Candidate gene studies in gallbladder cancer: a systematic review and meta-analysis

Abstract

Gallbladder cancer (GBC) is the most frequent biliary tract malignancy. Wide variations in GBC incidence and familial and epidemiological data suggest involvement of a genetic component in its etiopathogenesis. A systematic review of genetic association studies in GBC was performed by applying a meta-analysis approach and systematically reviewing PubMed database using appropriate terms. Odds ratios (ORs) and 95% confidence intervals (CIs) were appropriately derived for each gene-disease association using fixed and random effect models. Meta-regression with population size and genotyping method was also performed. Study quality was assessed using a 10-point scoring system designed from published guidelines. Following a review of 44 published manuscripts and one unpublished report, 80 candidate gene variants and 173 polymorphisms were analyzed among 1046 cases and 2310 controls. Majority of studies were of intermediate quality. Four polymorphisms with >3 separate studies were included in the meta-analysis [OGG1 (rs1052133), TP53 (rs1042522), CYP1A1 (rs1048943) and GSTM1 null polymorphism]. The meta-analysis demonstrated no significant associations of any of the above polymorphisms with GBC susceptibility except TP53 (rs1042522) polymorphism. To conclude, existing candidate gene studies in GBC susceptibility have so far been insufficient to confirm any association. Future research should focus on a more comprehensive approach utilizing potential gene-gene, gene-environment interactions and high-risk haplotypes.

Fig. 1

The average score of published genetic association studies in GBC, expressed as a percentage of total possible scores from 0 to 1, with standard error of the mean. Studies were divided into year of publication. There was an evidence of a trend towards improvement over time (R²=0.69; logarithmic trendline).

Fig. 2

ORs and 95% CIs of individual studies for the association between the OGG1 (rs1052133) polymorphism Cys allele, TP53 (rs1042522) polymorphism Arg allele, GSTM1 null polymorphism and CYP1A1 (rs1048943) Val allele and GBC. The size of the box is proportional to the weight of the study. CI, confidence interval

Fig 3

Funnel plot analysis to detect publication bias for the analyzed polymorphisms in GBC. Each dot represents an individual study for the indicated association. Log [OR], natural logarithm of odds ratio

Fig 4

Funnel plot of Precision by Log odds ratio. The filled circles are missed studies due to publication bias. The bottom diamonds show summary effect estimates before (open) and after (filled) publication bias adjustment.