Unusual effects of PCSK9 E670G (rs505151) variation in patients with in-stent restenosis: Variable effects on restenosis risk according to concomitant chronic conditions.

Recent reports showing that neo-atherosclerosis formation in stented coronary artery is characterized by the accumulation of lipid-laden macrophages within the neointima has strengthened the possibility that elevated low-density lipoprotein (LDL)-cholesterol may be a risk factor for in-stent restenosis (ISR). Protein Convertase Subtilisin/Kexin-9 (PCSK9) protein plays an important role in cholesterol metabolism by degrading of LDL receptors. The gain-of-function E670G (rs505151) mutation of the PCSK9 gene is a well-known genetic risk factor for hypercholesterolemia. This study evaluated for the first time the association of the E670G variation with the serum lipids, PCSK9 levels and concomitant diseases on the ISR risk. The study included 109 ISR, and 82 Non-ISR patients, based on the results of coronary angiography. Genotypes were determined using the real-time PCR and serum PCSK9 levels were measured by ELISA technique. The rare G allele of PCSK9 E670G (p < 0.05), hyperlipidemia (HL) (p < 0.001), and type 2 diabetes (T2DM) (p < 0.01) were associated with increased risk for ISR. In hyperlipidemic conditions, the E670G-G allele was associated with hypercholesterolemia and a higher risk of ISR (p < 0.001), while the E670G-AA genotype has been associated with a high prevalence of T2DM and hypertension. In addition, diabetic ISRs had higher serum PCSK9 levels (p < 0.05) and the E670G-AA genotype was associated with increased levels of diabetes markers. Our results indicated that the unusual effects of both G allele and AA genotype of the PCSK9 E670G variation may be involved in the risk of ISR in association with concomitant metabolic diseases.

This study evaluated the association of the Protein Convertase Subtilisin/Kexin-9 (PCSK9) E670G mutation with the serum lipids, PCSK9 levels and concomitant diseases on the in-stent restenosis (ISR) risk. The E670G-G allele, hyperlipidemia, and type 2 diabetes (T2DM) were found risk factors for ISR. In hyperlipidemic conditions, the E670G-G allele was associated with hypercholesterolemia and a higher risk of ISR, while the E670G-AA genotype has been associated with a high prevalence of T2DM and hypertension. Our results indicated that the unusual effects of both genotypes of the E670G that may be involved in the ISR risk in association with concomitant diseases.

The role of FAS gene variants in inflammatory bowel disease.

BACKGROUND/AIMS: The analysis of genes thought to be important in inflammatory bowel disease (IBD) has shown that more than half of IBD-related genes are also associated with other autoimmune diseases. The aim of this study was to detect a possible association between the polymorphisms of the (-670 A/G, -1377 G/A) fFas cell surface death receptor (FAS) gene promoter and susceptibility to IBD in the Turkish population. MATERIALS AND METHODS: In total, 125 patients with IBD, including 73 ulcerative colitis and 52 Crohn's disease and also 101 healthy controls without any pathological signs of IBD were considered for the study. Real-time polymerase chain reaction technique was used to detect FAS polymorphisms in this study. RESULTS: The analysis of FAS -670 A/G polymorphism indicated that the frequency of GG genotype was significantly increased in patients compared with controls (p<0.001). Additionally, AG genotype (p<0.001) and A allele (p<0.001) frequencies were higher in controls than in patients. The analysis of FAS -1377 G/A polymorphism revealed that the frequency of AA genotype was meaningfully increased in patients compared with controls (p<0.001). Additionally, GG genotype (p<0.001) and G allele (p<0.001) frequencies were increased in controls when compared with patients. CONCLUSION: FAS -670A/G GG genotype seemed to be a protective allele against IBD; however, AA genotype and A allele were associated with elevated risk of IBD. In the FAS -1377G/A polymorphism, frequencies of the G allele and GG genotype were observed to be protective against IBD, whereas AA, GA genotypes, and A allele frequency increased in the patient group.

