Background/Purpose:  JIA is the most common chronic
arthritis of childhood. Vitamin D is a potential immuno-modulator in many
conditions, including autoimmune diseases. Its influence in JIA is still
unclear. Specific polymorphisms of vitamin D receptor gene (VDR) have
recently been associated with different biologic responses to vitamin D itself.

Methods:  90 Italian children, adolescents and young adults with
poli- or oligoarticular
onset of JIA were studied. VDR polymorphisms were analysed by
PCR-based sequencing (CDX2 in
the promoter region) and PCR-based enzymatic digestions (FokI in exon 2, BsmI and ApaI in
intron 8, and TaqI in exon 9) in the genomic DNA from
blood of patients. 2221 healthy Italian unrelated
individuals have been used as controls for VDR polymorphism frequencies. Distribution
of VDR polymorphisms has been evaluated in patients vs controls, in patients with active and
inactive disease, and in patients with poli– or oligoarticular JIA.

Results:  The distribution of FokI, BsmI, and TaqI polymorphisms
did not show any significant difference between subjects with JIA and controls.
Conversely, significant statistical differences in the distribution of CDX2 and ApaI genotypes
were found, respectively with the CDX2 GG genotype (Yates-corrected
chi-square 6.56; Odds ratio=1.80; p=0.0104)
and the TT ApaI genotype (Yates-corrected chi-square
20.97; Odds ratio=2.67; p=0.0000),
both more frequent in JIA than in controls. Also the G allele of CDX2 (Yates-corrected chi-square 6.12; Odds
ratio=1.60; p=0.0134) and
the T allele of ApaI (Yates-corrected
chi-square 19.69; Odds ratio=2.05; p=0.0000)
was more frequent in JIA. No statistical
differences were found for all the analysed VDR polymorphisms, between the poliarticular vs oligoarticular
forms. No significant association was found between VDR polymorphisms and active or inactive
forms of JIA, neither with osteopenic or normal bone
mineral density status.

Conclusion:  Pathogenetic mechanisms influencing the predisposition to JIA are poorly elucidated and autoimmune dysfunctions are
strongly suspected. This genetic study found a significantly higher frequency
of the GG genotype of VDR CDX2 polymorphism and TT genotype of VDR ApaI polymorphism in patients with JIA. The CDX2polymorphism is located in
the promoter region of the VDR gene and has been associated with VDR mRNA expression, while the ApaI polymorphism has been associated with the stability of VDR mRNA. Therefore, we can speculate that CDX2 GG genotype and ApaI TT genotype can both influence the
expression of the VDR protein, presumably resulting in a reduced receptor
activity with subsequent decreased response to vitamin D and potential immunity
deregulation, favouring the development of JIA. Conversely, VDR polymorphisms seem not to have any
influence for patients’ active or non-active status, both for the oligoarticular and poliarticular
form of the disease.