It has been observed in our results
It has been observed in our results that patients carrying risk allele “a” are at the greater risk of developing psoriasis. Same results have been presented by Coto-Segura et al., 2011, in a study conducted on Spanish population where they reported association of VNTR polymorphism among the patients with psoriasis plaques; they observed that the patients with “aa” and “ab” genotypes are more prone to Psoriasis susceptibility than the patients with “bb” genotype (Coto-Segura et al., 2011). eNOS VNTR polymorphism has been found to be associated with different diseases such as Hypertension, aneurysmal subarachnoid hemorrhage, coronary heart disease, sickle cell disease, type II Diabetes mellitus and psoriasis (Coto-Segura et al., 2011, Jemaa et al., 2009, Staalso et al., 2014). There is also accumulating evidence that hypertension, diabetes, and hypercholesterolemia, ischemic cardiac disease are common associated diseases among Psoriasis patient (Garcia-Diez et al., 2008, Namazi, 2003, Neimann et al., 2006). Actually eNOS enzyme is calcium-dependent and participates in the regulation of blood pressure, platelet aggregation, leukocyte adherence, vascular smooth muscle cell mitogenesis and angiogenesis (Cines et al., 1998). As psoriasis involve hyperproliferative responses including excessive epidermal growth due autoimmunity mediated by T cells, it might be hypothesized that high concentrations of NO and its metabolites contribute as promoters of gene transcription and protein activation thus altering DNA methylation and promoting hyper proliferative responses including inflammation (Xu et al., 2002). However, the exact mechanism of these contributions is unknown. In our study the association with a allele might induce increased NO concentration which aggravate keratinocytes and epidermal proliferation leading to complexity of psoriasis. MTHFR is one of the crucial enzymes involved in metabolism of homocysteine to methionine and hence defect in the activity of it could lead to a defective pathway of DNA methylation. In the current study, three polymorphisms i.e. rs2274976 (G1793A), rs1801133 (C677T) and rs1801131 (A1298C) have been genotyped to study the association of MTHFR in risk of psoriasis. Among these, G1793A has never been studied in relation to pathogenesis of Psoriasis. The results of the current study suggest that genotype AA is frequently present among the patients as compared to healthy controls. Data from the current study demonstrated significant association of G1793A with susceptibility to psoriasis under both the recessive and dominant model. These results explain the role of A allele in conferring risk towards manifestation of psoriasis in cases. The 1793G>A in MTHFR polymorphism results in the change of arginine to glutamine at methoxy 594. This polymorphism has been reported to alter the enzyme activity (Frosst et al., 1995). Although there are very few reports available which mentions the genotyping of G1793A with any of the disease but most of the studies conducted showed negative association of this polymorphism with any of the disease. (Safarinejad et al., 2012) published no association of G1793A with the progression of clear cell renal cell carcinomas and tumor in Iranian population. Here it can be assumed that higher frequency of homozygous AA genotype among cases could be due to aberrant DNA methylation via defective folate metabolism leading towards hyperhomocysteinemia. Generally it is assumed that effects of homocysteine or its derivatives defective metabolism can lead to change in the elevation of oxidative stress, induction of endothelial barrier dysfunction, hypercoagulability, smooth muscle cell proliferation (Upchurch Jr et al., 1997). Furthermore, it can be hypothesized that increased production of oxidized low-density lipoproteins (low-LDL) by homocysteine and the enhanced uptake of ox-LDL by macrophages can be the determinants for the formation of defective cells which can play a critical role in atherosderotic lesions which in turn lead to aberrant stress physiology leading to hyper proliferative responses in epidermal proliferation (Majors et al., 1997). Thus, hyperhomocysteinemia which promotes the atherosclerotic and thrombotic process by modulating vascular cell proliferation and promoting prothrombotic activities in the vascular wall may contribute to the formation of autoimmune mediated cellular proliferation leading to increase susceptibility to psoriasis. In case of C677T, contradictory results were observed, where genotype distribution was found to be marginally associated with psoriasis. Here it has been observed that the association found was actually providing protection against disease susceptibility to psoriasis patients. C677T polymorphism has been studied extensively, where previous studies have shown conflicting results regarding the association of C677T with psoriasis susceptibility (Liew et al., 2012, Vasku et al., 2009), no association was observed among psoriasis patients and controls in a study conducted (Weger et al., 2008). While C677T was found to be conferring greater risk to psoriasis in a study conducted by (Baiqiu et al., 2000). Recently, (Izmirli et al., 2016) reported association of risk allele T with susceptibility to psoriasis in Turkish population. The other polymorphism studied in the present study was A1298C, which was not found to be associated with the disease. Methylation state of any gene is very important so it can be speculated that hypomethylation of MTHFR due to one of these polymorphisms might be able to induce risk to psoriasis. It has already been established that DNA methylation disorders are one of the key factors in development of psoriasis (Ruchusatsawat et al., 2006).