G/T substitution in intron 1 of the UNC13B gene is associated with increased risk of nephropathy in patients with type 1 diabetes

David-Alexandre Tregouet; Per-Henrik Groop; Steven McGinn; Carol Forsblom; Samy Hadjadj; Michel Marre; Hans-Henrik Parving; Lise Tarnow; Ralph Telgmann; Tiphaine Godefroy; Viviane Nicaud; Rachel Rousseau; Maikki Parkkonen; Anna Hoverfält; Ivo Gut; Simon Heath; Fumihiko Matsuda; Roger D Cox; Gbenga R Kazeem; Martin Farrall; Dominique Gauguier; Stefan-Martin Brand-Herrmann; Francois Cambien; Mark Lathrop; Nathalie Vionnet; EURAGEDIC Consortium

doi:10.2337/db08-0073

G/T substitution in intron 1 of the UNC13B gene is associated with increased risk of nephropathy in patients with type 1 diabetes

David-Alexandre Tregouet, Per-Henrik Groop, Steven McGinn, Carol Forsblom, Samy Hadjadj, Michel Marre, Hans-Henrik Parving, Lise Tarnow, Ralph Telgmann, Tiphaine Godefroy, Viviane Nicaud, Rachel Rousseau, Maikki Parkkonen, Anna Hoverfält, Ivo Gut, Simon Heath, Fumihiko Matsuda, Roger D Cox, Gbenga R Kazeem, Martin FarrallDominique Gauguier, Stefan-Martin Brand-Herrmann, Francois Cambien, Mark Lathrop, Nathalie Vionnet, EURAGEDIC Consortium

37 Citationer (Scopus)

Abstract

OBJECTIVE: Genetic and environmental factors modulate the susceptibility to diabetic nephropathy, as initiating and/or progression factors. The objective of the European Rational Approach for the Genetics of Diabetic Complications (EURAGEDIC) study is to identify nephropathy susceptibility genes. We report molecular genetic studies for 127 candidate genes for nephropathy.

RESEARCH DESIGN AND METHODS: Polymorphisms were identified through sequencing of promoter, exon, and flanking intron gene regions and a database search. A total of 344 nonredundant SNPs and nonsynonymous variants were tested for association with diabetic nephropathy (persistent albuminuria >/=300 mg/24 h) in a large type 1 diabetes case/control (1,176/1,323) study from three European populations.

RESULTS: Only one SNP, rs2281999, located in the UNC13B gene, was significantly associated with nephropathy after correction for multiple testing. Analyses of 21 additional markers fully characterizing the haplotypic variability of the UNC13B gene showed consistent association of SNP rs13293564 (G/T) located in intron 1 of the gene with nephropathy in the three populations. The odds ratio (OR) for nephropathy associated with the TT genotype was 1.68 (95% CI 1.29-2.19) (P = 1.0 x 10(-4)). This association was replicated in an independent population of 412 case subjects and 614 control subjects (combined OR of 1.63 [95% CI 1.30-2.05], P = 2.3 x 10(-5)).

CONCLUSIONS: We identified a polymorphism in the UNC13B gene associated with nephropathy. UNC13B mediates apopotosis in glomerular cells in the presence of hyperglycemia, an event occurring early in the development of nephropathy. We propose that this polymorphism could be a marker for the initiation of nephropathy. However, further studies are needed to clarify the role of UNC13B in nephropathy.

Originalsprog	Engelsk
Tidsskrift	Diabetes
Vol/bind	57
Udgave nummer	10
Sider (fra-til)	2843-50
Antal sider	8
ISSN	0012-1797
DOI	https://doi.org/10.2337/db08-0073
Status	Udgivet - okt. 2008

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10.2337/db08-0073

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Tregouet, D.-A., Groop, P.-H., McGinn, S., Forsblom, C., Hadjadj, S., Marre, M., Parving, H.-H., Tarnow, L., Telgmann, R., Godefroy, T., Nicaud, V., Rousseau, R., Parkkonen, M., Hoverfält, A., Gut, I., Heath, S., Matsuda, F., Cox, R. D., Kazeem, G. R., ... EURAGEDIC Consortium (2008). G/T substitution in intron 1 of the UNC13B gene is associated with increased risk of nephropathy in patients with type 1 diabetes. Diabetes, 57(10), 2843-50. https://doi.org/10.2337/db08-0073

