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Sci Rep. 2017 Nov 6;7(1):14595. doi: 10.1038/s41598-017-15062-9.

Genome-wide linkage and association study implicates the 10q26 region as a major genetic contributor to primary nonsyndromic vesicoureteric reflux.

Author information

1
Department of Clinical Genetics, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland.
2
National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland.
3
Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.
4
UCL Institute of Health Informatics, University College, London, NW1 2DA, UK.
5
Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, Bangkok, 10400, Thailand.
6
Jack Birch Unit of Molecular Carcinogenesis, Department of Biology, University of York, York, YO10 5DD, UK.
7
University Children's Hospital Zurich, Steinwiesstrasse 75, 8032, Zurich, Switzerland.
8
Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK.
9
University College Dublin School of Medicine, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland.
10
University College Dublin, Stillorgan Rd, Belfield, Dublin 4, Ireland.
11
Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
12
Royal Manchester Children's Hospital and Manchester Academic Health Sciences Centre, Manchester, UK.
13
Department of Pediatric Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia.
14
Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK. heather.cordell@newcastle.ac.uk.

Abstract

Vesicoureteric reflux (VUR) is the commonest urological anomaly in children. Despite treatment improvements, associated renal lesions - congenital dysplasia, acquired scarring or both - are a common cause of childhood hypertension and renal failure. Primary VUR is familial, with transmission rate and sibling risk both approaching 50%, and appears highly genetically heterogeneous. It is often associated with other developmental anomalies of the urinary tract, emphasising its etiology as a disorder of urogenital tract development. We conducted a genome-wide linkage and association study in three European populations to search for loci predisposing to VUR. Family-based association analysis of 1098 parent-affected-child trios and case/control association analysis of 1147 cases and 3789 controls did not reveal any compelling associations, but parametric linkage analysis of 460 families (1062 affected individuals) under a dominant model identified a single region, on 10q26, that showed strong linkage (HLOD = 4.90; ZLRLOD = 4.39) to VUR. The ~9Mb region contains 69 genes, including some good biological candidates. Resequencing this region in selected individuals did not clearly implicate any gene but FOXI2, FANK1 and GLRX3 remain candidates for further investigation. This, the largest genetic study of VUR to date, highlights the 10q26 region as a major genetic contributor to VUR in European populations.

PMID:
29097723
PMCID:
PMC5668427
DOI:
10.1038/s41598-017-15062-9
[Indexed for MEDLINE]
Free PMC Article

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