Sequence variants associating with urinary biomarkers

Stefania Benonisdottir; Ragnar P Kristjansson; Asmundur Oddsson; Valgerdur Steinthorsdottir; Evgenia Mikaelsdottir; Birte Kehr; Brynjar O Jensson; Gudny A Arnadottir; Gerald Sulem; Gardar Sveinbjornsson; Snaedis Kristmundsdottir; Erna V Ivarsdottir; Lotte K Vogel; Vinicius Tragante; Bjarni Gunnarsson; Hrafnhildur Linnet Runolfsdottir; Joseph G Arthur; Aimee M Deaton; Gudmundur I Eyjolfsson; Olafur B Davidsson; Folkert W Asselbergs; Astradur B Hreidarsson; Thorunn Rafnar; Gudmar Thorleifsson; Vidar Edvardsson; Gunnar Sigurdsson; Anna Helgadottir; Bjarni V Halldorsson; Gisli Masson; Hilma Holm; Pall T Onundarson; Olafur S Indridason; Rafn Benediktsson; Runolfur Palsson; Daniel F Gudbjartsson; Isleifur Olafsson; Unnur Thorsteinsdottir; Patrick Sulem; Kari Stefansson

doi:10.1093/hmg/ddy409

Sequence variants associating with urinary biomarkers

Stefania Benonisdottir, Ragnar P Kristjansson, Asmundur Oddsson, Valgerdur Steinthorsdottir, Evgenia Mikaelsdottir, Birte Kehr, Brynjar O Jensson, Gudny A Arnadottir, Gerald Sulem, Gardar Sveinbjornsson, Snaedis Kristmundsdottir, Erna V Ivarsdottir, Lotte K Vogel, Vinicius Tragante, Bjarni Gunnarsson, Hrafnhildur Linnet Runolfsdottir, Joseph G Arthur, Aimee M Deaton, Gudmundur I Eyjolfsson, Olafur B DavidssonFolkert W Asselbergs, Astradur B Hreidarsson, Thorunn Rafnar, Gudmar Thorleifsson, Vidar Edvardsson, Gunnar Sigurdsson, Anna Helgadottir, Bjarni V Halldorsson, Gisli Masson, Hilma Holm, Pall T Onundarson, Olafur S Indridason, Rafn Benediktsson, Runolfur Palsson, Daniel F Gudbjartsson, Isleifur Olafsson, Unnur Thorsteinsdottir, Patrick Sulem, Kari Stefansson

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Abstract

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. Two 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.

Original language	English
Pages (from-to)	1199-1211
Number of pages	13
Journal	Human Molecular Genetics
Volume	28
Issue number	7
Early online date	24 Nov 2018
DOIs	https://doi.org/10.1093/hmg/ddy409
Publication status	Published - 1 Apr 2019

Keywords

Adult
Aged
Alleles
Biomarkers/analysis
Female
Genetic Variation/genetics
Hematuria/genetics
Humans
Hydrogen-Ion Concentration
Iceland
Ketosis/genetics
Kidney/metabolism
Male
Middle Aged
Proteinuria/genetics
Sodium-Glucose Transporter 2/genetics
Whole Genome Sequencing/methods

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Benonisdottir, S., Kristjansson, R. P., Oddsson, A., Steinthorsdottir, V., Mikaelsdottir, E., Kehr, B., Jensson, B. O., Arnadottir, G. A., Sulem, G., Sveinbjornsson, G., Kristmundsdottir, S., Ivarsdottir, E. V., Vogel, L. K., Tragante, V., Gunnarsson, B., Runolfsdottir, H. L., Arthur, J. G., Deaton, A. M., Eyjolfsson, G. I., ... Stefansson, K. (2019). Sequence variants associating with urinary biomarkers. Human Molecular Genetics, 28(7), 1199-1211. https://doi.org/10.1093/hmg/ddy409

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title = "Sequence variants associating with urinary biomarkers",

abstract = "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. Two 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.",

keywords = "Adult, Aged, Alleles, Biomarkers/analysis, Female, Genetic Variation/genetics, Hematuria/genetics, Humans, Hydrogen-Ion Concentration, Iceland, Ketosis/genetics, Kidney/metabolism, Male, Middle Aged, Proteinuria/genetics, Sodium-Glucose Transporter 2/genetics, Whole Genome Sequencing/methods",

