Lateral Cephalogram and OPG	Ncoi, TaqI and VNTR-PCR	IL-1A, IL-1B and IL-1RN	No significant role of IL-1A and IL-1B variants in EARR was confirmed, IL-1RN VNTR may be associated with EARR, especially in girls.
	Gülden et al. [⁷[7] Gülden N, Eggermann T, Zerres K, Beer M, Meinelt A, Diedrich P. Interleukin-1 polymorphisms in relation to external apical root resorption (EARR). J Orofac Orthop 2009; 70(1):20-38. https://doi.org/10.1007/s00056-009-8808-6 https://doi.org/10.1007/s00056-009-8808-... ]	German	Not Mentioned	258	OPG	Ncoi and TaqI	IL1A and IL-1B	IL-1A polymorphism point to an association of the genotype 2-2 with EARR and IL-1B polymorphism in patients revealed no indication of a predisposition of EARR.
	Iglesias-Linares et al. [¹⁶[16] Iglesias-Linares A, Yañez-Vico R, Ballesta S, Ortiz-Ariza E, Mendoza-Mendoza A, Perea E, et al. Interleukin 1 gene cluster SNPs (rs1800587, rs1143634) influences post-orthodontic root resorption in endodontic and their contralateral vital control teeth differently. Int Endod J 2012; 45(11):1018-26.]	Spain	White	73	Lateral Cephalogram and OPG	HotStar Taq polymerase	IL-1A and IL-1B	The development of EARR in subjects with root-filled teeth who undergo orthodontic treatment might be attributable to genetic variations in the interleukin-1B gene
	Iglesias-Linares et al. [¹⁷[17] Iglesias-Linares A, Yañez-Vico R-M, Ortiz-Ariza E, Ballesta S, Mendoza-Mendoza A, Perea E, et al. Postorthodontic external root resorption in root-filled teeth is influenced by interleukin-1ß polymorphism. J Endod 2012; 38(3):283-87.]	Spain	Not Mentioned	146	Lateral Cephalogram and OPG	HotStar Taq polymerase	IL-1A and IL-1B	Genetic inheritance of IL-1B gene, in homozygous subjects is associated with a two times increased predisposition to have EARR secondary to orthodontic tooth movement in endodontically treated teeth.
	Sharab et al. [¹⁸[18] Sharab L, Morford L, Dempsey J, Falcão-Alencar G, Mason A, Jacobson E, et al. Genetic and treatment-related risk factors associated with external apical root resorption (EARR) concurrent with orthodontia. Orthod Craniofac Res 2015; 18(suppl 1):71-82. https://doi.org/10.1111/ocr.12078 https://doi.org/10.1111/ocr.12078... ]	USA	Caucasian	460	Lateral Cephalogram, OPG and occlusal	Not mentioned	P2RX7, CASP1, IL-1B, IL-1A and IL-1RN	EARR occurrence was associated with both genetic and treatment-related variables, which together explained 25% of the total variation associated with EARR in the sample tested.
IL-1RN	Linhartova et al. [³[3] Linhartova P, Cernochova P, Holla LI. IL1 gene polymorphisms in relation to external apical root resorption concurrent with orthodontia. Oral Dis 2013; 19(3):262-70. https://doi.org/10.1111/j.1601-0825.2012.01973.x https://doi.org/10.1111/j.1601-0825.2012... ]	Czech Republic	Not Mentioned	106	Lateral Cephalogram and OPG	Ncoi, TaqI and VNTR-PCR	IL-1A, IL-1B and IL-1RN	No significant role of IL-1A and IL-1B variants in EARR was confirmed, IL-1RN VNTR may be associated with EARR, especially in girls.
	Iglesias-Linares et al. [⁸[8] Iglesias-Linares A, Yanez-Vico RM, Ballesta-Mudarra S, Ortiz-Ariza E, Mendoza-Mendoza A, Perea-Perez E, et al. Interleukin 1 receptor antagonist (IL1RN) genetic variations condition post-orthodontic external root resorption in endodontically-treated teeth. Histol Histopathol 2013; 28(6):767-73. https://doi.org/10.14670/HH-28.767 https://doi.org/10.14670/HH-28.767... ]	Spain	Caucasian	93	Lateral Cephalogram and OPG	HotStar Taq polymerase	IL-1RN	IL-1RN gene associated with an increased risk of suffering post- orthodontic EARR in root-filled teeth.
	Pereira et al. [¹⁰[10] Pereira S, Lavado N, Nogueira L, Lopez M, Abreu J, Silva H. Polymorphisms of genes encoding P2X7R, IL-1B, OPG and RANK in orthodontic-induced apical root resorption. Oral Dis 2014; 20(7):659-67. https://doi.org/10.1111/odi.12185 https://doi.org/10.1111/odi.12185... ]	Portugal	Portuguese Caucasian	195	OPG	TaqI and Taq-man	IL-1B, IL-1RN and IRAK1	IRAK1 polymorphism is proposed as a protective variant for EARR.
	Iglesias-Linares et al. [¹⁶[16] Iglesias-Linares A, Yañez-Vico R, Ballesta S, Ortiz-Ariza E, Mendoza-Mendoza A, Perea E, et al. Interleukin 1 gene cluster SNPs (rs1800587, rs1143634) influences post-orthodontic root resorption in endodontic and their contralateral vital control teeth differently. Int Endod J 2012; 45(11):1018-26.]	Spain	White	54	Lateral Cephalogram and OPG	HotStar Taq polymerase	IL-1A, IL-1B and IL-1RN	Not only in the IL-1B gene are determinants of a predisposition to postorthodontic EARR.
	Sharab et al. [¹⁸[18] Sharab L, Morford L, Dempsey J, Falcão-Alencar G, Mason A, Jacobson E, et al. Genetic and treatment-related risk factors associated with external apical root resorption (EARR) concurrent with orthodontia. Orthod Craniofac Res 2015; 18(suppl 1):71-82. https://doi.org/10.1111/ocr.12078 https://doi.org/10.1111/ocr.12078... ]	USA	Caucasian	460	Lateral Cephalogram, OPG and occlusal	Not mentioned	P2RX7, CASP1, IL-1B, IL-1A and IL-1RN	EARR occurrence was associated with both genetic and treatment-related variables, which together explained 25% of the total variation associated with EARR in the sample tested.
	Guo et al. [¹⁹[19] Guo Y, He S, Gu T, Liu Y, Chen S. Genetic and clinical risk factors of root resorption associated with orthodontic treatment. Am J Orthod Dentofacial Orthop 2016; 150(2):283-89. https://doi.org/10.1016/j.ajodo.2015.12.028. https://doi.org/10.1016/j.ajodo.2015.12.... ]	China	Chinese	174	CBCT	Taq-man	IL-6 and IL-RN	IL-6 SNP GC is a risk factor for EARR.

