Vitamin D receptor gene variations and their haplotypic association: Possible impact on gastric cancer risk.

Background: Vitamin D receptor (VDR) gene alterations have been associated with the occurrence and prognosis of various types of cancers, but only few studies have focussed on gastric cancer (GC) risk. Objectives: This case-control study was conceived to evaluate possible association of VDR polymorphisms (Fok1, Taq1, and Cdx2) with GC risk. Materials and Methods: A total of 293 subjects, including 143 GC patients and 150 controls were included in this study. The genotypes were elucidated by polymerase chain reaction-restriction fragment length polymorphism followed by DNA sequencing. Results: The frequency of Fok1 genotypes (TC and TT) was found higher in GC cases compared to controls (P ≤ 0.05). In the stratified analysis, we observed a significant association of the (CT + TT) variant with GC risk in males, rural dwellers, smokers, and preobese cases, and those having no family history of Gastrointestinal cancer (P ≤ 0.05). In silico analysis predicted that the Fok1 variant impacts the stability and functional efficiency of the protein. Some exact haplotypes (CCG and CCA) of the VDR gene may act as low penetrance alleles in inclination to GC. Conclusion: VDR Fok1 polymorphism is significantly associated with GC risk in the Kashmiri population. Specific haplotypes in the VDR gene could act synergistically in the development of GC.

Mitochondrial uncoupling protein 2 (UCP2) gene polymorphism - 866 G/A in the promoter region is associated with type 2 diabetes mellitus among Kashmiri population of Northern India.

OBJECTIVE: The study aimed to evaluate the association of UCP2 gene polymorphism - 866 G/A and its expression with diabetes predisposition in the North Indian population. METHODS: The study involved 850 subjects, including 425 each T2DM and control subjects. The serum metabolic and clinical parameters were estimated using standard protocols. The PCR-RFLP based genotyping was performed to determine UCP2 gene polymorphism, while the expression was measured by real-time quantitative PCR. RESULTS: The genotypic and allelic frequencies showed a significant difference in cases compared to controls (p < 0.05). The diabetes patients had a 4.2-fold decrease in UCP2 gene expression. The expression was 29.8 and 8.4 fold lower in diabetes patients with homozygous (AA) and heterozygous (GA) mutation at - 866 locus of UCP2 nucleotide sequence, respectively. When categorized according to age and BMI, the T2DM subjects with age ≥ 50 and BMI ≥ 25 had a 5.53 and 8.2-fold decrease in UCP2 expression, respectively. The diabetes subjects with homozygous and heterozygous mutation demonstrated a pathological increase in serum metabolic and clinical parameters, which corroborated with UCP2 gene expression, indicating a strong association between the two. Intriguingly, we did not find any association between - 866 G/A polymorphism of UCP2 with serum insulin levels. CONCLUSION: Our investigation is the first among the studies conducted in Jammu and Kashmir to work on adipose tissue and UCP2 gene polymorphism. The association of - 866 G/A SNP of the UCP2 gene with its expression in diabetes patients appears to be an important genetic determinant in the progression of T2DM. Moreover, age ≥ 50 years and BMI ≥ 25 could be considered risk factors for developing T2DM in the studied population.

Implication of ARID1A Undercurrents and PDL1, TP53 Overexpression in Advanced Gastric Cancer.

AT-rich interactive domain-containing protein 1A (ARID1A), TP53 and programmed cell death-ligand 1 (PDL1) are involved in several protein interactions that regulate the expression of various cancer-related genes involved in the progression of the cell cycle, cell proliferation, DNA repair, and apoptosis. In addition, gene expression analysis identified some common downstream targets of ARID1A and TP53. It has been established that tumors formed by ARID1A-deficient cancer cells exhibited elevated PDL1 expression. However, the aberrations in these molecules have not been studied in this population especially in Gastric Cancer (GC). In this backdrop we aimed to investigate the role of the ARID1A mutation and expression of ARID1A, TP53 and PDL1 genes in the etiopathogenesis of Gastric Cancer (GC) in the ethnic Kashmiri population (North India). The study included 103 histologically confirmed GC cases. The mutations, if any, in exon-9 of ARID1A gene was analysed by Polymerase Chain Reaction (PCR) followed by Sanger sequencing. The mRNA expression of the ARID1A, TP53 and PDL1 genes was analysed by Quantitative real time-PCR (qRT-PCR). We identified a nonsense mutation (c.3219; C > T) in exon-9 among two GC patients (∼2.0%), which introduces a premature stop codon at protein position 1073. The mRNA expression of the ARID1A, TP53 and PDL1 gene was significantly reduced in 25.3% and elevated in 47.6 and 39.8% of GC cases respectively with a mean fold change of 0.63, 2.93 and 2.43. The data revealed that reduced mRNA expression of ARID1A and elevated mRNA expression of TP53 and PDL1 was significantly associated with the high-grade and advanced stage of cancer. Our study proposes that ARAD1A under-expression and overexpression of TP53 and PDL1 might be crucial for tumor progression with TP53 and PDL1 acting synergistically.

