Polymorphisms in the CD28/CTLA4/ICOS genes: Role in malignant melanoma susceptibility and prognosis?

The appearance of vitiligo and spontaneous regression of the primary lesion in melanoma patients illustrate a relationship between tumor immunity and autoimmunity. T lymphocytes play a major role both in tumor immunity and autoimmunity. CD28, Cytotoxic T lymphocyte antigen 4 (CTLA4) and inducible costimulator (ICOS) molecules are important secondary signal molecules in the T lymphocyte activation. Single nucleotide polymorphisms (SNPs) in the CD28/CTLA4/ICOS gene region were reported to be associated with several autoimmune diseases including, type-1 diabetes, SLE, autoimmune thyroid diseases and celiac disease. In this study, we investigated the association of SNPs in the CD28, CTLA4 and ICOS genes with the risk of melanoma. We also assessed the prognostic effect of the different polymorphisms in melanoma patients. Twenty-four tagging SNPs across the three genes and four additional SNPs were genotyped in a cohort of 763 German melanoma patients and 734 healthy German controls. Influence on prognosis was determined in 587 melanoma cases belonging to stage I or II of the disease. In general, no differences in genotype or allele frequencies were detected between melanoma patients and controls. However, the variant alleles for two polymorphisms in the CD28 gene were differentially distributed in cases and controls. Similarly no association of any polymorphism with prognosis, except for the rs3181098 polymorphism in the CD28 gene, was observed. In addition, individuals with AA genotype for rs11571323 polymorphism in the ICOS gene showed reduced overall survival. However, keeping in view the correction for multiple hypothesis testing our results suggest that the polymorphisms in the CD28, CTLA4 and ICOS genes at least do not modulate risk of melanoma and nor do those influence the disease prognosis in the investigated population

Association between the Cytotoxic T-Lymphocyte Antigen 4 +49G > A polymorphism and cancer risk: a meta-analysis

<p>Abstract</p> <p>Background</p> <p>As a key gene in the immunosurveillance of cell malignancy, Cytotoxic T-lymphocyte antigen 4 (CTLA-4 is an important negative regulator of T cell activation and proliferation. The CTLA-4 +49G > A polymorphism is one of the most commonly studied polymorphisms in this gene due to its association with cancer risks, but previous results have been conflicting.</p> <p>Methods</p> <p>We preformed a meta-analysis using 22 eligible case-control studies (including 32 datasets) with a total of 11,273 patients and 13,179 controls to summarize the existing data on the association between the <it>CTLA-4 </it>+49G > A polymorphism and cancer risk.</p> <p>Results</p> <p>Compared with the common <it>CTLA-4 </it>+49G > A GG genotype, the carriers of variant genotypes (<it>CTLA-4 </it>+49 GC/CC) had a 1.24-fold elevated risk of cancer (95% CI = 1.18-1.32, <it>P </it>< 0.05) under the dominant genetic model, as estimated using a fixed effect model. The effect of the <it>CTLA-4 </it>+49G > A polymorphism was further evaluated using stratification analysis. In four breast cancer studies, patients with the variant genotypes had a significantly increased risk of breast cancer (OR = 1.31, 95% CI = 1.17-1.48, <it>P </it>< 0.00001). A similar result was found in three skin cancer studies (OR = 1.30, 95% CI = 1.10-1.52, <it>P </it>= 0.001). In 26 solid tumor studies, subjects with the variant genotypes had a significantly higher risk of developing solid tumors (OR = 1.25, 95% CI = 1.18-1.33, <it>P </it>< 0.00001) compared with the 6 non-solid tumor studies (OR = 1.08, 95% CI = 0.79-1.48, <it>P </it>= 0.62). Patients with variant genotypes had significantly increased risk of non-epithelial tumors and epithelial tumors, with ORs of 1.23 (95% CI = 1.14-1.32, <it>P </it>< 0.00001) and 1.29 (95% CI = 1.17-1.41, <it>P </it>< 0.00001), respectively. It was also demonstrated that the increased risk of cancer associated with <it>CTLA-4 </it>+49G > A variant genotypes was more pronounced in Caucasians (OR = 1.29, 95% CI = 1.13-1.47, <it>P </it>= 0.0002), Asians (OR = 1.23, 95% CI = 1.16-1.32, <it>P </it>< 0.00001) and Chinese (OR = 1.23, 95% CI = 1.15-1.31, <it>P </it>< 0.00001).</p> <p>Conclusion</p> <p>Our meta-analysis suggests that the <it>CTLA-4 </it>+49G > A polymorphism genotypes (GA + AA) might be associated with an increased risk of cancer, especially in Caucasians and Chinese.</p

