TNF基因多态性与长寿人群认知衰老的相关性分析

Association of TNF gene polymorphisms with cognitive aging in longevity populations

摘要

目的：在广西长寿地区探讨肿瘤坏死因子（tumor necrosis factor， TNF）基因多态性与认知衰老的关联性。方法：纳入广西红水河流域和贺州地区年龄大于60岁的壮族老人共1 129例（男575例，女554例），分为长寿老人组（93.56±3.53）岁、长寿老人子女组（68.40±4.81）岁、本地老人对照组（69.30±5.50）岁和外地老人对照组（68.93±5.61）岁，记录受试者的受教育程度、血糖、血脂、C反应蛋白（C-reactive protein，CRP）等指标。利用简易智能状态评定（mini-mental state examination，MMSE）量表对受检人群进行认知水平评估和定义。用SNPscan^TM多重单核苷酸多态性（single nucleotide polymorphism，SNP）分型技术进行 TNF基因分型。应用Haploview4.2软件进行单倍体分析。采用SPSS软件进行方差分析、 t检验或卡方检验和logistic回归分析等统计学方法进行分析。结果：长寿老人子女组的MMSE量表评分[（25.56±3.07）分]优于本地老人对照组和外地老人对照组，其认知功能损害率是11.0%，低于本地老人对照组和外地老人对照组（P＜0.05）。在长寿老人组、长寿老人子女组和本地老人对照组的显性模型中，与 TNF rs1799964 TT基因型携带者比较，rs1799964 TC+CC基因型的个体患认知功能损害风险显著下降（P＜0.05）；与rs1800630 CC基因型携带者比较，rs1800630 CA+AA基因型的个体患认知功能损害风险显著降低（P＜0.05）；在等位基因模型中，携带rs1800630_A的个体认知功能损害发生率低于携带C等位基因的个体（OR值分别为0.341、0.311、0.457， P＜0.05），但在外地老人对照组rs1799964和rs1800630的基因型均与认知功能无相关性。在单倍型分析中发现， TNF C-A-C（rs1799964-rs1800630-rs1799724）单倍型在长寿老人组、长寿老人子女组和本地老人对照组与认知功能损害风险呈负相关关系（OR值分别为0.369、0.313、0.452，均 P＜0.05），而在外地老人对照组中无相关性。结论：在广西红水河流域地区人群中长寿老人直系子女认知功能维持较好， TNF rs1799964_C和rs1800630_A携带者患认知功能损害风险显著下降，是认知衰老的保护性遗传因素。

Abstract

Objective: To explore the association between tumor necrosis factor (TNF) gene polymorphisms and cognitive aging in longevity areas of Guangxi. Methods: A total of 1,129 elderly Zhuang individuals (575 males, 554 females), aged over 60 years, from the Hongshui River Basin and Hezhou region in Guangxi were included. They were divided into the longevous elderly (93.56±3.53 years), offspring of the longevous elderly (68.40±4.81 years), local elderly controls (69.30±5.50 years), and non-local elderly controls (68.93±5.61 years). The participants' educational level, blood glucose, blood lipids, C-reactive protein (CRP) and other indicators were recorded. Cognitive status was assessed and defined by the mini-mental state examination (MMSE) in the study population. Genotyping of the TNF gene was performed using the SNPscan ^TM multiplex single nucleotide polymorphism (SNP) genotyping assay. Haplotype analysis was conducted using Haploview 4.2 software. Statistical analyses were performed using SPSS software, including analysis of variance (ANOVA), t-test, chi-square test, and logistic regression analysis. Results: The offspring of the longevous elderly had significantly higher MMSE scores (25.56±3.07) than the local elderly controls and non-local elderly controls, and exhibited a lower cognitive impairment rate (11.0%) compared with the other two groups (P＜0.05). In the dominant genetic model of the longevous elderly, offspring of the longevous elderly, and local elderly controls, compared with the individuals carrying the TNF rs1799964 TT genotype, the individuals carrying the rs1799964 TC+CC genotype had a significantly reduced risk of cognitive impairment (P＜0.05). Compared with the individuals carrying the rs1800630_CC genotype, the individuals carrying the rs1800630 CA+AA genotype had a significantly lower risk of cognitive impairment (P＜0.05). In the allelic model, the individuals carrying the rs1800630_A allele showed a lower incidence of cognitive impairment than those carrying the C allele (OR=0.341, 0.311 and 0.457, respectively; P＜0.05). However, no association was found between the genotypes of rs1799964 and rs1800630 and cognitive function in the non-local elderly controls. Haplotype analysis revealed that the TNF C-A-C haplotype (rs1799964-rs1800630-rs1799724) was negatively correlated with the risk of cognitive impairment in the longevous elderly, offspring of the longevous elderly, and local elderly controls (OR=0.369, 0.313 and 0.452, respectively; all P＜0.05), whereas no such correlation was observed in the non-local elderly controls. Conclusion: In the population of the Hongshui River Basin in Guangxi, the direct offsprings of longevous individuals maintain relatively good cognitive function. The individuals carrying the TNF rs1799964_C and rs1800630_A alleles have a significantly reduced risk of cognitive impairment, serving as protective genetic factors against cognitive aging.

关键词

广西红水河流域 / 长寿 / 衰老 / 炎症 / TNF基因 / 单核苷酸多态性 / 认知功能损害 / 遗传变异

Key words

Hongshui River Basin in Guangxi / longevity / aging / inflammation / TNF gene / single nucleotide polymorphism / cognitive impairment / genetic variation

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基金资助

国家自然科学基金资助项目(32060188)