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G/T Substitution in Intron 1 of the UNC13B Gene Is Associated With Increased Risk of Nephropathy in Patients With Type 1 Diabetes
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...
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American Diabetes Association
2008
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| Acesso em linha: | https://ncbi.nlm.nih.gov/pmc/articles/PMC2551697/ https://ncbi.nlm.nih.gov/pubmed/18633107 https://ncbi.nlm.nih.govhttp://dx.doi.org/10.2337/db08-0073 |
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pubmed-25516972009-10-01 G/T Substitution in Intron 1 of the UNC13B Gene Is Associated With Increased Risk of Nephropathy in Patients With Type 1 Diabetes Trégouet, David-Alexandre Groop, Per-Henrik McGinn, Steven Forsblom, Carol Hadjadj, Samy Marre, Michel Parving, Hans-Henrik Tarnow, Lise Telgmann, Ralph Godefroy, Tiphaine Nicaud, Viviane Rousseau, Rachel Parkkonen, Maikki Hoverfält, Anna Gut, Ivo Heath, Simon Matsuda, Fumihiko Cox, Roger Kazeem, Gbenga Farrall, Martin Gauguier, Dominique Brand-Herrmann, Stefan-Martin Cambien, François Lathrop, Mark Vionnet, Nathalie Diabetes Genetics 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 × 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 × 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. American Diabetes Association 2008-10 /pmc/articles/PMC2551697/ /pubmed/18633107 http://dx.doi.org/10.2337/db08-0073 Text en Copyright © 2008, American Diabetes Association Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. |
| institution |
US National Library of Medicine |
| collection |
PubMed Central |
| language |
English |
| format |
Article |
| topic |
Genetics |
| spellingShingle |
Genetics Trégouet, David-Alexandre Groop, Per-Henrik McGinn, Steven Forsblom, Carol Hadjadj, Samy Marre, Michel Parving, Hans-Henrik Tarnow, Lise Telgmann, Ralph Godefroy, Tiphaine Nicaud, Viviane Rousseau, Rachel Parkkonen, Maikki Hoverfält, Anna Gut, Ivo Heath, Simon Matsuda, Fumihiko Cox, Roger Kazeem, Gbenga Farrall, Martin Gauguier, Dominique Brand-Herrmann, Stefan-Martin Cambien, François Lathrop, Mark Vionnet, Nathalie G/T Substitution in Intron 1 of the UNC13B Gene Is Associated With Increased Risk of Nephropathy in Patients With Type 1 Diabetes |
| description |
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 × 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 × 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. |
| author |
Trégouet, David-Alexandre Groop, Per-Henrik McGinn, Steven Forsblom, Carol Hadjadj, Samy Marre, Michel Parving, Hans-Henrik Tarnow, Lise Telgmann, Ralph Godefroy, Tiphaine Nicaud, Viviane Rousseau, Rachel Parkkonen, Maikki Hoverfält, Anna Gut, Ivo Heath, Simon Matsuda, Fumihiko Cox, Roger Kazeem, Gbenga Farrall, Martin Gauguier, Dominique Brand-Herrmann, Stefan-Martin Cambien, François Lathrop, Mark Vionnet, Nathalie |
| author_facet |
Trégouet, David-Alexandre Groop, Per-Henrik McGinn, Steven Forsblom, Carol Hadjadj, Samy Marre, Michel Parving, Hans-Henrik Tarnow, Lise Telgmann, Ralph Godefroy, Tiphaine Nicaud, Viviane Rousseau, Rachel Parkkonen, Maikki Hoverfält, Anna Gut, Ivo Heath, Simon Matsuda, Fumihiko Cox, Roger Kazeem, Gbenga Farrall, Martin Gauguier, Dominique Brand-Herrmann, Stefan-Martin Cambien, François Lathrop, Mark Vionnet, Nathalie |
| author_sort |
Trégouet, David-Alexandre |
| title |
G/T Substitution in Intron 1 of the UNC13B Gene Is Associated With Increased Risk of Nephropathy in Patients With Type 1 Diabetes |
| title_short |
G/T Substitution in Intron 1 of the UNC13B Gene Is Associated With Increased Risk of Nephropathy in Patients With Type 1 Diabetes |
| title_full |
G/T Substitution in Intron 1 of the UNC13B Gene Is Associated With Increased Risk of Nephropathy in Patients With Type 1 Diabetes |
| title_fullStr |
G/T Substitution in Intron 1 of the UNC13B Gene Is Associated With Increased Risk of Nephropathy in Patients With Type 1 Diabetes |
| title_full_unstemmed |
G/T Substitution in Intron 1 of the UNC13B Gene Is Associated With Increased Risk of Nephropathy in Patients With Type 1 Diabetes |
| title_sort |
g/t substitution in intron 1 of the unc13b gene is associated with increased risk of nephropathy in patients with type 1 diabetes |
| publisher |
American Diabetes Association |
| publisher_facet |
American Diabetes Association |
| publishDate |
2008 |
| url |
https://ncbi.nlm.nih.gov/pmc/articles/PMC2551697/ https://ncbi.nlm.nih.gov/pubmed/18633107 https://ncbi.nlm.nih.govhttp://dx.doi.org/10.2337/db08-0073 |
| _version_ |
1760735443948666880 |