Vitamin D pathway-related gene polymorphisms and their association with metabolic diseases: a literature review

Purpose: Given that the relationship between vitamin D status and metabolic diseases such as obesity and type 2 diabetes (T2D) remains unclear, this review will focus on the genetic associations, which are less prone to confounding, between vitamin D-related single nucleotide polymorphisms (SNPs) and metabolic diseases. Methods: A literature search of relevant articles was performed on PubMed up to December 2019. Those articles that had examined the association of vitamin D-related SNPs with obesity and/or T2D were included. Two reviewers independently evaluated the eligibility for the inclusion criteria and extracted the data. In total, 73 articles were included in this review. Results: There is a lack of research focussing on the association of vitamin D synthesis-related genes with obesity and T2D; however, the limited available research, although inconsistent, is suggestive of a protective effect on T2D risk. While there are several studies that investigated the vitamin D metabolism-related SNPs, the research focussing on vitamin D activation, catabolism and transport genes is limited. Studies on CYP27B1, CYP24A1 and GC genes demonstrated a lack of association with obesity and T2D in Europeans; however, significant associations with T2D were found in South Asians. VDR gene SNPs have been extensively researched; in particular, the focus has been mainly on BsmI (rs1544410), TaqI (rs731236), ApaI (rs7975232) and FokI (rs2228570) SNPs. Even though the association between VDR SNPs and metabolic diseases remain inconsistent, some positive associations showing potential effects on obesity and T2D in specific ethnic groups were identified. Conclusion: Overall, this literature review suggests that ethnic-specific genetic associations are involved. Further research utilizing large studies is necessary to better understand these ethnic-specific genetic associations between vitamin D deficiency and metabolic diseases

Investigation of CTLA-4 and CD28 Gene Polymorphisms in Patients with Diabetes Mellitus Type 2 Using PCR-RFLP in a Turkish Population