author = "Stefania Benonisdottir and Kristjansson, {Ragnar P} and Asmundur Oddsson and Valgerdur Steinthorsdottir and Evgenia Mikaelsdottir and Birte Kehr and Jensson, {Brynjar O} and Arnadottir, {Gudny A} and Gerald Sulem and Gardar Sveinbjornsson and Snaedis Kristmundsdottir and Ivarsdottir, {Erna V} and Vogel, {Lotte K} and Vinicius Tragante and Bjarni Gunnarsson and Runolfsdottir, {Hrafnhildur Linnet} and Arthur, {Joseph G} and Deaton, {Aimee M} and Eyjolfsson, {Gudmundur I} and Davidsson, {Olafur B} and Asselbergs, {Folkert W} and Hreidarsson, {Astradur B} and Thorunn Rafnar and Gudmar Thorleifsson and Vidar Edvardsson and Gunnar Sigurdsson and Anna Helgadottir and Halldorsson, {Bjarni V} and Gisli Masson and Hilma Holm and Onundarson, {Pall T} and Indridason, {Olafur S} and Rafn Benediktsson and Runolfur Palsson and Gudbjartsson, {Daniel F} and Isleifur Olafsson and Unnur Thorsteinsdottir and Patrick Sulem and Kari Stefansson",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2018. Published by Oxford University Press.",

year = "2019",

month = apr,

day = "1",

doi = "10.1093/hmg/ddy409",

language = "English",

volume = "28",

pages = "1199--1211",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

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Benonisdottir, S, Kristjansson, RP, Oddsson, A, Steinthorsdottir, V, Mikaelsdottir, E, Kehr, B, Jensson, BO, Arnadottir, GA, Sulem, G, Sveinbjornsson, G, Kristmundsdottir, S, Ivarsdottir, EV, Vogel, LK, Tragante, V, Gunnarsson, B, Runolfsdottir, HL, Arthur, JG, Deaton, AM, Eyjolfsson, GI, Davidsson, OB, Asselbergs, FW, Hreidarsson, AB, Rafnar, T, Thorleifsson, G, Edvardsson, V, Sigurdsson, G, Helgadottir, A, Halldorsson, BV, Masson, G, Holm, H, Onundarson, PT, Indridason, OS, Benediktsson, R, Palsson, R, Gudbjartsson, DF, Olafsson, I, Thorsteinsdottir, U, Sulem, P & Stefansson, K 2019, 'Sequence variants associating with urinary biomarkers', Human Molecular Genetics, vol. 28, no. 7, pp. 1199-1211. https://doi.org/10.1093/hmg/ddy409

TY - JOUR

T1 - Sequence variants associating with urinary biomarkers

AU - Benonisdottir, Stefania

AU - Kristjansson, Ragnar P

AU - Oddsson, Asmundur

AU - Steinthorsdottir, Valgerdur

AU - Mikaelsdottir, Evgenia

AU - Kehr, Birte

AU - Jensson, Brynjar O

AU - Arnadottir, Gudny A

AU - Sulem, Gerald

AU - Sveinbjornsson, Gardar

AU - Kristmundsdottir, Snaedis

AU - Ivarsdottir, Erna V

AU - Vogel, Lotte K

AU - Tragante, Vinicius

AU - Gunnarsson, Bjarni

AU - Runolfsdottir, Hrafnhildur Linnet

AU - Arthur, Joseph G

AU - Deaton, Aimee M

AU - Eyjolfsson, Gudmundur I

AU - Davidsson, Olafur B

AU - Asselbergs, Folkert W

AU - Hreidarsson, Astradur B

AU - Rafnar, Thorunn

AU - Thorleifsson, Gudmar

AU - Edvardsson, Vidar

AU - Sigurdsson, Gunnar

AU - Helgadottir, Anna

AU - Halldorsson, Bjarni V

AU - Masson, Gisli

AU - Holm, Hilma

AU - Onundarson, Pall T

AU - Indridason, Olafur S

AU - Benediktsson, Rafn

AU - Palsson, Runolfur

AU - Gudbjartsson, Daniel F

AU - Olafsson, Isleifur

AU - Thorsteinsdottir, Unnur

AU - Sulem, Patrick

AU - Stefansson, Kari

PY - 2019/4/1

Y1 - 2019/4/1

N2 - 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. Two 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.

AB - 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. Two 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.

KW - Adult

KW - Aged

KW - Alleles

KW - Biomarkers/analysis

KW - Female

KW - Genetic Variation/genetics

KW - Hematuria/genetics

KW - Humans

KW - Hydrogen-Ion Concentration

KW - Iceland

KW - Ketosis/genetics

KW - Kidney/metabolism

KW - Male

KW - Middle Aged

KW - Proteinuria/genetics

KW - Sodium-Glucose Transporter 2/genetics

KW - Whole Genome Sequencing/methods

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U2 - 10.1093/hmg/ddy409

DO - 10.1093/hmg/ddy409

M3 - Article

C2 - 30476138

SN - 0964-6906

VL - 28

SP - 1199

EP - 1211

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 7

ER -

Sequence variants associating with urinary biomarkers

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