Novel Risk Loci Identified in a Genome-Wide Association Study of Urolithiasis in a Japanese Population.

Asian People / genetics Calcium / blood Case-Control Studies Female Genetic Loci Genetic Predisposition to Disease / epidemiology Genome-Wide Association Study / methods Glomerular Filtration Rate Humans Japan / epidemiology Male Phenotype Prevalence Risk Assessment Uric Acid / blood Urolithiasis / genetics

genetics and development human genetics kidney stones

Journal

Journal of the American Society of Nephrology : JASN

ISSN: 1533-3450

Titre abrégé: J Am Soc Nephrol

Pays: United States

ID NLM: 9013836

Informations de publication

Date de publication:
05 2019

Historique:

received: 21 10 2018

accepted: 08 02 2019

pubmed: 13 4 2019

medline: 28 2 2020

entrez: 13 4 2019

Statut: ppublish

Résumé

A family history of urolithiasis is associated with a more than doubling of urolithiasis risk, and a twin study estimating 56% heritability of the condition suggests a pivotal role for host genetic factors. However, previous genome-wide association studies (GWAS) have identified only six risk-related loci. To identify novel urolithiasis-related loci in the Japanese population, we performed a large-scale GWAS of 11,130 cases and 187,639 controls, followed by a replication analysis of 2289 cases and 3817 controls. Diagnosis of urolithiasis was confirmed either by a clinician or using medical records or self-report. We also assessed the association of urolithiasis loci with 16 quantitative traits, including metabolic, kidney-related, and electrolyte traits (such as body mass index, lipid storage, eGFR, serum uric acid, and serum calcium), using up to 160,000 samples from BioBank Japan. The analysis identified 14 significant loci, including nine novel loci. Ten regions showed a significant association with at least one quantitative trait, including metabolic, kidney-related, and electrolyte traits, suggesting a common genetic basis for urolithiasis and these quantitative traits. Four novel loci were related to metabolic traits, obesity, hypertriglyceridemia, or hyperuricemia. The remaining ten loci were associated with kidney- or electrolyte-related traits; these may affect crystallization. Weighted genetic risk score analysis indicated that the highest risk group (top 20%) showed an odds ratio of 1.71 (95% confidence interval, 1.42 to 2.06) - 2.13 (95% confidence interval, 2.00 to 2.27) compared with the reference group (bottom 20%). Our findings provide evidence that host genetic factors related to regulation of metabolic and crystallization pathways contribute to the development of urolithiasis.

Sections du résumé

BACKGROUND

METHODS

To identify novel urolithiasis-related loci in the Japanese population, we performed a large-scale GWAS of 11,130 cases and 187,639 controls, followed by a replication analysis of 2289 cases and 3817 controls. Diagnosis of urolithiasis was confirmed either by a clinician or using medical records or self-report. We also assessed the association of urolithiasis loci with 16 quantitative traits, including metabolic, kidney-related, and electrolyte traits (such as body mass index, lipid storage, eGFR, serum uric acid, and serum calcium), using up to 160,000 samples from BioBank Japan.

RESULTS

The analysis identified 14 significant loci, including nine novel loci. Ten regions showed a significant association with at least one quantitative trait, including metabolic, kidney-related, and electrolyte traits, suggesting a common genetic basis for urolithiasis and these quantitative traits. Four novel loci were related to metabolic traits, obesity, hypertriglyceridemia, or hyperuricemia. The remaining ten loci were associated with kidney- or electrolyte-related traits; these may affect crystallization. Weighted genetic risk score analysis indicated that the highest risk group (top 20%) showed an odds ratio of 1.71 (95% confidence interval, 1.42 to 2.06) - 2.13 (95% confidence interval, 2.00 to 2.27) compared with the reference group (bottom 20%).

CONCLUSIONS

Our findings provide evidence that host genetic factors related to regulation of metabolic and crystallization pathways contribute to the development of urolithiasis.

Identifiants

DOI: 10.1681/ASN.2018090942 PMID: 30975718 PMC: PMC6493984

pubmed: 30975718

pii: ASN.2018090942

doi: 10.1681/ASN.2018090942

pmc: PMC6493984

doi:

Substances chimiques

Uric Acid 268B43MJ25

Calcium SY7Q814VUP

Types de publication

Journal Article Multicenter Study Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

855-864

Subventions

Organisme : NIDDK NIH HHS

ID : R01 DK115727

Pays : United States

Informations de copyright

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