Although a previously reported association of the LCE3C_LCE3B
-del with RA risk did not reach significance in our Dutch cohort, a meta-analysis combining our data and the previously reported Spanish and Chinese data 
confirmed the association of LCE3C_LCE3B
-del with RA.
Our study had a power of over 95% to find an association, although we based this calculation on the previously found OR of 1.45. When we recalculate the power using the OR of the meta-analysis (OR
1.31), the power of our study drops to 73%. A study population of 1256 samples will be needed to reach 80% power. The ORs observed in the Dutch population are in the same direction as seen in the previous studies 
and our meta-analysis showed a statistically significant association of the deletion with RA. This suggests that a larger population is necessary to prove whether the deletion is associated with RA. The contradictory findings from this study and the previous RA studies 
could also be caused by differences in the study population, e.g. disease phenotype or ethnicity. In addition, there is a discrepancy between the allele frequency of the deletion in the controls from Spain (55%) and China (54%) compared to The Netherlands (61%). This heterogeneity of LCE3C_LCE3B
-del allele frequency in control groups from different ethnic backgrounds was already known from previous studies 
. Indeed, a recent meta-analysis confirming an association between LCE3C_LCE3B
-del and psoriatic arthritis showed that the OR of the Spanish population was much higher than observed in an Italian population (1.66 versus 1.23) 
In our meta-analysis we used a recessive model, because this model fitted the LCE
data in the psoriasis study best, based on the Akaike Information Criteria 
which is in line with the two previous studies on LCE3
in patients with RA 
. Although we could not identify an association between the deletion and RA in the Dutch cohort, addition of the data to the other studies resulted in lower p-values than without this dataset, showing a significant contribution of the Dutch population to the overall results. The addition of our Dutch samples leads to a lower OR and a smaller CI than previously reported. The other two studies may have significantly overestimated the magnitude of the odds ratio, the so-called winner's curse 
. Due to publication bias it might be possible that some studies investigating the same subject have not been published, this information will be important to confirm the association between RA and the deletion as shown in this study.
In our subgroup analysis, we observed the strongest association in the RF positive patients. Larger datasets will be necessary to clarify whether the observed association is patient subset specific. In contrast to the results from our meta-analysis, genome-wide CNV analyses using the WTCCC RA dataset did not identify association with the LCE3
. One study only assessed rare CNVs (population frequency <5%) which excludes the LCE3C_LCE3B
. The other study included a probe covering the region that passed QC in their analysis (probe CNVR358.1, chr1:150,822,234–150,856,715 (UCSC genome browser hg18) 
). It might be possible that the region is associated with RA in the WTCCC dataset at lower significance level than their genome-wide significance threshold.
Until now, LCE3C_LCE3B-
del was found to be associated with psoriasis, psoriatic arthritis and RA in several populations 
, whereas no association was found for atopic dermatitis 
. Also in one study an association with systemic lupus erythematosus was found 
, implying that LCE3C_LCE3B
-del may be a common risk factor for (auto)immune diseases. The function of the LCE
genes has only been studied in skin in general 
and in relation to psoriasis 
. From these studies it is known that the LCE proteins are likely to be incorporated in the cornified cell envelope, which is an important structure in the barrier function of skin. When comparing normal and psoriasis skin, the genes of the LCE1, 2, 5
groups are mainly expressed in normal skin, whereas the LCE3
genes are predominantly expressed in psoriasis skin. Moreover, upon barrier disruption of normal skin the LCE1, 2, 5
gene-groups are downregulated, while the expression of the LCE3
genes is upregulated. Altogether, these data imply a role in barrier repair for the LCE3 proteins and a role in barrier maintenance for the other LCEs. As hypothesized by Docampo et al.
, the absence of LCE3B
could compromise barrier function of the epithelia and possibly facilitate the entrance of environmental antigens or pathogens. Since the LCE
genes are mainly expressed in skin and oral epithelia, these would be relevant tissues that could facilitate the entrance of antigens or pathogens, like the Epstein-Barr virus and the cytomegalovirus, thereby triggering RA. We reasoned that if this would be the case patients with LCE3C_LCE3B
-del might be exposed more readily to common antigens and therefore would have an earlier age of onset due to easy access of pathogens/triggers through the skin. However, we did not observe such an association between the genotype and age of RA onset.
Our meta-analysis showed that the LCE3B and LCE3C deletion is associated with RA, though the contribution of our large Dutch sample is small. Therefore it will be necessary to test even larger patient cohorts to shed more light on the possible association of the deletion in specific RA patient subsets. An interesting next step would be to perform functional studies to unravel the mechanisms underlying this association.