TNF, IL12B, and IFNG Gene Polymorphisms in Serbian Patients with Psoriasis

BACKGROUND: Psoriasis is a common chronic inflammatory skin disease with a strong genetic basis. Cytokines such as tumor necrosis factor alpha (TNF-alpha), interleukins (ILs) such are IL-12 and IL-23, and interferon gamma (IFN-gamma) are released from various inflammatory and resident cells, and have been implicated in the initiation/maintenance of inflammation. Certain alleles of the aforementioned cytokines may be associated with disease susceptibility/severity. OBJECTIVE: To investigate the association of three common functional gene polymorphisms, namely TNF -308 G/A (rs1800629), IL12B (encoding the p40 subunit of IL-12/23) +1188 A/C (rs3212227), and IFNG +874 T/A (rs2430561) with psoriasis development and severity in Serbian patients. METHODS: We genotyped 130 patients with psoriasis (26 of whom also had psoriatic arthritis) and 259 controls; rs1800629 and rs3212227, and rs2430561, by real-time PCR assay. RESULTS: The TNF GG genotype was detected at a higher frequency in patients with psoriasis compared to control subjects (OR, 1.420; 95% CI, 0.870~2.403) without statistical significance (p=0.191). Lack of the TNF G allele was associated with lower psoriasis severity (p=0.007). The IL12B AC genotype was underrepresented in the patients with psoriatic arthritis compared to healthy subjects (OR, 0.308; 95% CI, 0.090~1.057; p=0.049). The distribution of the rs2430561 allele and genotype frequencies was similar between patients with psoriasis and controls. CONCLUSION: Our study demonstrates an effect of the rs1800629 on psoriasis severity, and a marginal impact of the rs3212227 on susceptibility to psoriatic arthritis. Collectively, our results obtained in a Serbian cohort expand current knowledge regarding individual predisposition to psoriatic disease.

Association between HLA-DRB1 *01 and HLA-Cw*08 and outcome following HTLV-I infection

Human T cell lymphotropic virus type I [HTLV-I]-associated rnyelopa-thy/tropical spastic paraparesis [HAM/TSP] is an inflammatory disease which occurs in less than 2% of HTLV-I -infected individuals. High proviral load, high HTLV-I-specific CD8[+] cytotoxic T lymphocyte frequency [CTL] and host genetic factors such as HLA all appear to be associated with HTLV-I infection. Previous studies have shown that HLA-DRB1*01 increases the risk of HAM/TSP in Japanese HTLV-1 infected individuals. To investigate the association between HLA class II DRB1 alleles and HLA class I alleles [HLA-Cw*08, B54, A*02 and A-30] in HTLV-I infected individuals in Mashhad. Here we determined the frequency of HLA class II DRBl, using INNO-LIPA reverse hybridization line probe assay, and HLA class I alleles [HLA-Cw*08,B54, A*02 and A-30] by PCR-SSCP method in healthy controls, HAM/TSP patients and HTLV-I infected individuals born and resident in Mashhad. The frequency of HLA-DRB1*01 alleles in this population was different from other areas of Iran. The frequency of HLA-DRB1*01 was significantly increased in HAM/TSP patients compared with carriers [p 0.028; OR=9.4]. The frequency of HLA-Cw*08 was also significantly increased in HAM/TSP patients compared with controls [p=0.03; OR=13.5]. Our results may suggest that possession of HLA-DRB1*01 increases the risk of HAM/TSP in HTLV-I-infected individuals and HLA-Cw*08 correlates with low CTL immune response in HAM/TSP patients

