Although the multifactorial nature of RA is well known, genetic factors are considered to be strong determinants of these diseases, thus encouraging researchers to search for the responsible genes. PADI4 has been implicated in the pathogenesis, activity and severity of RA [23–24]. Since the first positive association between PADI − 94G/A and RA was reported in a Japanese population [15], a number of studies have reported the association between PADI − 94G/A polymorphisms and RA risk in different populations. Till now, there are several published meta-analyses regarding PADI4 -94G/A polymorphisms and RA risk [25–30]. Of these, two meta-analyses reported that there was significant association between PADI4 -94G/A polymorphism and RA risk both in Asian and European population [26, 28], while two meta-analyses reported that there was significant association only in Asian individuals [27, 29]. However, only one meta-analysis was conducted in a separate ethnic group [30]. Therefore, we performed this meta-analysis to assess the relationship between PADI − 94G/A polymorphism and RA risk in multi ethnic groups respectively.
Our meta-analysis involved 22 studies with 14514 RA cases and 21138 controls. The results showed that a significantly elevated risk of RA was associated with all variants of PADI4 -94G/A in the overall analysis. In the subgroup analyses by ethnicity, significant association was found in China as well as in Japan and USA. Compared with the previous meta-analyses [25–30], the current study involved more research in multi ethnic groups. And the effects of gene-environment interactions with respect to RA risk were also conducted by each separate ethnic group analysis. The sensitivity analysis confirmed the reliability and stability of the meta-analysis. Therefore, the findings from our meta-analysis provide a strong evidence for the association between PADI4 -94G/A polymorphism and RA in the three contries. It also indicated that the relationship between PADI4 -94G/A polymorphism and RA might be susceptible in different ethnicity.
Nevertheless, there are several limitations to this meta-analysis. First, because the papers searched in our study were limited to those openly published, it is possible that some non-published literature that may meet the inclusion criteria were missed. Second, non-English/Chinese articles and databases were not reviewed in our meta-analysis, thus might introduce some bias. Third, due to the relative small sample size of some studies or lack of necessary information, we did not perform further subgroup analyses. Finally, publication bias existed in our analysis, which indicated that other language studies should be included.
In conclusion, this meta-analysis demonstrates that the PADI4 -94G/A polymorphisms may represent a significant risk factor for RA in China, in Japan and USA. Ethnicity seems to play an important role in the genetic association of the disease. Further studies are needed to clarify this finding, since most available studies were conducted among Chinese and Japanese in this meta-analysis.