| Title: | Investigating linear and nonlinear associations of LDL cholesterol with incident chronic kidney disease, atherosclerotic cardiovascular disease and all-cause mortality: A prospective and Mendelian randomization study |
| Journal: | Atherosclerosis |
| Published: | 19 Nov 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/38029611/ |
| DOI: | https://doi.org/10.1016/j.atherosclerosis.2023.117394 |
Publication 8310
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Abstract
BACKGROUND AND AIMS: Observational studies suggest potential nonlinear associations of low-density lipoprotein cholesterol (LDL-C) with cardio-renal diseases and mortality, but the causal nature of these associations is unclear. We aimed to determine the shape of causal relationships of LDL-C with incident chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD) and all-cause mortality, and to evaluate the absolute risk of adverse outcomes contributed by LDL-C itself.</p>
METHODS: Observational analysis and one-sample Mendelian randomization (MR) with linear and nonlinear assumptions were performed using the UK Biobank of >0.3 million participants with no reported prescription of lipid-lowering drugs. Two-sample MR on summary-level data from the Global Lipid Genetics Consortium (N = 296,680) and the CKDGen (N = 625,219) was employed to replicate the relationship for kidney traits. The 10-year probabilities of the outcomes was estimated by integrating the MR and Cox models.</p>
RESULTS: Observationally, participants with low LDL-C were significantly associated with a decreased risk of ASCVD, but an increased risk of CKD and all-cause mortality. Univariable MR showed an inverse total effect of LDL-C on incident CKD (HR [95% CI]:0.84 [0.73-0.96]; p = 0.011), a positive effect on ASCVD (1.41 [1.29-1.53]; p<0.001), and no significant causal effect on all-cause mortality. Multivariable MR, controlling for high-density lipoprotein cholesterol (HDL-C) and triglycerides, identified a positive direct effect on ASCVD (1.32 [1.18-1.47]; p<0.001), but not on CKD and all-cause mortality. These results indicated that genetically predicted low LDL-C had an inverse indirect effect on CKD mediated by HDL-C and triglycerides, which was validated by a two-sample MR analysis using summary-level data from the Global Lipid Genetics Consortium (N = 296,680) and the CKDGen consortium (N = 625,219). Suggestive evidence of a nonlinear causal association between LDL-C and CKD was found. The 10-year probability curve showed that LDL-C concentrations below 3.5 mmol/L were associated with an increased risk of CKD.</p>
CONCLUSIONS: In the general population, lower LDL-C was causally associated with lower risk of ASCVD, but appeared to have a trade-off for an increased risk of CKD, with not much effect on all-cause mortality. LDL-C concentration below 3.5 mmol/L may increase the risk of CKD.</p>
14 Authors
- Zhenqian Wang
- Yang Xiao
- Jiawen Lu
- Chenfeng Zou
- Wenyu Huang
- Jiaying Zhang
- Siyang Liu
- Liyuan Han
- Feng Jiao
- Dechao Tian
- Yawen Jiang
- Xiangjun Du
- Ronald C W Ma
- Guozhi Jiang
1 Application
| Application ID | Title |
|---|---|
| 78619 | Comprehensive investigation into the relationship of genetic and environmental factors with metabolic diseases and cancer |
Enabling scientific discoveries that improve human health