Association of Vitamin D receptor gene variations with Gastric cancer risk in Kashmiri population.

Vitamin D receptor (VDR) mediates cellular processes like cell cycle arrest and apoptosis which effect cancer susceptibility. VDR single nucleotide polymorphisms (SNPs) have a significant influence on functioning of VDR protein and subsequently contribute to the risk of cancer occurrence and progression. The present case-control study was carried out between 2016 and 2020 to investigate the association of VDR BsmI/ApaITaqI SNPs with Gastric Cancer (GC) risk in ethnic Kashmiri population not only for establishing a molecular marker for GC but also to facilitate the outcomes of personalized medicine in future. The polymorphisms of BsmI and ApaI of the VDR gene were evaluated using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism followed by Di-Deoxy Sanger sequencing in 143 GC cases and 150 controls. The mean age (in years) was 53.5 ± 7.92 and 51.2 ± 8.25 and mean Body mass index was 22.68 ± 4.27 kg/m2 and 23.81 ± 3.71 kg/m2 for cases and controls respectively. The mean CEA levels of GC cases was 40.2 ± 10.9 ng/ml. Genotypic distribution of VDR BsmI differed significantly between GC cases and controls (GG vs GA + AA; adjusted P = 0.014) and followed dominant mode of inheritence. Stratification of VDR BsmI revealed that frequency of variant genotype (GA + AA) was significantly higher in Preobese GC cases (P = 0.001), GC patients consuming < 5 cups of salt tea/day (P < 0.0001) and with no family history of gastrointestinal cancer (P = 0.014) compared to healthy controls. ATC haplotype associated with high GC risk. In conclusion, our study suggests that VDR BsmI SNP has a significant association with increased risk of GC especially in preobese population and BsmI/ApaITaqI SNPs significantly decreased the overall survival in GC patients of Kashmiri population.

AT-rich Interaction Domain 1A Gene Variations: Genetic Associations and Susceptibility to Gastric Cancer Risk.

AT-rich interaction domain containing protein 1A (ARID1A), has recently emerged as a novel class of gene which acts as a potent tumor suppressor in numerous types of cancers such as Gastric, Breast, Ovarian, Colorectal, Lung cancers. ARID1A is involved in the regulation of various cellular processes such as proliferation, differentiation and DNA repair, yet its association with the susceptibility of cancer remains unknown. Here, we aimed to analyse the association of the ARID1A variants (Pro912Thr, Gln944Lys and Gln920Ter) with the risk of Gastric cancer (GC) in Kashmiri population. The study included 103 confirmed cases of GC and 163 normal controls. The genotypes were studied using Polymerase Chain Reaction. Different bioinformatic predictive tools were also used to analyse the possible effect of these SNP's on the resultant protein. The Pro912Thr and Gln920Ter variants of ARID1A showed significant difference in genotypic and allelic frequencies between the GC cases and controls (P < 0.05), whereas, the data did not reveal any correlation between Gln944Lys variant and Gastric cancer risk. Both Pro912Thr and Gln920Ter SNP's follow "Dominant mode of inheritance". In Silico analysis predicted that amino acid substitution of Pro912Thr SNP decreases the protein stability thus changing the functional properties of resultant protein, so backing the possibility of damaging effect of this SNP. Our study suggests that Pro912Thr and Gln920Ter SNP's of ARD1A gene are associated with increased risk of GC in Kashmiri population.