Gene	Author	Country	No of Case/ Control	EARR (> 2mm)			Control (< 2mm)
Gene	Author	Country	No of Case/ Control	CC	CT	TT	CC	CT	TT
				N (%)	N (%)	N (%)	N (%)	N (%)	N (%)
IL-1A	Iglesias-Linares et al. [2]	Spain	25/29	16 (29.6)	8 (14.8)	1 (1.8)	12 (22.2)	13 (24.1)	4 (7.4)
	Linhartova et al. [3]	Czech Republic	32/74	37 (50.0)	31 (41.9)	6 (8.1)	16 (50.0)	14 (43.8)	2 (6.2)
	Gulden et al. [7]	German	45/49	19 (42.2)	18 (40)	8 (17.7)	26 (59.1)	17 (38.6)	1 (2.3)
	Iglesias-Linares et al. [16]	Spain	30/43	16 (21.9)	11 (15.06)	3 (4.1)	20 (27.3)	15 (20.54)	8 (10.9)
	Iglesias-Linares et al. [17]	Spain	39/54	24 (61.5)	9 (23.1)	6 (15.4)	24 (44.4)	23 (42.6)	7 (13.0)
	Sharab et al. [18]	USA	67/67	28 (41.8)	28 (41.8)	11 (16.4)	32 (47.8)	29 (43.3)	6 (9.0)
IL-1RN	Iglesias-Linares et al. [2]	Spain	25/29	2 (3.7)	5 (9.7)	18 (33.3)	4 (7.4)	17 (31.8)	8 (14.8)
	Iglesias-Linares et al. [8]	Spain	39/54	1 (2.6)	6 (15.4)	32 (82.1)	11 (20.4)	27 (50.0)	16 (29.6)
	Sharab L et al. [18]	USA	67/67	3 (4.5)	23 (34.3)	41 (61.2)	0 (0.0)	29 (43.3)	38 (56.7)