Tregouet, D-A, Groop, P-H, McGinn, S, Forsblom, C, Hadjadj, S, Marre, M, Parving, H-H, Tarnow, L, Telgmann, R, Godefroy, T, Nicaud, V, Rousseau, R, Parkkonen, M, Hoverfält, A, Gut, I, Heath, S, Matsuda, F, Cox, RD, Kazeem, GR, Farrall, M, Gauguier, D, Brand-Herrmann, S-M, Cambien, F, Lathrop, M, Vionnet, N & EURAGEDIC Consortium 2008, 'G/T substitution in intron 1 of the UNC13B gene is associated with increased risk of nephropathy in patients with type 1 diabetes', Diabetes, bind 57, nr. 10, s. 2843-50. https://doi.org/10.2337/db08-0073

@article{652bb33f651e482284e59c7d41d3bdab,

title = "G/T substitution in intron 1 of the UNC13B gene is associated with increased risk of nephropathy in patients with type 1 diabetes",

abstract = "OBJECTIVE: Genetic and environmental factors modulate the susceptibility to diabetic nephropathy, as initiating and/or progression factors. The objective of the European Rational Approach for the Genetics of Diabetic Complications (EURAGEDIC) study is to identify nephropathy susceptibility genes. We report molecular genetic studies for 127 candidate genes for nephropathy.RESEARCH DESIGN AND METHODS: Polymorphisms were identified through sequencing of promoter, exon, and flanking intron gene regions and a database search. A total of 344 nonredundant SNPs and nonsynonymous variants were tested for association with diabetic nephropathy (persistent albuminuria >/=300 mg/24 h) in a large type 1 diabetes case/control (1,176/1,323) study from three European populations.RESULTS: Only one SNP, rs2281999, located in the UNC13B gene, was significantly associated with nephropathy after correction for multiple testing. Analyses of 21 additional markers fully characterizing the haplotypic variability of the UNC13B gene showed consistent association of SNP rs13293564 (G/T) located in intron 1 of the gene with nephropathy in the three populations. The odds ratio (OR) for nephropathy associated with the TT genotype was 1.68 (95% CI 1.29-2.19) (P = 1.0 x 10(-4)). This association was replicated in an independent population of 412 case subjects and 614 control subjects (combined OR of 1.63 [95% CI 1.30-2.05], P = 2.3 x 10(-5)).CONCLUSIONS: We identified a polymorphism in the UNC13B gene associated with nephropathy. UNC13B mediates apopotosis in glomerular cells in the presence of hyperglycemia, an event occurring early in the development of nephropathy. We propose that this polymorphism could be a marker for the initiation of nephropathy. However, further studies are needed to clarify the role of UNC13B in nephropathy.",

keywords = "Animals, Cell Line, Cell Line, Tumor, Diabetes Mellitus, Type 1, Diabetic Nephropathies, Gene Frequency, Genetic Predisposition to Disease, Genotype, Haplotypes, HeLa Cells, Humans, Introns, Nerve Tissue Proteins, Odds Ratio, Polymorphism, Single Nucleotide, Rats, Risk Factors, Journal Article, Research Support, Non-U.S. Gov't",

author = "David-Alexandre Tregouet and Per-Henrik Groop and Steven McGinn and Carol Forsblom and Samy Hadjadj and Michel Marre and Hans-Henrik Parving and Lise Tarnow and Ralph Telgmann and Tiphaine Godefroy and Viviane Nicaud and Rachel Rousseau and Maikki Parkkonen and Anna Hoverf{\"a}lt and Ivo Gut and Simon Heath and Fumihiko Matsuda and Cox, {Roger D} and Kazeem, {Gbenga R} and Martin Farrall and Dominique Gauguier and Stefan-Martin Brand-Herrmann and Francois Cambien and Mark Lathrop and Nathalie Vionnet and {EURAGEDIC Consortium}",

year = "2008",

month = oct,

doi = "10.2337/db08-0073",

language = "English",

volume = "57",

pages = "2843--50",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association",

number = "10",

}

TY - JOUR

T1 - G/T substitution in intron 1 of the UNC13B gene is associated with increased risk of nephropathy in patients with type 1 diabetes

