Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels
| العنوان: | Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels |
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| المؤلفون: | Robert Kraaij, Teresa Nutile, Peter Vollenweider, Cassianne Robinson-Cohen, Caroline S. Fox, André G. Uitterlinden, Sanaz Sedaghat, Cornelia M. van Duijn, Alanna C. Morrison, Meng Li, Bing Yu, Sahar Ghasemi, Zoltán Kutalik, Eric Boerwinkle, Alexanda Teumer, Jeroen van Rooij, Qiong Yang, Audrey Y. Chu, Jennifer E. Huffman, Bruce M. Psaty, Jun Liu, Najaf Amin, Jennifer A. Brody, Adrienne Tin, Rossella Sorice, Ming-Huei Chen, Marina Ciullo, Anna Köttgen, Yong Li, Ayse Demirkan, Owen M. Woodward, Melody Swen, Abbas Dehghan, Aurélien Macé, Barbara McKnight |
| المساهمون: | Epidemiology, Internal Medicine |
| المصدر: | Nature Communications Nature communications 9 (2018). doi:10.1038/s41467-018-06620-4 info:cnr-pdr/source/autori:Tin A.; Li Y.; Brody J.A.; Nutile T.; Chu A.Y.; Huffman J.E.; Yang Q.; Chen M.-H.; Robinson-Cohen C.; Mace A.; Liu J.; Demirkan A.; Sorice R.; Sedaghat S.; Swen M.; Yu B.; Ghasemi S.; Teumer A.; Vollenweider P.; Ciullo M.; Li M.; Uitterlinden A.G.; Kraaij R.; Amin N.; van Rooij J.; Kutalik Z.; Dehghan A.; McKnight B.; van Duijn C.M.; Morrison A.; Psaty B.M.; Boerwinkle E.; Fox C.S.; Woodward O.M.; Kottgen A./titolo:Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels/doi:10.1038%2Fs41467-018-06620-4/rivista:Nature communications/anno:2018/pagina_da:/pagina_a:/intervallo_pagine:/volume:9 Nature Communications, Vol 9, Iss 1, Pp 1-11 (2018) Nature Communications, 9:4228. Nature Publishing Group Nature communications, vol. 9, no. 1, pp. 4228 |
| بيانات النشر: | Nature Publishing Group, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Organic Cation Transport Proteins, Science, Glucose Transport Proteins, Facilitative, General Physics and Astronomy, Organic Anion Transporters, Genome-wide association study, Disease, Bioinformatics, Kidney Function Tests, General Biochemistry, Genetics and Molecular Biology, Article, Protein Structure, Secondary, 03 medical and health sciences, chemistry.chemical_compound, Exome/genetics, Genetic Predisposition to Disease, Glucose Transport Proteins, Facilitative/chemistry, Glucose Transport Proteins, Facilitative/genetics, Glucose Transport Proteins, Facilitative/metabolism, Humans, Meta-Analysis as Topic, Organic Anion Transporters/chemistry, Organic Anion Transporters/genetics, Organic Anion Transporters/metabolism, Organic Cation Transport Proteins/chemistry, Organic Cation Transport Proteins/genetics, Organic Cation Transport Proteins/metabolism, Uric Acid/blood, MD Multidisciplinary, medicine, Exome, lcsh:Science, Exome sequencing, Genetic association, Multidisciplinary, biology, business.industry, Lesinurad, serum urate levels, General Chemistry, medicine.disease, 3. Good health, Gout, Uric Acid, 030104 developmental biology, chemistry, biology.protein, SLC22A12, lcsh:Q, business, SLC2A9 |
| الوصف: | Elevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Previous GWAS identified common variants with modest effects on serum urate. Here we report large-scale whole-exome sequencing association studies of serum urate and kidney function among ≤19,517 European ancestry and African-American individuals. We identify aggregate associations of low-frequency damaging variants in the urate transporters SLC22A12 (URAT1; p = 1.3 × 10−56) and SLC2A9 (p = 4.5 × 10−7). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 × 10−3). Selected rare variants in SLC22A12 are validated in transport studies, confirming three as loss-of-function (R325W, R405C, and T467M) and illustrating the therapeutic potential of the new URAT1-blocker lesinurad. In SLC2A9, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. These findings provide new insights into the genetic architecture of serum urate, and highlight molecular targets in SLC22A12 and SLC2A9 for lowering serum urate and preventing gout. Elevated serum urate levels are a risk factor for gout. Here, Tin et al. perform whole-exome sequencing in 19,517 individuals and detect low-frequency genetic variants in urate transporter genes, SLC22A12 and SLC2A9, associated with serum urate levels and confirm their damaging nature in vitro and in silico. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2041-1723 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::09617704df3edc2b2becb350d2b1af49Test https://doi.org/10.1038/s41467-018-06620-4Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....09617704df3edc2b2becb350d2b1af49 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
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