Genetic Association of Albuminuria with Cardiometabolic Disease and Blood Pressure - PubMed (original) (raw)

Genetic Association of Albuminuria with Cardiometabolic Disease and Blood Pressure

Mary E Haas et al. Am J Hum Genet. 2018.

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.

Copyright © 2018. Published by Elsevier Inc.

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Figures

Figure 1

Figure 1

Association of Albuminuria with Incident Disease Endpoints in UK Biobank aIncident disease adjusted for age, sex, current smoking status, body mass index, systolic blood pressure, diastolic blood pressure, baseline diabetes, and baseline hyperlipidemia unless otherwise specified. bAdjusted for age, sex, current smoking status, body mass index, systolic blood pressure, diastolic blood pressure, waist-to-hip ratio, and baseline hyperlipidemia. cAdjusted for age, age2, current smoking status, body mass index, baseline diabetes, and baseline hyperlipidemia. Bars indicate 95% confidence interval for hazard ratio.

Figure 2

Figure 2

Genome-wide Association Study of Albuminuria in UK Biobank Identifies 32 Loci 33 genome-wide significant loci (including one previously published) are indicated by red points. Red line indicates genome-wide significance threshold (p = 9 × 10−9); blue line indicates conventional significance threshold (p = 5 × 10−8).

Figure 3

Figure 3

Association of Genetic Predisposition to Increased Albuminuria with Risk of Cardiometabolic Disease in UK Biobank Two-stage least-squares regression using albuminuria genetic risk score as instrumental variable; age, sex, genotyping array, and first ten genetic PCs as covariates. Results are standardized to 1-SD increase in albuminuria due to the genetic risk score. (A) Genetic risk score composed of all 46 albuminuria variants. (B) Genetic risk score composed of 43 albuminuria variants after applying directional MR Steiger filtering to remove variants potentially acting in the incorrect direction. Bars indicate 95% confidence interval for odds ratio.

Figure 4

Figure 4

Bidirectional Mendelian Randomization Identifies Suggestive Causal Effects of Albuminuria on Blood Pressure and of Blood Pressure on Albuminuria (A) Mendelian randomization of albuminuria genetic risk scores on blood pressure in UK Biobank (n = 381,833). Two-stage least-squares regression using albuminuria genetic risk score as instrumental variable on blood pressure outcome; age, sex, genotyping array, and first ten genetic PCs as covariates. Results are standardized to 1-SD increase in albuminuria due to the genetic risk score. Genetic risk scores were composed of 44 albuminuria variants after applying directional MR Steiger filtering to remove variants potentially acting in the incorrect direction. (B) Mendelian randomization of blood pressure genetic risk scores on albuminuria. Effects of variants on systolic or diastolic blood pressure were determined in ICBP (nmax = 201,529) and thus corrected for hypertensive medication use and adjusted for body mass index. Two-stage least-squares regression using blood pressure genetic risk score as instrumental variable on albuminuria outcome in UK Biobank (n = 381,833); age, sex, genotyping array, and first ten genetic PCs as covariates. Results are standardized to 1-mmHg increase in blood pressure due to the genetic risk score. 47 or 52 variants were used to construct scores specific for systolic or diastolic blood pressure, respectively. Directional MR Steiger filtering removed no variants. SNPs in score, number of SNPs remaining after directional MR Steiger filtering applied. Bars indicate 95% confidence interval for effect on blood pressure (top) or albuminuria (bottom).

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