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J Am Soc Nephrol. 2018 Feb;29(2):462-476. doi: 10.1681/ASN.2016080875. Epub 2017 Nov 1.

Chromatin Conformation Links Distal Target Genes to CKD Loci.

Author information

1
Experimental Cardiology, Department of Cardiology, Thoraxcenter Erasmus University Medical Center, Rotterdam, The Netherlands; and.
2
Department of Pediatrics, Wilhelmina Children's Hospital.
3
Regenerative Medicine Center Utrecht, Department of Pediatrics.
4
Department of Nephrology and Hypertension, Division of Internal Medicine and Dermatology.
5
Department of Cardiology, Division Heart and Lungs, and.
6
Epigenomics Facility, Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
7
Experimental Cardiology, Department of Cardiology, Thoraxcenter Erasmus University Medical Center, Rotterdam, The Netherlands; and K.L.Cheng-2@umcutrecht.nl.

Abstract

Genome-wide association studies (GWASs) have identified many genetic risk factors for CKD. However, linking common variants to genes that are causal for CKD etiology remains challenging. By adapting self-transcribing active regulatory region sequencing, we evaluated the effect of genetic variation on DNA regulatory elements (DREs). Variants in linkage with the CKD-associated single-nucleotide polymorphism rs11959928 were shown to affect DRE function, illustrating that genes regulated by DREs colocalizing with CKD-associated variation can be dysregulated and therefore, considered as CKD candidate genes. To identify target genes of these DREs, we used circular chromosome conformation capture (4C) sequencing on glomerular endothelial cells and renal tubular epithelial cells. Our 4C analyses revealed interactions of CKD-associated susceptibility regions with the transcriptional start sites of 304 target genes. Overlap with multiple databases confirmed that many of these target genes are involved in kidney homeostasis. Expression quantitative trait loci analysis revealed that mRNA levels of many target genes are genotype dependent. Pathway analyses showed that target genes were enriched in processes crucial for renal function, identifying dysregulated geranylgeranyl diphosphate biosynthesis as a potential disease mechanism. Overall, our data annotated multiple genes to previously reported CKD-associated single-nucleotide polymorphisms and provided evidence for interaction between these loci and target genes. This pipeline provides a novel technique for hypothesis generation and complements classic GWAS interpretation. Future studies are required to specify the implications of our dataset and further reveal the complex roles that common variants have in complex diseases, such as CKD.

KEYWORDS:

3D chromatin structure; DNA regulatory elements; STARR-seq; chronic kidney disease; circular chromosome conformation capture (4C) sequencing; transcriptional regulation

PMID:
29093029
PMCID:
PMC5791087
DOI:
10.1681/ASN.2016080875
[Indexed for MEDLINE]
Free PMC Article

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