Abazar  Roustazadeh

OBJECTIVES /BACKGROUND:
Multiple sclerosis (MS) is a chronic debilitating disease with unknown pathogenesis. Recent studies indicated that pathogen recognition receptors such as Toll-like receptor 4 (TLR4) may have a role in pathogenesis of MS. The aim of the study was to evaluate the association of rs1927911 polymorphism in TLR4 gene with MS.

MATERIAL and METHOD:
Four hundred subjects including 200 MS patients and 200 healthy individuals were recruited in the study. Patients were included secondary-progressive (SP), primary-progressive (PP) and relapsing- remitting (RR) subtypes. Polymerase chain reaction-restriction fragment length polymorphism (PCR- RFLP) was performed to identify rs1927911 genotypes in TLR4 gene.

RESULT:
The mean age of healthy and MS group was 34.22 ± 1.3 and 33.2 ± 0.98, respectively. The frequency of TT, TC and CC was 29/52, 132/128 and 39/20 respectively in MS compared to healthy subjects. Genotype and allele distribution were significantly different between the both groups (P<0.05). In addition, TC (OR= 1.849, 95 % CI= 1.105-3.095, P=0.019) and CC (OR= 3.497,95 % CI=1.728-7.076, P=0.001) genotypes had increased the risk of MS.

DISCUSSION:
The main finding of our study was that genotype and allele distribution of rs1927911 polymorphism in the non-coding region of TLR4 had an association with MS. The number of people suffered from MS is increasing worldwide(26). Recent studies indicated that current therapeutic options for MS are disappointing because the exact mechanism of MS is unknown(27). It is believed that the interactions between gene and environment may be one of the most important factors in etiology of MS(26). Toll like receptors have a critical role in innate and acquired immune response. Previous studies suggested that polymorphism within TLR gene could affect signaling pathways related to TLRs and increase the risk of autoimmune diseases(28). Evidences regarding the role of TLR4 in pathogenesis of MS have been collected in some studies. Identification of gene polymorphism within TLR4 could increase our knowledge of MS pathogenesis. Korner group(29) investigated the association of Asp299Gly polymorphism in TLR4 with MS. Their findings showed that there is no association between this polymorphism and MS subtypes and severity of the disease which was in agreement with Reindl findings[30]. However, Korner et.al showed that peripheral blood mononuclear cells (PBMCs) from heterozygote Asp299Gly have a lower proliferation in response to Lipopolysaccharides (LPS) stimulation(29). We searched in PubMed, Google, and dbSNP databases, and found that there are only a few studies regarding the TLR4 polymorphisms and MS. To the best of our knowledge, this is the first study that investigated rs1927911 polymorphism in Iranian MS patients. This polymorphism has been investigated in many other diseases. Zhao group investigated rs1927911 polymorphism in sporadic Parkinson diseases in Han Chinese population(17). They showed that there were no differences in genotype and allele distributions between the groups. However, our findings indicated that rs1927911 heterozygote TC and homozygote CC had a higher distribution between MS patients. Hence, we found that there is an association between rs1927911 genotype and allele distribution with MS in Iranian patients. Frequency of C allele was significantly higher in MS group compared to control group. Cho group(18) surveyed rs1927911 in Koran pediatric patients to dedicate an association with autoimmune thyroid disease. They showed that the frequency of C allele in grave disease is significantly higher than control group which is in agreement with our finding. Davis group(19) investigated rs1927911 in patients suffered from rheumatoid arthritis to study the relation of polymorphism with disease progression. They found an association between rs1927911 genotypes and disease activity. They concluded that this relation is independent of other covariates. We found that TC and CC allele respectively had an odds ratio 1.84 and 3.49. These findings indicated that rs1927911 heterozygote and mutant homozygote genotypes may be risk factors for MS. Some studies indicated that TLR4 knockout models had an aggravating disease which indicated the critical roles of TLR4 in the developing of MS(8). In a systematic review, Moura group(22) investigated the TLR4 and TLR9 polymorphisms including rs1927911 in association with cervical cancer. Their Analysis by bioinformatics tools showed that studied polymorphisms in TLR4 could change intracellular signaling and patterns of proteins in immune cells. They concluded that these polymorphisms could increase the risk of cervical cancers. Gene variations of TLR2, TLR3 and TLR4 have been investigated by Dutta group(23) in Guillain-Barré syndrome (GBS). They showed no increased risk of GBS in relation to TLR4 polymorphism which is in contrast to our findings.