Nadda Neeti, Yadav Renu, Roy Neelanjana, Singh Nita, Kumar Sonu, Paul Shashi Bala, Gamanagatti Shivanand, Saraya Anoop, Nayak Baibaswata
Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India.
Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India.
Front Immunol. 2024 Dec 5;15:1459749. doi: 10.3389/fimmu.2024.1459749. eCollection 2024.
Human leukocyte antigen-G (HLA-G) is a cancer-associated immune checkpoint protein implicated in tumor-driven immune escape mechanisms. This study was undertaken to determine genetic variations at the 3'-UTR of the HLA-G gene that may alter its expression, identify risk alleles and genotypes for their association with hepatocellular carcinoma (HCC), and treatment responses in the Indian population.
Case-control genetic association study of HLA-G gene UTR polymorphisms with HCC and response to locoregional therapy (LRT).
HCC cases (n = 100) and healthy controls (n = 110) were recruited for the genetic association study, of which 88 patients received LRT. Single nucleotide polymorphisms (SNPs) at the HLA-G 3'-UTR gene were genotyped by sequencing and PCR-RFLP. The genetic association of 14 SNPs with HCC and LRT responses was determined using population genetic approaches.
Three of the 14 SNPs (rs1707, rs1710, and rs1063320) were found to be genetically associated with HCC risk and treatment responses. These three UTR SNPs are important for miRNA binding. We did not observe significant association of the most studied SNP, rs371194629 (INDEL, +2960), with HCC or treatment response. Serum sHLA-G levels were found to be significantly (p = 0.027) higher in HCC patients as compared to healthy controls. Highly prevalent UTR haplotypes in Indian HCC patients were UTR-4, -1, and -7 whereas in healthy controls it was UTR-3, and 15 as determined by a linkage disequilibrium (LD) plot using 8 SNPs.
HLA-G SNPs are genetically associated with HCC and treatment response. Haplotypes associated with high levels of HLA-G expression are more prevalent in HCC than in healthy controls.
Population genetic approaches were used to study HLA-G gene polymorphisms in the Indian population for its genetic association with HCC risk, treatment response and altered gene expression. Out of the 14 SNPs studied for HLA-G UTR, three were linked to HCC and response to locoregional therapy. Linkage disequilibrium and UTR haplotyping analysis show that the UTR-4 haplotype linked to high HLA-G levels, is more common in HCC patients, while the UTR-3 haplotype, linked to low HLA-G levels, is more common in healthy controls. This study is the first to look at the UTR types based on HLA-G gene polymorphisms of Indian HCC patients and their response to therapy.
人类白细胞抗原-G（HLA-G）是一种与癌症相关的免疫检查点蛋白，参与肿瘤驱动的免疫逃逸机制。本研究旨在确定HLA-G基因3'-UTR的遗传变异，这些变异可能改变其表达，识别与肝细胞癌（HCC）及其在印度人群中的治疗反应相关的风险等位基因和基因型。
对HLA-G基因UTR多态性与HCC及局部区域治疗（LRT）反应进行病例对照遗传关联研究。
招募100例HCC患者和110例健康对照进行遗传关联研究，其中88例患者接受了LRT。通过测序和PCR-RFLP对HLA-G 3'-UTR基因的单核苷酸多态性（SNP）进行基因分型。使用群体遗传学方法确定14个SNP与HCC和LRT反应的遗传关联。
14个SNP中的3个（rs1707、rs1710和rs1063320）被发现与HCC风险和治疗反应存在遗传关联。这3个UTR SNP对miRNA结合很重要。我们未观察到研究最多的SNP rs371194629（插入缺失，+2960）与HCC或治疗反应有显著关联。与健康对照相比，HCC患者血清sHLA-G水平显著升高（p = 0.027）。通过使用8个SNP的连锁不平衡（LD）图确定，印度HCC患者中高度流行的UTR单倍型是UTR-4、-1和-7，而在健康对照中是UTR-3和-15。
HLA-G SNP与HCC及治疗反应存在遗传关联。与高水平HLA-G表达相关的单倍型在HCC中比在健康对照中更普遍。
采用群体遗传学方法研究印度人群中HLA-G基因多态性与HCC风险及治疗反应和基因表达改变的遗传关联。在研究的14个HLA-G UTR SNP中，3个与HCC及局部区域治疗反应相关。连锁不平衡和UTR单倍型分析表明，与高HLA-G水平相关的UTR-4单倍型在HCC患者中更常见，而与低HLA-G水平相关的UTR-3单倍型在健康对照中更常见。本研究首次基于印度HCC患者的HLA-G基因多态性及其治疗反应研究UTR类型。
