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Correlation Between CDKAL1 Rs10946398c>A Single Nucleotide Open Life Sci. 2017; 12: 501–509 Research Article Yunyi Liang, Yi Shu, Haizhao Luo, Riqiu Chen, Zhifu Zeng* Correlation between CDKAL1 rs10946398C>A single nucleotide polymorphism and type 2 diabetes mellitus susceptibility: A meta-analysis https://doi.org/10.1515/biol-2017-0059 showed people with AA or CA genotype had decreased Received September 19, 2017; accepted October 17, 2017 risk of developing T2DM compared to CC genotype (OR=0.83, P<0.05); For a homozygous genetic model (CC Abstract: Objective The purpose of this meta- vs AA), the OR was calculated through random effect analysis was to assess the correlation between CDKAL1 model for statistical heterogeneity among the included rs10946398C>A single nucleotide polymorphism (SNP) 13 studies. The combined OR was 1.33 which indicated and type 2 diabetes mellitus (T2DM) susceptibility by people with CC genotype had increased risk of developing pooling the open published studies. Method Electronic T2DM. Conclusion According to the present results, searching of PubMed, EMBASE, Medline, Cochrane, CDKAL1 rs10946398C>A single nucleotide polymorphism China Biology Medicine disc (CBM) and China National had correlation with the susceptibility of type 2 diabetes Knowledge Infrastructure (CNKI) databases were mellitus. performed by two reviewers independently to collect the open published studies related to CDKAL1 rs10946398C>A Keywords: type 2 diabetes mellitus; CDKAL1 gene; single nucleotide polymorphism and T2DM susceptibility. susceptibility; polymorphism; meta-analysis. The association between CDKAL1 rs10946398C>A single nucleotide polymorphism and T2DM susceptibility was expressed by odds ratio (OR) and the corresponding 95% confidence interval (95%CI). Results Thirteen studies with a total of 13,966 T2DM and 14,274 controls were 1 Introduction finally included for analysis in this meta-analysis. Of the Type 2 diabetes mellitus (T2DM) is a metabolic disorder included 13 publications, 2 studies were carried out in caused by insufficient insulin secretion or insulin Europe, 8 in Asia, 2 in Africa and 1 in Latin America. Being resistance [1,2]. Epidemiological studies have suggested significant statistical heterogeneity, the data was pooled that T2DM is a multifactor genetically heterogeneous through random effect model. In a dominant genetic disease that involves in the effects of multiple genes and model, there was significant correlation between CDKAL1 environmental factors [3,4]; thus, its pathogenesis is rs10946398C>A SNP and T2DM risk (OR=1.22, P<0.05). In a complex and the cause of this disease has not yet been dominant genetic model people with CC or CA genotype fully elucidated. CDKAL1 is a newly identified gene that had increased risk of developing T2DM; Because of is relevant to T2DM pathogenesis [5,6]. However, research statistical heterogeneity for the included studies in a on the relationship between CDKAL1 gene rs10946398 site recessive genetic model (AA+CA vs CC), the data was polymorphism and T2DM is inconclusive [7-9]. Wu et al. calculated by random effect method. The combined data [10] evaluated the correlation between common variants of CDKAL1 gene and type 2 diabetes. The authors found *Corresponding author: Zhifu Zeng, Department of Endocrinology, in Chinese Hans, the common variants of rs10946398C>A Lishui People’s Hospital, Lishui Zhejiang Province, 323000 PR China. single nucleotide polymorphism was associated with No.15 Dazhong Road, Liandu District Lishui City Zhejiang Province, the susceptibility of type 2 diabetes mellitus. However, 323000 PR China, E-mail: [email protected] Cruz [9] didn’t find the correlations in all genetic models. Yunyi Liang, Yi Shu, Haizhao Luo, Department of Endocrinology, Nanhai People’s Hospital of Foshan City 528200 China In this study, a meta-analysis has been conducted to Riqiu Chen, Department of Endocrinology, Lishui People’s Hospital, comprehensively and quantitatively evaluate previous Lishui Zhejiang Province, 323000 PR China study results to obtain medical evidence on the relationship Open Access. © 2017 Yunyi Liang et al., published by De Gruyter Open. This work is licensed under the Creative Commons Attribution- NonCommercial-NoDerivs 4.0 License. 502 Y. Liang, et al. between CDKAL1 gene rs10946398 polymorphism and (CC, CA and AA) for CDKAL1 rs10946398 from each T2DM susceptibility. included studies were also extracted. The data was cross examined by the two reviewers to make consensus. A third reviewer (Fuzhi Zeng) was consulted if disagreement was 2 Methods encountered. 