Sequence variants associating with urinary biomarkers

被引：29

作者：

Benonisdottir, Stefania ^{[1
]}

Kristjansson, Ragnar P. ^{[1
]}

Oddsson, Asmundur ^{[1
]}

Steinthorsdottir, Valgerdur ^{[1
]}

Mikaelsdottir, Evgenia ^{[1
]}

Kehr, Birte ^{[2
]}

Jensson, Brynjar O. ^{[1
]}

Arnadottir, Gudny A. ^{[1
]}

Sulem, Gerald ^{[1
]}

Sveinbjornsson, Gardar ^{[1
]}

Kristmundsdottir, Snaedis ^{[1
,3
]}

Ivarsdottir, Erna V. ^{[1
,4
]}

Tragante, Vinicius ^{[1
,5
]}

Gunnarsson, Bjarni ^{[1
]}

Runolfsdottir, Hrafnhildur Linnet ^{[6
,7
]}

Arthur, Joseph G. ^{[1
,8
]}

Deaton, Aimee M. ^{[1
]}

Eyjolfsson, Gudmundur I. ^{[9
]}

Davidsson, Olafur B. ^{[1
]}

Asselbergs, Folkert W. ^{[5
,10
,11
,12
,13
]}

Hreidarsson, Astradur B. ^{[14
]}

Rafnar, Thorunn ^{[1
]}

Thorleifsson, Gudmar ^{[1
]}

Edvardsson, Vidar ^{[6
,7
,15
]}

Sigurdsson, Gunnar ^{[14
,16
]}

Helgadottir, Anna ^{[1
]}

Halldorsson, Bjarni V. ^{[1
,3
,14
]}

Masson, Gisli ^{[1
]}

Holm, Hilma ^{[1
]}

Onundarson, Pall T. ^{[6
,17
]}

Indridason, Olafur S. ^{[18
]}

Benediktsson, Rafn ^{[6
,14
]}

Palsson, Runolfur ^{[6
,7
,18
]}

Gudbjartsson, Daniel F. ^{[1
,4
]}

Olafsson, Isleifur ^{[19
]}

Thorsteinsdottir, Unnur ^{[1
,6
]}

Sulem, Patrick ^{[1
]}

Stefansson, Kari ^{[1
,6
]}

机构：

[1] Amgen Inc, deCODE Genet, Reykjavik, Iceland

[2] BIH, Berlin, Germany

[3] Reykjavik Univ, Sch Sci & Engn, Reykjavik, Iceland

[4] Univ Iceland, Sch Engn & Nat Sci, Reykjavik, Iceland

[5] Univ Utrecht, Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands

[6] Univ Iceland, Fac Med, Reykjavik, Iceland

[7] Mayo Clin, Rare Kidney Stone Consortium, Rochester, MN USA

[8] Stanford Univ, Dept Stat, Stanford, CA 94305 USA

[9] Icelandic Med Ctr Laeknasetrid, Lab Mjodd RAM, Reykjavik, Iceland

[10] Netherlands Heart Inst, Durrer Ctr Cardiovasc Res, Utrecht, Netherlands

[11] UCL, Fac Populat Hlth Sci, Inst Cardiovasc Sci, London, England

[12] UCL, Farr Inst Hlth Informat Res, London, England

[13] UCL, Inst Hlth Informat, London, England

[14] Natl Univ Hosp Iceland, Landspitali, Internal Med Serv, Div Endocrinol & Metab Med, Reykjavik, Iceland

[15] Natl Univ Hosp Iceland, Landspitali, Childrens Med Ctr, Reykjavik, Iceland

[16] Icelandic Heart Assoc, Kopavogur, Iceland

[17] Natl Univ Hosp Iceland, Landspitali, Dept Lab Hematol, Reykjavik, Iceland

[18] Natl Univ Hosp Iceland, Landspitali, Internal Med Serv, Div Nephrol, Reykjavik, Iceland

[19] Natl Univ Hosp Iceland, Landspitali, Dept Clin Biochem, Reykjavik, Iceland

来源：

HUMAN MOLECULAR GENETICS | 2019年 / 28卷 / 07期

基金：

英国科研创新办公室;

关键词：

GENOME-WIDE ASSOCIATION; GENETIC ARCHITECTURE; MUTATIONS; MEGALIN; DISEASE; PATHOPHYSIOLOGY; HETEROGENEITY; MANAGEMENT; HEMATURIA; INSIGHTS;

D O I：

10.1093/hmg/ddy409

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Urine dipstick tests are widely used in routine medical care to diagnose kidney and urinary tract and metabolic diseases. Several environmental factors are known to affect the test results, whereas the effects of genetic diversity are largely unknown. We tested 32.5 million sequence variants for association with urinary biomarkers in a set of 150 274 Icelanders with urine dipstick measurements. We detected 20 association signals, of which 14 are novel, associating with at least one of five clinical entities defined by the urine dipstick: glucosuria, ketonuria, proteinuria, hematuria and urine pH. These include three independent glucosuria variants at SLC5A2, the gene encoding the sodium-dependent glucose transporter (SGLT2), a protein targeted pharmacologically to increase urinary glucose excretion in the treatment of diabetes. TVro variants associating with proteinuria are in LRP2 and CUBN, encoding the co-transporters megalin and cubilin, respectively, that mediate proximal tubule protein uptake. One of the hematuria-associated variants is a rare, previously unreported 2.5 kb exonic deletion in COL4A3. Of the four signals associated with urine pH, we note that the pH-increasing alleles of two variants (POU2AF1, WDR72) associate significantly with increased risk of kidney stones. Our results reveal that genetic factors affect variability in urinary biomarkers, in both a disease dependent and independent context.

引用

页码：1199 / 1211

页数：13

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