| Title: | Genetically-predicted life-long lowering of low-density lipoprotein cholesterol is associated with decreased frailty: A Mendelian randomization study in UK biobank |
| Journal: | EBioMedicine |
| Published: | 9 Jul 2019 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/31300347/ |
| DOI: | https://doi.org/10.1016/j.ebiom.2019.07.007 |
| URL: | http://www.thelancet.com/article/S2352396419304426/pdf |
Publication 4985
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
Abstract
BACKGROUND: High circulating low-density lipoprotein cholesterol (LDL-C) is a major risk factor for atherosclerosis and age-associated cardiovascular events. Long-term dyslipidaemia could contribute to the development of frailty in older individuals through its role in determining cardiovascular health and potentially other physiological pathways.</p>
METHODS: We conducted Mendelian randomization (MR) analyses using genetic variants to estimate the effects of long-term LDL-C modification on frailty in UK Biobank (n = 378,161). Frailty was derived from health questionnaire and interview responses at baseline when participants were aged 40 to 69 years, and calculated using an accumulation-of-deficits approach, i.e. the frailty index (FI). Several aggregated instrumental variables (IVs) using 50 and 274 genetic variants were constructed from independent single-nucleotide polymorphisms (SNPs) to instrument circulating LDL-C concentrations. Specific sets of variants in or near genes that encode six lipid-lowering drug targets (HMGCR, PCSK9, NPC1L1, APOB, APOC3, and LDLR) were used to index effects of exposure to related drug classes on frailty. SNP-LDL-C effects were available from previously published studies. SNP-FI effects were obtained using adjusted linear regression models. Two-sample MR analyses were performed with the IVs as instruments using inverse-variance weighted, MR-Egger, weighted median, and weighted mode methods. To address the stability of the findings, MR analyses were also performed using i) a modified FI excluding the cardiometabolic deficit items and ii) data from comparatively older individuals (aged ≥60 years) only. Several sensitivity analyses were also conducted.</p>
FINDINGS: On average 0.14% to 0.23% and 0.16% to 0.31% decrements in frailty were observed per standard deviation reduction in LDL-C exposure, instrumented by the general IVs consisting of 50 and 274 variants, respectively. Consistent, though less precise, associations were observed in the HMGCR-, APOC3-, NPC1L1-, and LDLR-specific IV analyses. In contrast, results for PCSK9 were in the same direction but more modest, and null for APOB. All sensitivity analyses produced similar findings.</p>
INTERPRETATION: A genetically-predicted life-long lowering of LDL-C is associated with decreased frailty in midlife and older age, representing supportive evidence for LDL-C's role in multiple health- and age-related pathways. The use of lipid-lowering therapeutics with varying mechanisms of action may differ by the extent to which they provide overall health benefits.</p>
16 Keywords
- Adult
- Aged
- Biological Specimen Banks
- Cholesterol, HDL
- Cholesterol, LDL
- Female
- Frailty
- Genetic Predisposition to Disease
- Humans
- Lipid Metabolism
- Male
- Mendelian Randomization Analysis
- Middle Aged
- Polymorphism, Single Nucleotide
- Risk Factors
- United Kingdom
6 Authors
- Qi Wang
- Yunzhang Wang
- Kelli Lehto
- Nancy L. Pedersen
- Dylan M. Williams
- Sara Hägg
Enabling scientific discoveries that improve human health