Graves' disease (GD) is a thyroid-specific autoimmune disease affecting 0.25–1.09% of the Chinese population
]. To this day, the mechanisms of GD have been widely studied from the environmental factors to the genetic factors
]. However, the results are inconsistent and the exact mechanisms are still unrevealed. Among genetic risk factors, the cytotoxic T lymphocyte associated-4
) gene is one of the widely investigated. CTLA-4
gene, which encodes a vital negative regulatory molecule of the immune system
], has been demonstrated as candidate gene of GD
]. To date, three polymorphisms (+49A/G, -318C/T and CT60) have been suggested as GD risk factors in the Chinese population. However, the results were inconsistent. Therefore, we performed a comprehensive meta-analysis to assess the association and to get more conclusive results.
This meta-analysis, including a total of 28 case–control studies in 21 publications, investigated three most widely studied polymorphisms in the CTLA-4
gene. We found that the +49A/G polymorphism was associated with an increased risk of GD in the Chinese population, and the G allele carriers might have a higher risk of disease than the AA homozygote carriers. The results suggested a significant association between this polymorphism in the Chinese population, which is consistent with some other populations, such as the UK population
] and the Iranian population
]. Our results indicated that the increase in the risk is more evident in the Chinese population than in other populations, suggesting possible roles of ethnic differences in genetic backgrounds and the environment. In addition, the +49A/G polymorphism is located in exon 1, and results in a threonine-to-alanine conversion at codon 17 in the peptide leader sequence of the CTLA-4 protein. It reported that this polymorphism was associated with lower mRNA levels of the soluble alternative splice form of CTLA-4
]. Thus, our results could be partly explained that the variant carriers might have lower mRNA levels of the protein of the CTLA-4, and then have increased risk of the disease. In future, more studies should be performed in the Chinese population to validate these results.
A total of 999 cases and 702 controls from 7 case–control studies were included for the -318C/T polymorphism. The results suggested that the T allele carriers might be associated with a decreased risk of GD compared with CC homozygote carriers. As for the CT60 polymorphism, 818 cases and 1159 controls from 4 case–control studies were included, and the results also indicated a decrease in the risk of GD. Considering the included case–control studies for both polymorphisms were relatively small, larger number of relevant studies are needed in future to validate these results.
Hitherto, many studies have already been published focusing on the genetic risk factors of the GD among the Chinese population. For instance, Chu reported that a non-synonymous single-nucleotide polymorphism rs40401 (P27S) of the interleukin 3
) gene was associated with increased risk of GD
]; Guo found the rs568408 polymorphism in the interleukin-12
) gene was also associated with increased risk of GD
]. In addition, polymorphisms in the ADRB2
] were also found to be associated with GD in Chinese population. These genes were all suggested as the candidate genes for GD in Chinese population. In future, the associations between these polymorphisms and the GD risk in Chinese population are needed to be validated by more case–control studies.
In the present meta-analysis, sensitivity analysis was performed and stability of the results was guaranteed. Publication bias was assessed by Begg’s funnel plot and Egger’s test
]. No significant publication bias was found for the -318C/T and the CT60 polymorphism analysis, suggesting the results of these two polymorphisms were more reliable. However, we found significant publication bias for the +49A/G polymorphism. The reason might be that some reports were not published, especially for those with negative results. The results might affect the strength of the association, thus, large scale case–control studies are needed to assess the association between the +49A/G polymorphism and GD risk.
We have to mention the heterogeneity. We found significant heterogeneity for the +49A/G polymorphism. Since all participants were Chinese, the genetic background might not be taken as a factor for the heterogeneity for +49A/G polymorphism. However, some other factors, such as gender, age and location might affect the heterogeneity. In addition, we found no heterogeneity for the -318C/T and the CT60 polymorphisms, which suggested that the association for these two polymorphisms are more reliable than the +49A/G polymorphism.
It is reported that GD occurs more frequently but less severe in women than in men. In China, the different condition of disease in men and women might be similar to the situation of the world. In our study, the data was not analyzed by gender because of the lack of original information for these populations. In future, such subgroup studies are also needed to be carried out. Moreover, the cases and controls in this meta-analysis were mostly based on Han nationality, but not in the minorities. In order to get comprehensive results of the Chinese population, studies based on the minorities are also needed.
There are several limitations in this meta-analysis. First, the quantity of enrolled published studies was not very ideal, especially for the -318C/T and CT60 polymorphism. This might cause some potential publication bias, although the results of the above mentioned bias tests was not significant for these two polymorphisms. Second, data were not stratified into subgroups according to some other factors such as age, gender, location and ethnicity (Han or others), due to the lack of information in the original studies. Third, the interactions between genetic factors and environmental factors were not discussed for these three polymorphisms. Fourth, the current meta-analysis only investigated the three most widely studied polymorphisms, and some other polymorphisms with fewer reports were not included. And in future, if there were more case–control studies, new meta-analysis should be conducted. Despite of these limitations, we have minimized the bias through the whole process based on means in study identification, data selection and statistical analysis as well as in the control of publication bias and sensitivity, and got a more reliable result.