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Research Paper|Volume 13, Issue 22|pp 24655—24674

Identification and replication of novel genetic variants of ABO gene to reduce the incidence of diseases and promote longevity by modulating lipid homeostasis

Xiaolin Ni1,2, Chen Bai3,4, Chao Nie5, Liping Qi6, Yifang Liu7, Huiping Yuan1, Xiaoquan Zhu1, Liang Sun1, Qi Zhou1, Yan Li5, Hefu Zhen5, Huabing Su8, Rongqiao Li8, Rushu Lan8, Guofang Pang8, Yuan Lv8, Wei Zhang8, Fan Yang1,2, Yao Yao3,4, Chen Chen1, Zhaoping Wang1, Danni Gao9, Nan Zhang1, Shenqi Zhang1,2, Li Zhang1,2, Zhu Wu1, Caiyou Hu8, Yi Zeng3,4, Ze Yang1,2
  • 1The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, P.R. China
  • 2Graduate School of Peking Union Medical College, Chinese Academy of Medical Science, Beijing 100730, P.R. China
  • 3Center for the Study of Aging and Human Development and Geriatrics Division, Medical School of Duke University, Durham, NC 27708, USA
  • 4Center for Healthy Aging and Development Studies, National School of Development, Peking University, Beijing 100871, P.R. China
  • 5BGI-Shenzhen, Shenzhen, Guangdong 518083, P.R. China
  • 6College of Science and Technology, Hebei Agricultural University, Cangzhou 061100, Hebei, P.R. China
  • 7Joint Graduate Program of Peking-Tsinghua-NIBS, School of Life Sciences, Tsinghua University, Beijing 100084, P.R. China
  • 8Jiangbin Hospital, Guangxi Zhuang Autonomous Region, Nanning 530021, P.R. China
  • 9Peking University Fifth School of Clinical Medicine, Beijing 100191, P.R. China
Received: June 11, 2021Accepted: September 10, 2021Published: November 22, 2021
https://doi.org/10.18632/aging.203700

Copyright: © 2021 Ni et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.