ArticleHuman molecular genetics2019
Enhancer deletion and allelic effects define a regulatory molecular mechanism at the VLDLR cholesterol GWAS locus.
Article in Human molecular genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers, 1 of them a synthesis that pooled it.
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Who cites it
5 citing papers in PubMed, 1 synthesis or guideline pooled it, 10 citations in OpenAlex.
- Minority-centric meta-analyses of blood lipid levels identify novel loci in the Population Architecture using Genomics and Epidemiology (PAGE) study.PLoS genetics · 2020Pooled it
- Sexually dimorphic renal expression of mouse Klotho is directed by a kidney-specific distal enhancer responsive to HNF1b.Communications biology · 2024Article
- Sexually dimorphic renal expression ofResearch square · 2024Article
- A common variant in 11q23.3 associated with hyperlipidemia is mediated by the binding and regulation of GATA4.NPJ genomic medicine · 2022Article
- Lipoprotein receptor signalling in atherosclerosis.Cardiovascular research · 2020Review
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) are heritable risk factors for cardiovascular disease, yet the molecular mechanisms underlying the majority of blood lipid-associated genome-wide association studies signals remain elusive. One association signal is located in intron 3 of VLDLR; rs3780181-A is a risk allele associated (P ≤ 2 × 10-9) with increased TC and LDL-C. We investigated variants, genes and mechanisms underlying this association signal. We used a functional genetic approach to show that the intronic region spanning rs3780181 exhibited 1.6-7.6-fold enhancer activity in human HepG2 hepatocyte, THP-1 monocyte and Simpson-Golabi-Behmel Syndrome (SGBS) preadipocyte cells and that the rs3780181-A risk allele showed significantly less enhancer activity compared with the G allele, consistent with the direction of an expression quantitative trait locus in liver. In addition, rs3780181 alleles showed differential binding to multiple nuclear proteins, including stronger IRF2 binding to the rs3780181 G allele. We used a CRISPR-cas9 approach to delete 475 and 663 bp of the putative enhancer element in HEK293T kidney cells; compared to expression of mock-edited cell lines, the homozygous enhancer deletion cell lines showed 1.2-fold significantly (P < 0.04) decreased expression of VLDLR, as well as 1.5-fold decreased expression of SMARCA2, located 388 kb away. Together, these results identify an enhancer of VLDLR expression and suggest that altered binding of one or more factors bound to rs3780181 alleles decreases enhancer activity and reduces at least VLDLR expression, leading to increased TC and LDL-C.
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Registered trials
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