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Am J Hum Genet. 2018 Oct 4;103(4):461-473. doi: 10.1016/j.ajhg.2018.08.004. Epub 2018 Sep 13.

Genetic Association of Albuminuria with Cardiometabolic Disease and Blood Pressure.

Author information

1
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
2
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
3
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
4
Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol BS8 2BN, UK.
5
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA. Electronic address: skathiresan1@mgh.harvard.edu.

Abstract

Excretion of albumin in urine, or albuminuria, is associated with the development of multiple cardiovascular and metabolic diseases. However, whether pathways leading to albuminuria are causal for cardiometabolic diseases is unclear. We addressed this question using a Mendelian randomization framework in the UK Biobank, a large population-based cohort. We first performed a genome-wide association study for albuminuria in 382,500 individuals and identified 32 new albuminuria loci. We constructed albuminuria genetic risk scores and tested for association with cardiometabolic diseases. Genetically elevated albuminuria was strongly associated with increased risk of hypertension (1.38 OR; 95% CI, 1.27-1.50 per 1 SD predicted increase in albuminuria, p = 7.01 × 10-14). We then examined bidirectional associations of albuminuria with blood pressure which suggested that genetically elevated albuminuria led to higher blood pressure (2.16 mmHg systolic blood pressure; 95% CI, 1.51-2.82 per 1 SD predicted increase in albuminuria, p = 1.22 × 10-10) and that genetically elevated blood pressure led to more albuminuria (0.005 SD; 95% CI 0.004-0.006 per 1 mmHg predicted increase in systolic blood pressure, p = 2.45 × 10-13). These results support the existence of a feed-forward loop between albuminuria and blood pressure and imply that albuminuria could increase risk of cardiovascular disease through blood pressure. Moreover, they suggest therapies that target albuminuria-increasing processes could have antihypertensive effects that are amplified through inhibition of this feed-forward loop.

KEYWORDS:

Mendelian randomization; albuminuria; blood pressure; cardiometabolic disease; cardiovascular disease; genetic risk score; genome-wide association study; hypertension; polygenic risk score; urine albumin excretion; urine albumin:creatinine ratio

PMID:
30220432
PMCID:
PMC6174360
DOI:
10.1016/j.ajhg.2018.08.004
[Indexed for MEDLINE]
Free PMC Article

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