Objective: The aim of this study is to investigate whether specific polymorphisms in the CTLA-4 and CD28 gene are associated with Type 2 diabetes mellitus (T2DM). Methods: Blood samples were collected from 241 individuals (72 patients with T2DM and 169 healthy individuals) and DNA was isolated. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to detect the frequencies of CTLA-4 NM_005214.3:c.49A > G and c.-319C > T, and CD28 NM_006139.1:c.534+17T > C polymorphisms in T2DM patients in the Sanliurfa Population. Results: The data suggested that body mass index (BMI), total cholesterol (TC), triglyceride (TG), lowdensity lipoprotein cholesterol (LDL-c) and haemoglobin A1c (HbA1c) were significantly higher in T2DM patients than in the control individuals (p G, c.-319C > T genotype and allele of CTLA-4 gene and c.534+17T > C of the CD28 gene in T2DM patients compared to healthy individuals (p > 0.05). Conclusion: The CTLA-4 gene c.49A >G and c.-319C >T and CD28 gene c.534+17T > C polymorphisms did not represent an important risk factor for this disease in a group of the Turkish population. Keywords: CD28, CTLA-4, T2DM, polymorphism "Investigación de Polimorfismos en los Genes CTLA-4 y CD28 en Pacientes con Diabetes Mellitus Tipo 2 Usando PCR-RFLP en una Población Turca" RESUMEN Objetivo: El objetivo de este estudio es investigar si los polimorfismos específicos en los genes CTLA-4 y CD28 se hallan asociados con la diabetes mellitus tipo 2 (DMT2). Métodos: Se recogieron muestras de sangre de 241 individuos (72 pacientes con DMT2 y 169 individuos sanos) y se aisló el ADN. Se usó un método de polimorfismo de la longitud de los fragmentos de restricción-reacción en cadena por la polimerasa (PCR-RFLP), con el fin de detectar las frecuencias de CTLA-4 NM_005214.3:c.49A > G y c. 319C > T, y los polimorfismos CD28 NM_006139.1:c.534 + 17T > C en pacientes con DMT2 en la población de Sanliurfa. Resultados: Los datos sugirieron que el índice de masa corporal (IMC), el colesterol total (CT), el triglicérido (TG), el colesterol de lipoproteína de baja densidad (CLBD) y la hemoglobina A1c (HbA1c) eran significativamente más altas en los pacientes con DMT2 que en los individuos del grupo control (p G, c. -319C > el genotipo de T y el alelo del gene CTLA-4 y c.534+17T > C del gene de CD28 en pacientes con DMT2 comparados a los individuos sanos (p > 0.05). Conclusión: Los polimorfismos del gene CTLA-4 c.49A > G y el gene de c. -319C > T, y los polimorfismos del gene CD28 c.534 + 17T > C no representaron un factor de riesgo importante para esta enfermedad en un grupo de la población turca. Palabras claves: CD28, CTLA-4, DMT2, polimorfism

Determination of ApaI and TaqI Polymorphisms of VDR Gene in a Group of Turkish Patients with Colorectal Cancer

Colorectal cancer (CRC) is the leading cause of cancer death among human around the world. The vitamin D receptor gene (VDR) is a member of the nuclear receptor super family, which is expressed in the tissue of gastrointestinal tract, known to modulate the rate of cell proliferation. We aimed to investigate the genotype and allele frequencies and association of the VDR gene: c.1025-49G>T (ApaIG>T) and c.1056T>C (TaqIT>C) polymorphisms with CRC in Turkish patients. Fifty-six patients with CRC and 169 healthy individuals were enrolled to study, and their DNA was isolated. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used to detect the frequency of c.1025-49G>T and c.1056T>C polymorphisms. The prevalence of the c.1025-49G>T and c.1056T>C alleles and the genotype frequencies in patients with CRC was similar to that in the normal population. The investigated polymorphisms in the VDR gene do not represent I significant risk factor for CRC in our populatio

Investigation of CTLA-4 and CD28 Gene Polymorphisms in Patients with Diabetes Mellitus Type 2 Using PCR-RFLP in a Turkish Population

Objective: The aim of this study is to investigate whether specific polymorphisms in the CTLA-4 and CD28 gene are associated with Type 2 diabetes mellitus (T2DM). Methods: Blood samples were collected from 241 individuals (72 patients with T2DM and 169 healthy individuals) and DNA was isolated. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to detect the frequencies of CTLA-4 NM_005214.3:c.49A > G and c.-319C > T, and CD28 NM_006139.1:c.534+ 17T > C polymorphisms in T2DM patients in the Sanliurfa Population. Results: The data suggested that body mass index (BMI), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-c) and haemoglobin A1c (HbA1c) were significantly higher in T2DM patients than in the control individuals (p G, c.-319C > T genotype and allele of CTLA-4 gene and c.534+ 17T > C of the CD28 gene in T2DM patients compared to healthy individuals (p > 0.05). Conclusion: The CTLA-4 gene c.49A > G and c.-319C > T and CD28 gene c.534+ 17T > C polymorphisms did not represent an important risk factor for this disease in a group of the Turkish populatio