Author	Selection	Comparability	Exposure	Study Methodologies	Genetic Analysis	Score
Al-Al-Qawasmi et al. [¹[1] Al-Qawasmi RA, Hartsfield JK Jr., Everett ET, Flury L, Liu L, Foroud TM, et al. Genetic predisposition to external apical root resorption. Am J Orthod Dentofacial Orthop 2003; 123(3):242-52. https://doi.org/10.1067/mod.2003.42 https://doi.org/10.1067/mod.2003.42... ]	* (1)	0	0	* (1)	***** (5)	7
Iglesias-Linares et al. [²[2] Iglesias-Linares A, Yanez-Vico R, Ballesta-Mudarra S, Ortiz-Ariza E, Ortega-Rivera H, Mendoza-Mendoza A, et al. Postorthodontic external root resorption is associated with IL1 receptor antagonist gene variations. Oral Dis 2012; 18(2):198-205. https://doi.org/10.1111/j.1601-0825.2011.01865.x https://doi.org/10.1111/j.1601-0825.2011... ]	**** (4)	* (1)	* (1)	** (2)	***** (5)	13
Linhartova et al. [³[3] Linhartova P, Cernochova P, Holla LI. IL1 gene polymorphisms in relation to external apical root resorption concurrent with orthodontia. Oral Dis 2013; 19(3):262-70. https://doi.org/10.1111/j.1601-0825.2012.01973.x https://doi.org/10.1111/j.1601-0825.2012... ]	****(4)	*(1)	**(2)	**(2)	******(6)	15
Gülden et al. [⁷[7] Gülden N, Eggermann T, Zerres K, Beer M, Meinelt A, Diedrich P. Interleukin-1 polymorphisms in relation to external apical root resorption (EARR). J Orofac Orthop 2009; 70(1):20-38. https://doi.org/10.1007/s00056-009-8808-6 https://doi.org/10.1007/s00056-009-8808-... ]	**(2)	0	0	*(1)	*****(5)	8
Pereira et al. [¹⁰[10] Pereira S, Lavado N, Nogueira L, Lopez M, Abreu J, Silva H. Polymorphisms of genes encoding P2X7R, IL-1B, OPG and RANK in orthodontic-induced apical root resorption. Oral Dis 2014; 20(7):659-67. https://doi.org/10.1111/odi.12185 https://doi.org/10.1111/odi.12185... ]	*(1)	0	0	*(1)	******(6)	8
Iglesias-Linares et al. [¹⁶[16] Iglesias-Linares A, Yañez-Vico R, Ballesta S, Ortiz-Ariza E, Mendoza-Mendoza A, Perea E, et al. Interleukin 1 gene cluster SNPs (rs1800587, rs1143634) influences post-orthodontic root resorption in endodontic and their contralateral vital control teeth differently. Int Endod J 2012; 45(11):1018-26.]	**** (4)	* (1)	* (1)	** (2)	***** (5)	13
Iglesias-Linares et al. [¹⁷[17] Iglesias-Linares A, Yañez-Vico R-M, Ortiz-Ariza E, Ballesta S, Mendoza-Mendoza A, Perea E, et al. Postorthodontic external root resorption in root-filled teeth is influenced by interleukin-1ß polymorphism. J Endod 2012; 38(3):283-87.]	**** (4)	* (1)	* (2)	** (2)	***** (4)	13
Sharab et al. [¹⁸[18] Sharab L, Morford L, Dempsey J, Falcão-Alencar G, Mason A, Jacobson E, et al. Genetic and treatment-related risk factors associated with external apical root resorption (EARR) concurrent with orthodontia. Orthod Craniofac Res 2015; 18(suppl 1):71-82. https://doi.org/10.1111/ocr.12078 https://doi.org/10.1111/ocr.12078... ]	****(4)	* (1)	**(2)	*(1)	******(6)	14
Guo et al. [¹⁹[19] Guo Y, He S, Gu T, Liu Y, Chen S. Genetic and clinical risk factors of root resorption associated with orthodontic treatment. Am J Orthod Dentofacial Orthop 2016; 150(2):283-89. https://doi.org/10.1016/j.ajodo.2015.12.028. https://doi.org/10.1016/j.ajodo.2015.12.... ]	** (2)	0	* (1)	** (2)	**** (4)	9