AU - Tregouet, David-Alexandre

AU - Groop, Per-Henrik

AU - McGinn, Steven

AU - Forsblom, Carol

AU - Hadjadj, Samy

AU - Marre, Michel

AU - Parving, Hans-Henrik

AU - Tarnow, Lise

AU - Telgmann, Ralph

AU - Godefroy, Tiphaine

AU - Nicaud, Viviane

AU - Rousseau, Rachel

AU - Parkkonen, Maikki

AU - Hoverfält, Anna

AU - Gut, Ivo

AU - Heath, Simon

AU - Matsuda, Fumihiko

AU - Cox, Roger D

AU - Kazeem, Gbenga R

AU - Farrall, Martin

AU - Gauguier, Dominique

AU - Brand-Herrmann, Stefan-Martin

AU - Cambien, Francois

AU - Lathrop, Mark

AU - Vionnet, Nathalie

AU - EURAGEDIC Consortium

PY - 2008/10

Y1 - 2008/10

N2 - OBJECTIVE: Genetic and environmental factors modulate the susceptibility to diabetic nephropathy, as initiating and/or progression factors. The objective of the European Rational Approach for the Genetics of Diabetic Complications (EURAGEDIC) study is to identify nephropathy susceptibility genes. We report molecular genetic studies for 127 candidate genes for nephropathy.RESEARCH DESIGN AND METHODS: Polymorphisms were identified through sequencing of promoter, exon, and flanking intron gene regions and a database search. A total of 344 nonredundant SNPs and nonsynonymous variants were tested for association with diabetic nephropathy (persistent albuminuria >/=300 mg/24 h) in a large type 1 diabetes case/control (1,176/1,323) study from three European populations.RESULTS: Only one SNP, rs2281999, located in the UNC13B gene, was significantly associated with nephropathy after correction for multiple testing. Analyses of 21 additional markers fully characterizing the haplotypic variability of the UNC13B gene showed consistent association of SNP rs13293564 (G/T) located in intron 1 of the gene with nephropathy in the three populations. The odds ratio (OR) for nephropathy associated with the TT genotype was 1.68 (95% CI 1.29-2.19) (P = 1.0 x 10(-4)). This association was replicated in an independent population of 412 case subjects and 614 control subjects (combined OR of 1.63 [95% CI 1.30-2.05], P = 2.3 x 10(-5)).CONCLUSIONS: We identified a polymorphism in the UNC13B gene associated with nephropathy. UNC13B mediates apopotosis in glomerular cells in the presence of hyperglycemia, an event occurring early in the development of nephropathy. We propose that this polymorphism could be a marker for the initiation of nephropathy. However, further studies are needed to clarify the role of UNC13B in nephropathy.

AB - OBJECTIVE: Genetic and environmental factors modulate the susceptibility to diabetic nephropathy, as initiating and/or progression factors. The objective of the European Rational Approach for the Genetics of Diabetic Complications (EURAGEDIC) study is to identify nephropathy susceptibility genes. We report molecular genetic studies for 127 candidate genes for nephropathy.RESEARCH DESIGN AND METHODS: Polymorphisms were identified through sequencing of promoter, exon, and flanking intron gene regions and a database search. A total of 344 nonredundant SNPs and nonsynonymous variants were tested for association with diabetic nephropathy (persistent albuminuria >/=300 mg/24 h) in a large type 1 diabetes case/control (1,176/1,323) study from three European populations.RESULTS: Only one SNP, rs2281999, located in the UNC13B gene, was significantly associated with nephropathy after correction for multiple testing. Analyses of 21 additional markers fully characterizing the haplotypic variability of the UNC13B gene showed consistent association of SNP rs13293564 (G/T) located in intron 1 of the gene with nephropathy in the three populations. The odds ratio (OR) for nephropathy associated with the TT genotype was 1.68 (95% CI 1.29-2.19) (P = 1.0 x 10(-4)). This association was replicated in an independent population of 412 case subjects and 614 control subjects (combined OR of 1.63 [95% CI 1.30-2.05], P = 2.3 x 10(-5)).CONCLUSIONS: We identified a polymorphism in the UNC13B gene associated with nephropathy. UNC13B mediates apopotosis in glomerular cells in the presence of hyperglycemia, an event occurring early in the development of nephropathy. We propose that this polymorphism could be a marker for the initiation of nephropathy. However, further studies are needed to clarify the role of UNC13B in nephropathy.

KW - Animals

KW - Cell Line

KW - Cell Line, Tumor

KW - Diabetes Mellitus, Type 1

KW - Diabetic Nephropathies

KW - Gene Frequency

KW - Genetic Predisposition to Disease

KW - Genotype

KW - Haplotypes

KW - HeLa Cells

KW - Humans

KW - Introns

KW - Nerve Tissue Proteins

KW - Odds Ratio

KW - Polymorphism, Single Nucleotide

KW - Rats

KW - Risk Factors

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.2337/db08-0073

DO - 10.2337/db08-0073

M3 - Journal article

C2 - 18633107

SN - 0012-1797

VL - 57

SP - 2843

EP - 2850

JO - Diabetes

JF - Diabetes

IS - 10

ER -

G/T substitution in intron 1 of the UNC13B gene is associated with increased risk of nephropathy in patients with type 1 diabetes

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