Association of LPP and TAGAP Polymorphisms with Celiac Disease Risk: A Meta-Analysis

Background: Lipoma preferred partner (LPP) and T-cell activation Rho GTPase activating protein (TAGAP) polymorphisms might influence the susceptibility to celiac disease. Therefore, we performed a meta-analysis by identifying relevant studies to estimate the risks of these polymorphisms on celiac disease. Methods: The PubMed, Web of Science and Embase databases were searched (up to October 2016) for LPP rs1464510 and TAGAP rs1738074 polymorphisms. Results: This meta-analysis included the same 7 studies for LPP rs1464510 and TAGAP rs1738074. The minor risk A allele at both rs1464510 and rs1738074 carried risks (odds ratios) of 1.26 (95% CI: 1.22–1.30) and 1.17 (95% CI: 1.14–1.21), respectively, which contributed to increased risks in all celiac disease patients by 10.72% and 6.59%, respectively. The estimated lambdas were 0.512 and 0.496, respectively, suggesting that a co-dominant model would be suitable for both gene effects. Conclusions: This meta-analysis provides robust estimates that polymorphisms in LPP and TAGAP genes are potential risk factors for celiac disease in European and American. Prospective studies and more genome-wide association studies (GWAS) are needed to confirm these findings, and some corresponding molecular biology experiments should be carried out to clarify the pathogenic mechanisms of celiac disease.

. Funnel plot for LPP rs1464510 (A vs. C) with CD.   The epidemiology of celiac disease. The conflict results of genetic risk with celiac disease in different population based studies.
 Hypothesis statement We propose there are associations between gene polymorphisms LPP rs1464510 and TAGAP rs1738074 and celiac disease.  Description of study outcomes The pooled OR and 95% confidence interval  Type of exposure Genetic markers  Type of study designs used The population based genetic epidemiological observational studies of celiac disease.

 Study population
The populations from the whole world are all is considered our analysis. Reporting of search strategy should include  Qualifications of searchers Two reviewers independently went through all titles and abstracts of the identified studies.

Method of addressing articles published in languages other than English
We had a restriction on language; our searching was limited to English.

Method of handling abstracts and unpublished studies
We included proceedings papers and assessed them for eligibility according to our inclusion and exclusion criteria.
Unpublished studies were excluded in our analysis.  Description of any contact with authors It is applicable; we contact the authors when we needed. Reporting of methods should include  Description of relevance or appropriateness of studies assembled for assessing the hypothesis to be tested Detailed inclusion and exclusion criteria are described in the Methods section.

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Rationale for the selection and coding of data Data extracted from each of the studies were relevant to the population characteristics name of first author, year of publication, region of study population, source of controls, genotype method, diagnostic criteria, the number of cases and controls, the risk allele frequency in cases and controls, and the Hard-Weinberg Equilibrium (HWE).  Assessment of confounding Detailed inclusion is described in the Methods section.

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Assessment of study quality, including blinding of quality assessors; stratification or regression on possible predictors of study results Sensitivity analyses by several quality indicators such as study size, study objects' ethnic, and another influent factors, in the Methods section.
 Assessment of heterogeneity Heterogeneity of the studies was explored with I 2 statistic that provides the relative amount of variance of the summary effect due to the between-study heterogeneity, detailed inclusion is described in the Methods section.

Description of statistical methods in sufficient detail to be replicated
Description of methods of meta-analyses, sensitivity analyses, meta-regression and assessment of publication bias are detailed in the methods. We performed fixed effects and random effects meta-analysis with Stata (Ver. 12) and the Comprehensive Meta-Analysis software (Ver. 12). Tables and  graphics  Tables 1-4, Figures 1-3, Tables S1-S3, Figures S1 and S2

Provision of appropriate
Reporting of results should include  Graph summarizing individual study estimates and overall estimate Figure 2 and Figure 3  Table giving descriptive information for  each study included  Table 1  Results of sensitivity testing Table S3  Indication of statistical uncertainty of findings 95% confidence intervals were presented with all summary estimates, I 2 values and results of sensitivity analyses.
Reporting of discussion should include  Quantitative assessment of bias The forest plot and Egg's regression.  Justification for exclusion All studies were excluded based on the pre-defined inclusion criteria in methods section.
 Assessment of quality of included studies Brief discussion included in Methods section. We recommend analyses that would correct for regression dilution bias.  Disclosure of funding source No separate funding was necessary for the undertaking of this systematic review.