Association of NID2 gene single nucleotide polymorphisms with glioma risk and prognosis in Chinese Han population

Academic Background

Glioma is the most common primary intracranial tumor, characterized by high mortality and poor prognosis. Despite some progress in diagnostic and treatment strategies, conventional therapies have limited improvement on the prognosis of glioma patients. Currently, the specific pathogenesis of glioma remains unclear, but it is closely related to environmental and genetic factors. Ionizing radiation is considered a confirmed environmental risk factor, while genetic polymorphisms, telomere maintenance, genetic syndromes, and familial aggregation are genetic factors associated with glioma susceptibility and prognosis. Although genome-wide association studies (GWAS) have identified loci associated with glioma risk in certain genes, such as TP53, EGFR, CDKN2A/B, and TERT, these studies have mainly focused on European and American populations. Therefore, it is necessary to determine the role of genetic variations associated with glioma development in the Chinese Han population.

NID2 (nidogen-2), as a cell adhesion protein, can bind to collagen I and IV and laminin, participating in many physiological and pathological processes by regulating embryogenesis, cell adhesion and migration, and cancer invasion and metastasis. Previous studies have shown that NID2 is a prognostic biomarker for various cancers (such as colorectal cancer, breast cancer, bladder cancer, and oral squamous cell carcinoma). NID2 has also been validated as a potential brain tumor-related molecule. Due to the limited research on the association between NID2 polymorphisms and glioma risk and prognosis, this study aims to investigate the impact of single nucleotide polymorphisms (SNPs) in the NID2 gene on glioma risk and prognosis in the Chinese Han population.

Research Data Source

This article was co-authored by researchers from Northwest University and Hainan Medical University in China, namely Jie Hao, Congmei Huang, Weiwei Zhao, Lin Zhao, Xiuxia Hu, Wenjie Zhang, Le Guo, Xia Dou, Tianbo Jin, and Mingjun Hu. The study was published in the journal “Neuromolecular Medicine”, included in Volume 26, Page 27 of 2024, submitted on July 24, 2023, and accepted on October 5, 2023.

Research Methods and Process

Study Subjects

This study included 529 glioma patients and 478 healthy controls from the Department of Neurosurgery at Chang’an District Hospital in Xi’an, China. The patients collected from various medical schools were all of Chinese Han ethnicity and were first diagnosed with glioma, of which 409 were diagnosed with astrocytoma. According to the World Health Organization (WHO) classification of central nervous system tumors, most patients received surgery, radiotherapy, or chemotherapy after diagnosis. Socio-demographic information, clinical information, and follow-up data were collected for all subjects. All participants signed written informed consent and were fully informed about the study before participation. The study was approved by the Ethics Committee of Chang’an District Hospital in Xi’an and the experimental procedures complied with the Declaration of Helsinki.

SNP Genotyping

Information on the NID2 gene location on chromosome 14 was obtained from the Ensembl database. Based on the 1000 Genomes Project, dbSNP database, and Vannoportal database scoring principles, 4 SNPs with minor allele frequency (MAF) less than 0.05 and call rate greater than 95% were randomly selected for subsequent studies. Subsequently, sample DNA was extracted using a whole blood genomic DNA isolation kit, and DNA concentration was measured using NanoDrop 2000 (Thermo Fisher Scientific). Genotyping was performed using the high-throughput platform Agena MassARRAY based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), and the detection results were interpreted and organized using Agena Typeranalyzer software. Simultaneously, about 5% of the samples were randomly re-genotyped, and the consistency of repeated genotyping was 100%.

Statistical Analysis

Mann-Whitney U and χ2 tests were used to evaluate differences in clinical characteristics of study subjects. The Plink 1.90 program was used to analyze the association between NID2 variants and glioma risk under different genetic models (allelic, codominant, dominant, recessive, and additive models). Pairwise gene interactions between two loci (SNPs) were detected using binomial logistic regression, and statistical analysis was performed using SPSS 26.0 software. Kaplan-Meier method was used to plot overall survival (OS) and progression-free survival (PFS) curves.

Research Results

Characteristics of Study Subjects

The study subjects were divided into 529 glioma patients (284 males, 245 females) and 478 healthy controls (255 males, 223 females), with mean ages of 40.55 ± 18.10 years and 40.00 ± 13.84 years, respectively. There were no significant differences between the two groups in demographic variables (such as age, gender, smoking status, drinking habits, and BMI). Astrocytoma patients accounted for approximately 77.30% of all glioma patients.

Association between NID2 SNPs and Glioma Risk

The relationship between NID2 polymorphisms and glioma risk was investigated using five genetic models, adjusting for covariates. The results showed that rs11846847 and rs1874569 significantly increased glioma risk under the allelic model. Furthermore, rs1874569 was significantly associated with poorer prognosis in glioma patients, particularly the CC genotype was associated with shorter overall survival and progression-free survival in high-grade glioma patients.

Regression Analysis

Kaplan-Meier survival analysis and Cox proportional hazards regression analysis revealed that rs11846847 significantly increased glioma risk in populations under 40 years of age, while rs1874569 had a significant association with glioma risk in drinking populations. Meanwhile, Gross Total Resection surgery or chemotherapy improved prognosis in Chinese Han glioma patients. This suggests that NID2 variants may be driving factors in tumor progression regulation.

Conclusion and Value

This is the first study to provide evidence of the association between NID2 SNPs and glioma risk and prognosis, indicating that NID2 variants may be potential risk factors for glioma. The study not only fills a theoretical gap in related research on the Chinese Han population but also provides new ideas and methods for future medical testing and treatment strategies, highlighting its scientific and practical value.

Although the study has certain limitations, such as a single sample source and not considering certain high-risk environmental factors, the research results undoubtedly provide valuable data support for further exploring the pathogenesis of glioma. In the future, the sample size will be expanded, and more data information will be supplemented to comprehensively evaluate the relationship between NID2 and glioma risk and prognosis.

The research conducted in this article provides preliminary evidence for the association between NID2 gene SNPs and glioma risk and prognosis in the Chinese Han population, which has important potential application value.