Identification of 22 novel loci associated with urinary biomarkers of albumin, sodium, and potassium excretion

Zanetti, Daniela; Rao, Abhiram; Gustafsson, Stefan; Assimes, Themistocles L.; Montgomery, Stephen B.; Ingelsson, Erik

doi:10.1016/j.kint.2018.12.017

Cited by 37 publications

(38 citation statements)

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“…The mean age, body mass index, UNa/UCr, and urinary potassium/UCr were 56.88, 27.39, 10.60, and 8.48, respectively, in the discovery population and were 56.87, 27.42, 10.62, and 8.44, respectively, in the replication population (Zanetti et al, 2019). Using these baseline characteristics, the average 24-h sodium excretion was estimated to be approximately 2.6 g per day for women and 3.7 g per day for men, well above the recommended restriction of <2 g per day of sodium intake ( Supplementary Table S8).…”

Section: Sodium Intake Estimationmentioning

confidence: 91%

Mendelian Randomization Analysis Reveals a Causal Effect of Urinary Sodium/Urinary Creatinine Ratio on Kidney Function in Europeans

Zhang

Zheng

Gaunt

et al. 2020

Front. Bioeng. Biotechnol.

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Salt restriction was recommended in clinical practice guideline for chronic kidney disease (CKD) treatment, but its effect on kidney outcomes remains conflicting. We aimed to test the causal effect of salt intake, using estimated 24-h sodium excretion from spot urinary sodium/urinary creatinine (UNa/UCr) ratio as a surrogate, on renal function using two-sample Mendelian randomization (MR). Genetic instruments for UNa/UCr were derived from a recent genome-wide association study of 218,450 European-descent individuals in the UK Biobank. Kidney outcomes were creatininebased estimated glomerular filtration rate (eGFRcrea) (N = 567,460) and CKD (eGFRcrea < 60 ml/min/1.73 m 2 , N cases = 41,395, N controls = 439,303) from the CKDGen consortium. Cystatin C-based eGFR (eGFRcys) and eGFRcrea singlenucleotide polymorphisms associated with blood urea nitrogen (BUN) were used for sensitivity analyses. MR revealed a causal effect of UNa/UCr on higher eGFRcrea [β = 0.14, unit change in log ml/min/1.73 m 2 per UNa/UCr ratio; 95% confidence interval (CI) = 0.07-0.20, P = 2.15 × 10 −5 ] and a protective effect against CKD risk (odds ratio = 0.24, 95% CI = 0.14 to 0.41, P = 1.20 × 10 −7). The MR findings were confirmed by MR-Egger regression, weighted median MR, and mode estimate MR, with less evidence of existence of horizontal pleiotropy. Consistent positive causal effect of UNa/UCr on eGFRcys was also detected. On the other hand, bidirectional MR suggested inconclusive results of CKD, eGFRcrea, eGFRcrea (BUN associated), and eGFRcys on UNa/UCr. The average 24-h sodium excretion was estimated to be approximately 2.6 g per day for women and 3.7 g per day for men. This study provides evidence that sodium excretion, well above the recommendation of <2 g per day of sodium intake, might not have a harmful effect on kidney function. Clinical trials are warranted to evaluate the sodium restriction target on kidney function.

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Section: Sodium Intake Estimationmentioning

confidence: 91%

Mendelian Randomization Analysis Reveals a Causal Effect of Urinary Sodium/Urinary Creatinine Ratio on Kidney Function in Europeans

Zhang

Zheng

Gaunt

et al. 2020

Front. Bioeng. Biotechnol.

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“…In line with our TWAS finding, NPNT is significantly upregulated in glomeruli of diabetic nephropathy mouse model vs. non-diabetic mouse (p=6.4x10 -4 , fold change 1.3, in top 2%, accessed through www.neproseq.org). 56 Furthermore, a variant near PRRC2C was recently associated with albuminuria in the UK Biobank, 57 and rare mutations in VPS33B gene cause arthrogryposis, renal dysfunction, and cholestasis-1 (ARCS1) syndrome involving proximal-tubular dysfunction and usually death by the age of 1. 58…”

Section: Expression and Epigenetic Analysesmentioning

confidence: 99%

Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen

Salem¹,

Todd²,

Sandholm³

et al. 2019

JASN

158

175

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BackgroundAlthough diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown.MethodsTo identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function.ResultsOur GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition (BMP7) or renal biology (COLEC11 and DDR1).ConclusionsThe 16 diabetic kidney disease–associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.

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“…None of these 33 genetic instruments were associated with the urinary sodium-to-creatinine ratio or urinary potassium-to-creatinine ratio at the genome-wide significance level (P < 5 Â 10 À8 ) in a large-scale GWAS of UKB participants (n ¼ 327,613) ( Supplementary Table S5). 24 Using similar selection procedures, the number of genetic instruments retained for BUN was 24, which explained 1.18% of the variance of log(BUN). For example, using eGFRcr as the complementary kidney function biomarker, the BUN index SNP at SLC14A2, a urea transporter, 25,26 was removed because of an insignificant association with eGFRcr (rs41301139; P ¼ 0.14) (Supplementary Table S6).…”

Section: Selection Of Genetic Instruments For Kidney Functionmentioning

confidence: 99%

“…Table S5. Association of the 33 genetic instruments of eGFRcr with urine sodium-to-creatinine ratio and urine potassium-to-creatinine ratio in large scale GWAS of UKB participants (N¼327,613, Zanetti et al 24 ). Table S6.…”

Section: Supplementary Materials Supplementary File (Pdf)mentioning

confidence: 99%

A bidirectional Mendelian randomization study supports causal effects of kidney function on blood pressure

Coresh

et al. 2020

Kidney International

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Blood pressure and kidney function have a bidirectional relation. Hypertension has long been considered as a risk factor for kidney function decline. However, whether intensive blood pressure control could promote kidney health has been uncertain. The kidney is known to have a major role in affecting blood pressure through sodium extraction and regulating electrolyte balance. This bidirectional relation makes causal inference between these two traits difficult. Therefore, to examine the causal relations between these two traits, we performed twosample Mendelian randomization analyses using summary statistics of large-scale genome-wide association studies. We selected genetic instruments more likely to be specific for kidney function using meta-analyses of complementary kidney function biomarkers (glomerular filtration rate estimated from serum creatinine [eGFRcr], and blood urea nitrogen from the CKDGen Consortium). Systolic and diastolic blood pressure summary statistics were from the International Consortium for Blood Pressure and UK Biobank. Significant evidence supported the causal effects of higher kidney function on lower blood pressure. Based on the mode-based Mendelian randomization method, the effect estimates for one standard deviation (SD) higher in log-transformed eGFRcr was-0.17 SD unit (95 % confidence interval:-0.09 to-0.24) in systolic blood pressure and-0.15 SD unit (95% confidence interval:-0.07 to-0.22) in diastolic blood pressure. In contrast, the causal effects of blood pressure on kidney function were not statistically significant. Thus, our results support causal effects of higher kidney function on lower blood pressure and suggest preventing kidney function decline can reduce the public health burden of hypertension.

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Identification of 22 novel loci associated with urinary biomarkers of albumin, sodium, and potassium excretion

Cited by 37 publications

References 50 publications

Mendelian Randomization Analysis Reveals a Causal Effect of Urinary Sodium/Urinary Creatinine Ratio on Kidney Function in Europeans

Mendelian Randomization Analysis Reveals a Causal Effect of Urinary Sodium/Urinary Creatinine Ratio on Kidney Function in Europeans

Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen

A bidirectional Mendelian randomization study supports causal effects of kidney function on blood pressure

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