Abstract
Genes related to human longevity have not been studied so far, and need to be investigated thoroughly. This study aims to explore the relationship among ABO gene variants, lipid levels, and longevity phenotype in individuals (≥90yrs old) without adverse outcomes. A genotype-phenotype study was performed based on 5803 longevity subjects and 7026 younger controls from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Four ABO gene variants associated with healthy longevity (rs8176719 C, rs687621 G, rs643434 A, and rs505922 C) were identified and replicated in the CLHLS GWAS data analysis and found significantly higher in longevity individuals than controls. The Bonferroni adjusted p-value and OR range were 0.013-0.020 and 1.126-1.151, respectively. According to the results of linkage disequilibrium (LD) analysis, the above four variants formed a block on the ABO gene (D’=1, r2range = 0.585-0.995). The carriers with genotypes rs687621 GG, rs643434 AX, or rs505922 CX (prange = 2.728 x 10-107-5.940 x 10-14; ORrange = 1.004-4.354) and haplotype CGAC/XGXX (p = 2.557 x 10-27; OR = 2.255) had a substantial connection with longevity, according to the results of genetic model analysis. Following the genotype and metabolic phenotype analysis, it has been shown that the longevity individuals with rs687621 GG, rs643434 AX, and rs505922 CX had a positive association with HDL-c, LDL-c, TC, TG (prange = 2.200 x 10-5-0.036, ORrange = 1.546-1.709), and BMI normal level (prange = 2.690 x 10-4-0.026, ORrange = 1.530-1.997). Finally, two pathways involving vWF/ADAMTS13 and the inflammatory markers (sE-selectin/ICAM1) that co-regulated lipid levels by glycosylation and effects on each other were speculated. In conclusion, the association between the identified longevity-associated ABO variants and better health lipid profile was elucidated, thus the findings can help in maintaining normal lipid metabolic phenotypes in the longevity population.
Highlights
A healthy life span is a complex phenotype that is influenced by both genetic and environmental factors
The raw data was collected from genome-wide association studies (GWAS) phases I and II, and data quality control procedures were followed for the sample screening
We identified and replicated four SNPs in the ABO gene that were associated with healthy aging and longevity, including rs8176719, rs687621, rs643434, and rs505922, and three of these variants have never been identified in previous studies on longevity
Summary
A healthy life span is a complex phenotype that is influenced by both genetic and environmental factors. Many reported studies have revealed that individuals with a life span of ≥ 90 years had several healthy genetic variants, indicating the importance of genetic contribution to a longer life span. Some of these variants were found to be associated with plasma lipid homeostasis that could delay the onset or prevent diseases and promote a longer life span [4]. Previous studies have identified a few loci associated with longevity involving lipid metabolisms, such as APOE Ɛ2, TOMM40 rs2075650, FOXO3A rs2802292, CETP rs5882, HLA-DQB1 rs1049107, and rs1049100 in individuals with an exceptionally long life span [10,11,12,13]
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