Genetics of diabetic neuropathy: study of VEGF gene

Vascular factors in conjunction with metabolic issues are involved in both etiopathogenesis of diabetic neuropathy [DNU], and more remarkably in [repair] phase, when the net balance between neuroregenerative/degenerative reactions is dictated to some extent by these factors. The ischemic nature of DNU indicates the importance of re-establishment of blood vessels. VEGF, a growth factor which, in addition to its hemodynamic effects, possesses an [angiogenic] capacity has been the subject of extensive investigations in DNU, especially, interventional therapies. The impacts of racial and inherited backgrounds in the development of DNU suggest that the genetic issues partially govern the outcome of diabetic late complications, including DNU. By conducting a candidate gene case-control association study, present study explores the possibility if the inter-individual variations of VEGF gene structure by any means encode the genetic susceptibility/resistance in the course of DNU. The distribution of VEGF gene polymorphisms frequencies were analyzed at positions -7[*]C/T, -1001 [*]G/C, -1154[*]G/A and -2578[*]C/A and were evaluated by ARMS-PCR in 248 type 1 diabetic subjects [81 DNU[+], 167 DNU[-] and 113 healthy controls, all from [British-Caucasian] origin. When the frequency of the polymorphic alleles/genotypes between patients and controls, and also between two subgroups within patients' group with each other [DNU[+] vs. DNU[-]] or with healthy controls were compared, only in one situation a significant difference was evident. The distribution of a VEGF gene polymorphism at promoter region [-7[*]C/T] at allelic [but not at genotypic] level was notably different between diabetics, with and without neuropathy, while the minor allele [T] conferred a protective effect [P=0.03; OR = 1.75]. The present study may imply a prognostic value for VEGF gene polymorphism at promoter region [-7[*]C/T] in DNU. However, it requires further studies to appreciate better the phenotypic impact of this polymorphism in this chronic complication of diabetes. A catalog of candidate genes polymorphisms that functionally reflect a protection/predisposition to DNU can provide the genotypic profile that can be useful to reasonably predict the overall behavior of diabetic subjects to the metabolic derangements relative to development of DNU, which in turn may require adoption of relevant preventive and therapeutic measures

[Candidate gene analysis in diabetic retinopathy: eNOS gene]

Background: due to homeostatic and regulatory potentials of nitric oxide [NO] in vascular physiology, regulatory systems that determine NO bio-synthesis and bioavailability have been the subject of extensive research in molecular medicine. In the field of vascular system pathophysiology, endothelial nitric oxide synthase [eNOS] which is the major producer and regulator of NO in vascular tissues has received the most attention. Impairment of NO bioavailability [NO quenching] is a common feature in poorly controlled diabetics due to increased catabolism and decreased production of NO. Such impairment in severe forms could end to vasodilation breakdown in peripheral tissues [mainly in skeletal muscles] and defective regional blood flow, that in turn disturb insulin-dependent glucose uptake ensuing insulin resistance state

Methods: the phenotypic impact of an eNOS gene polymorphism at position 786*C/T [that its functionality has been revealed already] on genetic propensity to diabetic retinopathy is evaluated in a British-Caucasian population with type 1 diabetes [T1DM]

Results: in contrast to genotypes, there was a significant difference in distribution of allele frequencies between T1DM patients [n= 249] and healthy controls [n= 104] [p= 0/036], that may imply eNOS and/or NO involvement in development of T1DM. Most notably a significant difference also was evident in allele frequency between retinopaths [n= 134] and healthy controls [p= 0/02]. No significant difference was detected when the genotype/allele frequencies were compared between retinopaths [n= 134] and non-retinopaths diabetics [n= 115] [p=NS]

Conclusion: our data is compatible with previous studies which demonstrated that allele C of eNOS 786*C/T polymorphism is associated with increased HbA1c levels. By emphasizing the phenotypic and prognostic value of the abovementioned polymorphism, our data calls for further investigations to find out whether this polymorphism can be employed as a genetic marker in clinical medicine to recognize high-risk diabetics at the time of diabetes onset/diagnosis

[Genetics of type 1 diabetes: study of TNF-alpha gene]

Background: type 1 diabetes [T1DM] is an organ specific auto-immune disease, which is resulted by selective destruction of islet cells. Insulitis as the initial event prior to T1DM development is featured mainly by lymphocytic infiltration, that may recede frequently leading to healthy state [benign insulitis]. Among the issues that govern which of these outcome lie ahead in insulitis are the genetic background of the host and also the immunological circumstances in islets' micro-environment

Methods: as a "case-control association study" the impact of a polymorphism within TNF- gene at position -308*G/A on genetic susceptibility to T1DM is analyzed in a British-Caucasian population [248 cases and 118 healthy controls]

Results: the distribution of genotype/allele frequencies between patients and controls did not reflect significant differences [p= NS]

Conclusion: since the crucial role of TNF- in development of T1DM is well established, our data may confer that the examined polymorphic marker does not have functional effects on TNF- gene expression, influencing the local or systemic level of this pro-inflammatory cytokine. However, in addition to addressing the uncertainties in "genotype-phenoype" correlations in complex diseases [i.e. T1DM], the negative results of our study also may instead draw attention to the potential impacts of post-transcriptional regulatory mechanisms relative to gene structural-based regulatory systems