The scope of this study was to study the association of STAT4 (rs7582694) gene polymorphism with two autoimmune diseases, e.g., multiple sclerosis (MS) and juvenile onset systemic lupus erythematosus patients (JO-SLE) and its relation to disease severity.
The STAT 4 CC genotype and GC genotype frequencies were significantly more detected in MS patients than in controls (p = 0.01 and 0.05 respectively). The frequency of the STAT4 C allele was significantly higher in patients with MS than in controls (p = 0.01). There were no significant difference between clinical parameters of MS patients and genotypic pattern. Meanwhile, no significant difference was detected in Kurtzke’s Expanded Disability Status Scale (EDSS) comparing different STATE 4 genotypes (p = 0.07).
The present findings met with the findings of another study conducted on MS patients that demonstrated that IL-17 F CT genotype and C allele may be associated with a susceptibility to MS in Egyptian population by a gender-dependent mechanism that contributes to unique predisposition in females. So, this rs763780 can be considered a risk factor for the development of MS in the Egyptian population (Atya et al. 2017).
In contrary, Liang et al. (2012) demonstrated no association between the STAT4 rs7574 865T allele and MS. Since the subgroup of analysis for multiple sclerosis in their study included no more than five studies for the meta-analysis, they could not draw funnel plots for each of them. This may not have enough power to explore the association between the STAT4 rs7574865 single-nucleotide polymorphism (SNP) and MS.
The STAT 4 CC genotype and GC genotype frequencies were significantly more detected in JO-SLE patients than in controls (p = 0.001 and 0.01 respectively). The frequency of the STAT4 C allele was significantly higher in patients with JO-JSLE than in controls (p = 0.001). That met with findings of another study (Taylor et al. 2011); they found that the SNP rs7574865 of STAT4 resulted in being associated with younger age at diagnosis (OR = 1.22). Also, Liang et al. (2012) demonstrated a statistically significant contribution of STAT4 to juvenile SLE incidence in the mainland Chinese female population. The frequency of the same genetic variant resulted in being slightly higher in SLE Japanese patients with an age of onset lower than 20 years as compared with patients with age ≥ 20 years (El-Saadany et al. 2016). Another study (Zhou et al. 2014) demonstrated a statistically significant contribution of STAT4 to juvenile idiopathic arthritis.
In addition, Hammad et al. (2017) found that rs2004640 T allele and TT genotype and GTA haplotype of rs 10954213, rs2004640, and rs2280714, respectively, can be considered as risk factors for the development of SLE in Egyptian children. The presence of the rs2004640 T allele increases the risk of development of nephritis in Egyptian children with SLE.
On the other hand, Raafat et al. (2015) found that STAT4 polymorphism was not associated with an increased risk of SLE in Egyptian females; this may be attributed to the difference in the method of genotyping that was performed by the real-time PCR allelic discrimination technique in the previous study.
In the present study, comparing both CC and GC patients versus GG in JO-SLE patients showed that patient’s malar rash, photosensitivity, and hair falling were significantly more detected in the CC subtype. Also, comparing both CC versus GC showed that patient’s malar rash, photosensitivity, and hair falling were significantly more detected in the CC subtype. Other studies reported the significant association between the SNP rs7574865 of STAT4 genotypes and the presence of photosensitivity (Taylor et al. 2008).
Increased 24-h protein in urine (mg/24 h) and ANA positivity, Anti ds-DNA, anti Sm antibodies’ detection and decreased C3 and C4 levels showed a significantly difference in CC patients of the present study. Meanwhile, only increased 24-h protein in urine (mg/24 h) and ANA positivity were significantly more detected in GC patients.
Other studies determined the strong association between STAT4 rs7574865 polymorphism and with severity of SLE. Piotrowski et al. (2012) found that SNP was significantly associated with more badly renal symptoms in SLE. Also, Taylor et al. (2011) agreed that for SLE patients, C allele in rs7574865 correlated with proteinuria, C3 and C4 levels, and anti-dsDNA positivity. On the other hand, El-Saadany et al. (2016) found that the C allele or CC homozygous is a significant risk genetic molecular marker to predict SLE susceptibility but they found no association for lupus nephritis. Possible explanations for these findings might be the difference in ethnic groups.
The present study showed that JO-SLE patients with a CC homozygous had higher SLEAI and damage index than with other genotypes. This is in accordance with Raafat et al. (2015) and Taylor et al. (2011)) Interestingly, Bolin et al. (2013) reported the significant association of STAT4 CC polymorphism with severe renal insufficiency in lupus nephritis.