Quality Assessment	Measure of Agreement Between Raters	Kappa Score
Selection	1	0.857
Comparability	0.769
Exposure	1
Study Methodologies	1
Genetic Analysis	1

Gene	Genotypes	Odds Ratio (OR)	95% CI		p-value
			Lower	Upper
IL-1A (-889)	CC vs. TT	0.941	0.389	2.273	0.892
	CT vs. TT	0.735	0.356	1.517	0.405
	CC + CT vs. TT	0.863	0.395	1.884	0.711
	CC vs. CT + TT	1.109	0.703	1.749	0.656
IL-1RN (+2018)	CC vs. TT	0.117	0.033	0.422	0.001^* * Significant difference (<0.05).
	CT vs. TT	0.118	0.053	0.262	0.001^* * Significant difference (<0.05).
	CC + CT vs. TT	0.114	0.054	0.239	0.001^* * Significant difference (<0.05).
	CC vs. CT + TT	0.535	0.137	2.091	0.368

Gene	Models	Q Statistics	p-value^* * p-value for Q statistics.	I2 Statistics (%)
IL-1A (-899)	CC vs. TT	9.464	0.092	47.168
	CT vs. TT	6.241	0.283	19.884
	CC+CT vs. TT	8.067	0.153	38.021
	CC vs. CT+TT	8.487	0.131	41.086
IL-1RN (+2018)	CC vs. TT	1.229	0.541	0.001
	CT vs. TT	0.037	0.982	0.001
	CC+CT vs. TT	0.372	0.830	0.001
	CC vs. CT+TT	5.110	0.078	60.863

Gene	Genotypes	Begg's Test	Egger's Test
IL-1A (-889)	CC vs. TT	0.707	0.826
	CT vs. TT	1.000	0.722
	CC + CT vs. TT	0.707	0.782
	CC vs. CT + TT	0.259	0.209
IL-1RN (+2018)	CC vs. TT	1.000	0.937
	CT vs. TT	1.000	0.942
	CC + CT vs. TT	1.000	0.745
	CC vs. CT + TT	0.296	0.264

[1] Correspondence: Dr. Saidi Jaafar, School of Dental Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia. E-mail:saidijaafar@usm.my

Brasil

Brasil

External Apical Root Resorption and IL-1A, IL-1RN Gene Polymorphisms: A Systematic Review and Meta-Analysis of Prospective Studies

ABSTRACT

Objective:

Material and Methods:

Results:

Conclusion: