Author:
Wang Yutong,Zhang Li,Zhang Wenqiang,Tang Mingshuang,Cui Huijie,Wu Xueyao,Zhao Xunying,Chen Lin,Yan Peijing,Yang Chao,Xiao Chenghan,Zou Yanqiu,Liu Yunjie,Zhang Ling,Yang Chunxia,Yao Yuqin,Li Jiayuan,Liu Zhenmi,Jiang Xia,Zhang Ben
Abstract
Abstract
Background
This study aims to comprehensively investigate the phenotypic and genetic relationships between four common lipids (high-density lipoprotein cholesterol, HDL-C; low-density lipoprotein cholesterol, LDL-C; total cholesterol, TC; and triglycerides, TG), chronic kidney disease (CKD), and estimated glomerular filtration rate (eGFR).
Methods
We first investigated the observational association of lipids (exposures) with CKD (primary outcome) and eGFR (secondary outcome) using data from UK Biobank. We then explored the genetic relationship using summary statistics from the largest genome-wide association study of four lipids (N = 1,320,016), CKD (Ncase = 41,395, Ncontrol = 439,303), and eGFR(N = 567,460).
Results
There were significant phenotypic associations (HDL-C: hazard ratio (HR) = 0.76, 95%CI = 0.60–0.95; TG: HR = 1.08, 95%CI = 1.02–1.13) and global genetic correlations (HDL-C: $${r}_{g}$$
r
g
= − 0.132, P = 1.00 × 10–4; TG: $${r}_{g}$$
r
g
= 0.176; P = 2.66 × 10–5) between HDL-C, TG, and CKD risk. Partitioning the whole genome into 2353 LD-independent regions, twelve significant regions were observed for four lipids and CKD. The shared genetic basis was largely explained by 29 pleiotropic loci and 36 shared gene-tissue pairs. Mendelian randomization revealed an independent causal relationship of genetically predicted HDL-C (odds ratio = 0.91, 95%CI = 0.85–0.98), but not for LDL-C, TC, or TG, with the risk of CKD. Regarding eGFR, a similar pattern of correlation and pleiotropy was observed.
Conclusions
Our work demonstrates a putative causal role of HDL-C in CKD and a significant biological pleiotropy underlying lipids and CKD in populations of European ancestry. Management of low HDL-C levels could potentially benefit in reducing the long-term risk of CKD.
Graphical Abstract
Funder
the National Key R&D Program of China
the National Natural Science Foundation of China
the Recruitment Program for Young Professionals of China
the Promotion Plan for Basic Medical Sciences and the Development Plan for Cutting-Edge Disciplines, Sichuan University
other Projects from West China School of Public Health and West China Fourth Hospital, Sichuan University
Publisher
Springer Science and Business Media LLC
Subject
General Biochemistry, Genetics and Molecular Biology,General Medicine
Reference62 articles.
1. Wu N, Qin Y, Chen S, Yu C, Xu Y, Zhao J, et al. Association between metabolic syndrome and incident chronic kidney disease among Chinese: a nation-wide cohort study and updated meta-analysis. Diabetes Metab Res Rev. 2021;37(7): e3437.
2. Emanuelsson F, Nordestgaard BG, Tybjaerg-Hansen A, Benn M. Impact of LDL cholesterol on microvascular versus macrovascular disease: a Mendelian randomization study. J Am Coll Cardiol. 2019;74(11):1465–76.
3. Das Pradhan A, Glynn RJ, Fruchart JC, MacFadyen JG, Zaharris ES, Everett BM, et al. Triglyceride lowering with pemafibrate to reduce cardiovascular risk. N Engl J Med. 2022;387(21):1923–34.
4. Group HTRC, Writing C, Sammons E, Hopewell JC, Chen F, Stevens W, et al. Long-term safety and efficacy of anacetrapib in patients with atherosclerotic vascular disease. Eur Heart J. 2022;43(14):1416–24.
5. Martin L, Hutchens M, Hawkins C. Trial watch: clinical trial cycle times continue to increase despite industry efforts. Nat Rev Drug Discov. 2017;16(3):157.