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  • br Discussion The etiology of autoimmune diseases

    2020-05-14


    Discussion The etiology of autoimmune diseases including psoriasis is intricate and a composite of environmental and biological factors. There are very limited studies available that report the association analysis of ACE I/D polymorphism with psoriasis risk. In the current study we report on association of ACE I/D polymorphism among Pakistani population. Previous studies done on different population showed the presence of I allele responsible to increase the susceptibility to psoriasis in Turkish, Austrian and Chinese Taiwanese population (Chang et al., 2007, Ozkur et al., 2004, Weger et al., 2007, Yang et al., 2014). In contradiction to their findings, the data in the current study suggest a significant association of the D allele in increasing the risk to the susceptibility to Psoriasis in our subjects. Although some of the studies do not support the hypothesis presented in the current study such as (Al-Awadhi et al., 2007) who reported no correlation between psoriasis arthritis patients and ACE I/D polymorphism in the Kuwaiti population. Similarly no association was detected in the risk of psoriasis and ACE I/D polymorphism in the Spanish population (Coto-Segura et al., 2009). ACE is the key regulator of Kinin-kallikrein system as well as the rennin angiotensin system. Involvement of ACE in both systems provides evidence for its role in producing the pro-inflammatory responses. ACE is expressed in multiple tissues such as the immune cells, vascular endothelium and skin (Smallridge et al., 1986). ACE plays a role in conversion of angiotensin I into angiotensin II, furthermore it has been observed that it plays a catalytic role in the conversion of bradykinin to kinin which is a degradation product of the angiotensin-renin system. While Angiotensin II is an intricate pro-inflammatory regulator, which carries the capability to enhance and sustain immune responses in many autoimmune diseases (Nataraj et al., 1999). In the current study homozygosity for the ACE I allele did not reveal any difference among patients and controls. While, interestingly homozygous D AM095 mg was significantly different among cases and controls, the odds ratio 1.93 revealed D allele to increase the risk of development of psoriasis in the patients. As, it has been reported previously that elevated frequency of II genotype can reduce the inactivation of bradykinin (Murphey et al., 2000). ACE is involved in the degradation of an intricate neuropeptide known as SP, a member of tacykinin family; it increases the vasodilation and vascular permeability. This in turns upregulates the expression of intercellular adhesion molecule-1 (ICAM-1) on human dermal microvascular endothelial cells and AM095 mg stimulates the proliferation of human T lymphocytes, which enhances the expression of pro inflammatory cytokines (Kanda and Watanabe, 2002, Maggi, 1997, Quinlan et al., 1998). These phenomena contribute to the development of psoriatic lesions (Nickoloff and Nestle, 2004). (Chang et al., 2007) have demonstrated in their study that homozygotes for D had the highest levels of serum ACE, which can lead to its enhanced activity i.e. degradation of the bradykinin and SP, resulting in increase of the inflammatory responses. Hence, results of the current study seem to indicate that both the homozygotes and heterozygotes for the D allele could have elevated serum activity of ACE and thus they have interrupt the inflammatory activities, which can lead to the manifestation of the psoriasis in patients. The gene encoding eNOS is located on chromosome 7q35–36. The eNOS 4a/b polymorphism of the 27-bp VNTR in intron 4 has 2 common alleles: 4a with 4 repeats (GAAGTCTAGACCTGCTGC (A/G)GGGGTGAG) and 4b with 5 repeats (Thameem et al., 2008). VNTR 4a/b polymorphism role needs further elucidation; it is suggested to regulate the expression of eNOS by the formation of small RNAs (sirRNAs). Endothelial cells containing five copies present higher quantities of sirRNA and lower levels of mRNA of eNOS, when compared with cells that contain four copies (Silva et al., 2011). NO participates in neurotransmission, endothelial vasodilatation, immunity and carcinogenesis. It is synthesized by NOS enzyme family: endothelial NOS (eNOS), neuronal NOS (nNOS) and inducible NOS (iNOS) (Ramirez-Patino et al., 2013). Furthermore, it also maintains the basal vascular tone as well as involve in many other processes such as neurotransmission, vasodilatation, keratinocyte proliferation and apoptosis (Yang et al., 2015). NO is also believed to be involved in stress physiology and stress-related disease processes. Stress has been considered to be a major contributor towards the autoimmune diseases, it also works in producing inflammation and infection via NO pathway (Esch et al., 2002).