Irak-4 rs4251481 gene variant: as a risk factor on inflammatory bowel disease

Background/aim: Abnormal immune response occurs in individuals who have alleles associated with innate and adaptive immune mechanisms that predispose to inflammatory bowel disease (IBD). Interleukin-1 receptor-associated kinase 4 (IRAK-4) involved in the pathway produces cytokines that initiate and maintain inflammation through Toll-like receptors and interleukin-1 receptors on the membranes of innate immune cells are stimulated with antigens. It was aimed to investigate whether IRAK-4 rs3794262 and rs4251481 polymorphisms predispose to IBD and the possible effects of these polymorphisms by examining these gene polymorphisms with the clinic and prognostic parameters of IBD. Materials and methods: Real-time PCR technique was used to detect IRAK-4 polymorphisms in 107 patients with IBD and 103 healthy controls. Results: As a result of experimental studies, the frequency of occurrence of rs4251481 polymorphism related AG genotype (P = 0.029) and G allele (P = 0.005) was found to increase statistically in patients compared to controls. In the control group, the rs4251481 AA genotype rate of incidence increased compared with the patient group (P = 0.005). Conclusion: Consequently, this is the first study in terms of both polymorphisms on IBD. These results suggest that rs4251481 AG genotype and G allele are associated with increased IBD risk in patients.

Toll-Like Receptor 2 (TLR-2) Gene Polymorphisms in Type 2 Diabetes Mellitus.

OBJECTIVE: Innate immunity factors are associated with type 2 diabetes (T2DM) and its complications. Therefore, T2DM has been suggested to be an immune-dependent disease. Elevated fasting glucose level and higher concentrations of innate immunity soluble molecules are not only related with insulin resistance, but inflammation is also an important factor in beta cell dysfunction in T2DM. Toll-like receptor 2 (TLR-2), which has an important role in inducing innate immune cells, is thought to have suppressive roles on immune responses in T2DM. We therefore aimed to investigate the possible role of TLR-2 del -196-174 and Arg753Gln variants in T2DM pathogenesis. MATERIALS AND METHODS: This study was designed as a case-control study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used to genotype the two variants in 100 T2DM patients and 98 agematched controls. RESULTS: We found significantly higher frequencies of TLR-2 del -196-174 DD genotype (P=0.003), ID genotype (P=0.009) and D allele (P=0.001) in patients compared with controls. In addition, the II genotype (P=0.001) and the I allele (P=0.003) frequencies were elevated in healthy controls. We did not find any significant differences in frequency distribution for the Arg753Gln variant in study groups. CONCLUSION: We suggest that carrying the D allele of the TLR-2 del -196-174 variant may be related as a risk factor for T2DM.

ROS related enzyme levels and its association to molecular signaling pathway in the development of head and neck cancer.

Given the prevalence and annual incidence of cancer, head and neck cancer is affecting more than 600,000 people each year. In this research, it was decided to investigate that which genes are involved and how MPO, NQO1, SOD2 enzyme levels effective to develop of head and neck cancer and for the first time at the tissue level. 35 tumor tissues in all head and neck anatomy and their surrounding tissue (70 in total) were enclosed the research that received surgery. Determination of the apoptosis genes expression levels (Mtch1, Akt1, Caspase3, Caspase9, Bcl2, Mdm2, mTOR) were determined by RT-PCR techniques and the same patients' sample used for ROS associated oxidant-antioxidant system by using MPO, NQO1, SOD2 enzyme levels using ELISA method. According to statistical results, caspase 9 gene was found statistically high expressed in early stage in contrast to late stage (p=0,013). Level of SOD2, NQO1 and MPO was determined and only MPO level was found significantly important on tumor tissues p=0,008).  Specially, our findings for high expression of Cas9 on early stage were thought to be the target for treatment with its well-known initiator role of the apoptosis. Our results suggest that the higher level of MPO in tumor tissues and indicates that it has some role on pathology of head and neck cancers. We believe that, our research will lead the proposal in-vivo studies and will open new areas on therapeutic targets.