2.1 Publication searching 2.4 Statistical analysis Electronic searching of PubMed, EMBASE Medline, Cochrane, China Biology Medicine disc (CBM) and China Stata 11.0 (for meta-analysis) was used to deal with the data National Knowledge Infrastructure (CNKI) databases was analysis. Firstly, the data extracted from each included performed by two reviewers (Yunyi Liang and Yi Shu) publication was tested for statistical heterogeneity independently to collect the open published studies related through chi-square test [11] and the inconsistency was to CDKAL1 rs10946398C>A SNP and T2DM susceptibility. calculated by I2 [12]. If significant statistical heterogeneity The electronic searching words were described as follows: existed among the included studies, the data was CDKAL1 gene, T2DM, susceptibility, rs10946398 and pooled by random effect method otherwise the data was genetic polymorphism. The studies searching process was calculated by fixed effect methods. The odds ratio (OR) done by two reviewers (Yunyi Liang and Yi Shu) and cross was used to demonstrate the correlation between DKAL1 checked. The references of included publications were rs10946398C>A single nucleotide polymorphism and also reviewed to find additional suitable studies. T2DM susceptibility. The publication bias was evaluated by Begg’s funnel plot and Egger’s line regression test. Two tail p≤0.05 was considered statistical significance. 2.2 Publication inclusion and exclusion criteria 3 Results The study inclusion criteria were: ① Open published studies about CDKAL1 rs10946398C>A SNP and T2DM 3.1 General characteristics of the included susceptibility with the language restriction of English thirteen studies and Chinese; ② The study was restrict to case-control or cohort study; ③ The study should provide the genotype After searching the electronic databases, 364 publications distribution; ④ The T2DM patients had confirmed were initially identified. After reading the title, abstract diagnosis according to WHO DM diagnostic criteria; and full text paper, 351 studies were did not meet the ⑤ Subjects in the control group did not have family inclusion criteria and were excluded. 13 studies [7-10, history of DM. The publication exclusion criteria were: ① 13-21] with a total of 13966 T2DM and 14274 controls were Duplicated publications; ② Case report or review study finally included for analysis in this meta-analysis, Figure type; ③ Studies published in other language; ④ The 1. Of the included 13 publications, 2 studies were carried original study did not provided genotype distribution or out in Europe, 8 in Asia, 2 in Africa and 1 in Latin America. enough data to calculate the OR. The detailed information for the included studies were showed in Table 1. 2.3 Data extraction 3.2 Genotype distribution Two reviewers (Haizhao Luo and Riqiu Chen) independently reviewed the whole paper to extract The median CC, CA and AA genotype distribution frequency the necessary information and data. The general for T2DM group were 0.22, 0.49 and 0.28. And for control characteristics of the included studies such as first and group, the median distribution frequency CC, CA and AA corresponding authors, the paper publication year, and genotype were 0.18, 0.48 and 0.34 respectively. There was the race of subjects were extracted and cross checked no statistical difference for the CC, CA and AA genotype by the two reviewers. The data of genotype distribution distribution between the two groups (P>0.05), Figure 2. Correlation between CDKAL1 rs10946398C>A single nucleotide polymorphism... 503 Records identified through Additional records identified database searching through other sources (n = 364 ) (n = 0 ) Identification Records after duplicates removed (n =360) Screening Records screened (n = 360 ) Records excluded (n = 340) Full-text articles assessed Eligibility for eligibility (n = 20 ) Full-text articles excluded, with reasons (n = 7 ) Studies included in quantitative synthesis (meta-analysis) Included (n = 13 ) Figure 1. Publication inclusion flow-chart of this meta-analysis Table 1. General information for the included studies Authors Year Region Race Case Control CC CA AA CC CA AA Grarup [13] 2007 Europe Caucasus 184 424 244 159 422 281 Scott [7] 2007 Europe Caucasus 171 549 440 150 539 486 Lewis [14] 2008 Africa African 353 442 138 357 513 185 Wu [10] 2008 Asia East Asian 106 212 106 319 922 666 Hu [8] 2009 Asia East Asian 360 912 578 306 866 613 Cruz [9] 2010 Latin America America 52 225 242 51 224 244 Han [15] 2010 Asia East Asian 227 498 273 177 484 330 Lin [16] 2010 Asia East Asian 310 757 463 195 666 567 Wen [17] 2010 Asia East Asian 226 574 365 175 542 420 Cooke [18] 2012 Africa African 968 1269 416 453 683 258 Chen [19] 2013 Asia East Asian 97 221 125 296 559 264 Al-Sinani [20] 2015 Asia Europa 401 460 131 140 126 28 Sun [21] 2015 Asia East Asian 108 231 108 99 294 215 504 Y. Liang, et al. 3.3 Statistical heterogeneity evaluation 3.4 Dominant genetic model (CC+CA vs AA) The statistical heterogeneity for the included studies were For significant heterogeneity, the data was pooled evaluate by I2 test. In the dominant genetic model (CC+CA through random effect model. In dominant genetic vs AA), the I2=71.4% indicating significant statistical model, there was significant correlation between heterogeneity was existed. For the recessive genetic model CDKAL1 rs10946398C>A single nucleotide polymorphism (AA +CC vs CC), the statistical heterogeneity was significant (OR=1.22, P<0.05). In dominant genetic model people with I2=73.0%. Significant heterogeneity also found in with CC or CA genotype had increased risk of developing homozygous genetic model (CC vs AA) with the I2=79.7%.
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