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Association of Genetic Variants in Enamel-Formation Genes with Dental

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Association of Genetic Variants in Enamel-Formation Genes with Dental medRxiv preprint doi: https://doi.org/10.1101/2020.09.19.20198044; this version posted September 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. 1 Association of genetic variants in enamel-formation genes with dental caries: A 2 meta- and gene-cluster analysis 3 Xueyan Li1 PhD, Di Liu2 MD, Yang Sun3 PhD, Jingyun Yang4,5,6,7 PhD, Youcheng Yu3 4 PhD 5 6 1Department of Stomatology, Eye & Ent Hospital of Fudan University, Shanghai 200031, 7 China 8 2Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital 9 Medical University, Beijing 100069, China 10 3Department of Stomatology, Zhongshan Hospital, Fudan University, Shanghai 200032, 11 China 12 4Division of Statistics, School of Economics, Shanghai University, Shanghai 200444, 13 China 14 5Research Center of Financial Information, Shanghai University, Shanghai 200444, 15 China 16 6Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL 60612, 17 USA 18 7Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 19 60612, USA 20 21 22 Correspondence should be addressed to 23 Youcheng Yu 24 Department of Stomatology 25 Zhongshan Hospital, Fudan University 26 180 Fengling Road 27 Shanghai, 200032 28 China 29 E-mail: [email protected] 30 31 or 1 NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.09.19.20198044; this version posted September 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. 32 Jingyun Yang 33 Division of Statistics 34 School of Economics 35 Shanghai University 36 99 Shangda Rd, Baoshan Dist 37 Shanghai, 200444 38 China 39 Tel: 86-21-66136063 40 Fax: 86-21-66134978 41 Email: [email protected] 42 43 Running title: Enamel formation genes and dental caries 44 Keywords: Enamel; dental caries; genetic variant; meta-analysis 45 2 medRxiv preprint doi: https://doi.org/10.1101/2020.09.19.20198044; this version posted September 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. 46 Abstract 47 Previous studies have reported the association between multiple genetic variants in 48 enamel formation-related genes and the risk of dental caries with inconsistent results. We 49 performed a systematic literature search of the PubMed, Cochrane Library, HuGE and 50 Google Scholar databases for studies published before March 21, 2020 and conducted 51 meta-, gene-based and gene-cluster analysis on the association between genetic variants 52 in enamel- formation-related genes and the risk of dental caries. Our systematic literature 53 search identified 21 relevant publications including a total of 24 studies for analysis. The 54 genetic variant rs17878486 in AMELX was significantly associated with dental caries risk 55 (OR=1.40, 95% CI: 1.02-1.93, P=0.037). We found no significant association between 56 the risk of dental caries with rs12640848 in ENAM (OR=1.15, 95% CI: 0.88-1.52, 57 P=0.310), rs1784418 in MMP20 (OR=1.07, 95% CI: 0.76-1.49, P=0.702) and rs3796704 58 in ENAM (OR=1.06, 95% CI: 0.96-1.17, P=0.228). Gene-based analysis indicated that 59 multiple genetic variants in AMELX showed joint association with the risk of dental 60 caries (6 variants; P<10-5), so did genetic variants in MMP13 (3 variants; P=0.004), 61 MMP2 (3 variants; P<10-5), MMP20 (2 variants; P<10-5) and MMP3 (2 variants; P<10-5). 62 The gene-cluster analysis indicated a significant association between the genetic variants 63 in this enamel-formation gene cluster and the risk of dental caries (P<10-5). The present 64 meta-analysis revealed that genetic variant rs17878486 in AMELX were associated with 65 dental caries, and multiple genetic variants in enamel-formation-related genes jointly 66 contribute to the risk of dental caries, supporting the role of genetic variants in the 67 enamel-formation genes in the etiology of dental caries. 68 3 medRxiv preprint doi: https://doi.org/10.1101/2020.09.19.20198044; this version posted September 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. 69 Introduction 70 Dental caries is one of the most common oral diseases, with an age-standardized global 71 prevalence of untreated dentine carious lesions being around 9% in the primary dentition 72 and around 35% in the permanent dentition during the last three decades1. Dental caries is 73 a major public health concern, leading to tooth pain or loss and many other concomitants 74 such as trouble in learning, eating or sleeping2. Dental caries remains to be very common 75 despite the adoption of various preventive measures. 76 Dental caries results from continued localized demineralization of the dental enamel and 77 dentine. It is a chronic disease with a multi-factorial etiology, involving the complex 78 interactions between genetic, environmental and behavioral factors such as fluoride 79 exposure, diet and oral hygiene3-5. Although previous studies have been successful in 80 revealing the factors associated with the risk of dental caries6-8, more studies are needed 81 to validate these findings, identify additional factors, and elucidate their exact roles in the 82 etiology of dental caries. 83 The quality and quantity of enamel plays a direct role in the susceptibility to dental caries. 84 Enamel formation related genes, such as AMBN, AMELX, TUFT1, KLK4 and ENAM, 85 represent a cluster of genes that are involved in the pathway of odontogenesis of dentin- 86 containing teeth3, 9. Previous studies examined the association of genetic variants in this 87 gene cluster with dental caries susceptibility, with inconsistent results10-12. Therefore, we 88 performed this meta-analysis to examine the association between multiple genetic 89 variants in this gene cluster and the risk of dental caries. Considering that the effect of 90 individual genetic variant may be small, we also performed a gene-based and gene- 4 medRxiv preprint doi: https://doi.org/10.1101/2020.09.19.20198044; this version posted September 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. 91 cluster analysis to explore the joint association of multiple genetic variants in this gene 92 cluster with the risk of dental caries. 93 Materials and Methods 94 Ethical approval and informed consent statements are not required due to the systematic 95 review and meta-analytic nature of this study. 96 Eligibility Criteria 97 We adopted the following inclusion criteria to determine study eligibility: 1) studies on 98 human subjects; 2) the studies has case and control group, with the case group including 99 subjects who had caries or high caries and the control group being care-free or having 100 low/very low caries; and 3) the studies reported data on genetic variants in enamel 101 formation genes for subjects in both the case group and the control group. We chose the 102 studies with a larger sample size if multiple studies used overlapping data. 103 Two authors (XL and JY) performed an extensive literature search of the PubMed, 104 Cochrane Library, HuGE and Google Scholar databases for studies published before 105 March 21, 2020. The keywords used in the literature search are provided in the online 106 supplementary file. 107 We retrieved all potentially relevant publications to evaluate study eligibility. We 108 manually searched the references in all identified studies for research that might have 109 been missed during the literature search. We also relied on Google Scholar’s ‘cited by’ 110 tool to search for potential publications that cited the studies identified in the literature 111 search. The two authors performed the literature search independently. The search was 5 medRxiv preprint doi: https://doi.org/10.1101/2020.09.19.20198044; this version posted September 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. 112 limited to studies published in English. Any disagreement was resolved by group 113 discussion (XL, SY and JY). 114 Data Extraction 115 Two authors (DL and JY) independently extracted the following data from the eligible 116 studies according to a pre-specified protocol for data extraction: name of the first author, 117 year of publication, characteristics of the study participants, including sample size, mean 118 age, distribution of gender, race/country of origin of the participants, screening method 119 for dental caries, and genotype data for participants in the case and the control group. 120 Any discrepancies were resolved in a group meeting. The quality of the included studies 121 was assessed by two authors (DL and JY) independently using the Newcastle–Ottawa 122 Scale (NOS)13.
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