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HTR1A a Novel Type 1 Diabetes Susceptibility Gene on Chromosome 5p13-q13

Asad, Samina; Nikamo, Pernilla; Gyllenberg, Alexandra; Bennet, Hedvig LU ; Hansson, Ola; Wierup, Nils; Carlsson, Annelie LU ; Forsander, Gun; Ivarsson, Sten LU and Larsson, Helena LU , et al. (2012) In PLoS ONE 7(5).
Abstract
Background: We have previously performed a genome-wide linkage study in Scandinavian Type 1 diabetes (T1D) families. In the Swedish families, we detected suggestive linkage (LOD <= 2.2) to the chromosome 5p13-q13 region. The aim of our study was to investigate the linked region in search for possible T1D susceptibility genes. Methodology/Principal Findings: Microsatellites were genotyped in the Scandinavian families to fine-map the previously linked region. Further, SNPs were genotyped in Swedish and Danish families as well as Swedish sporadic cases. In the Swedish families we detected genome-wide significant linkage to the 5-hydroxytryptamine receptor 1A (HTR1A) gene (LOD 3.98, p<9.8x10(-6)). Markers tagging two separate genes; the... (More)
Background: We have previously performed a genome-wide linkage study in Scandinavian Type 1 diabetes (T1D) families. In the Swedish families, we detected suggestive linkage (LOD <= 2.2) to the chromosome 5p13-q13 region. The aim of our study was to investigate the linked region in search for possible T1D susceptibility genes. Methodology/Principal Findings: Microsatellites were genotyped in the Scandinavian families to fine-map the previously linked region. Further, SNPs were genotyped in Swedish and Danish families as well as Swedish sporadic cases. In the Swedish families we detected genome-wide significant linkage to the 5-hydroxytryptamine receptor 1A (HTR1A) gene (LOD 3.98, p<9.8x10(-6)). Markers tagging two separate genes; the ring finger protein 180 (RNF180) and HTR1A showed association to T1D in the Swedish and Danish families (p<0.002, p<0.001 respectively). The association was not confirmed in sporadic cases. Conditional analysis indicates that the primary association was to HTR1A. Quantitative PCR show that transcripts of both HTR1A and RNF180 are present in human islets of Langerhans. Moreover, immunohistochemical analysis confirmed the presence of the 5-HTR1A protein in isolated human islets of Langerhans as well as in sections of human pancreas. Conclusions: We have identified and confirmed the association of both HTR1A and RFN180, two genes in high linkage disequilibrium (LD) to T1D in two separate family materials. As both HTR1A and RFN180 were expressed at the mRNA level and HTR1A as protein in human islets of Langerhans, we suggest that HTR1A may affect T1D susceptibility by modulating the initial autoimmune attack or either islet regeneration, insulin release, or both. (Less)
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PLoS ONE
volume
7
issue
5
publisher
Public Library of Science
external identifiers
  • wos:000305340700010
  • scopus:84860435923
ISSN
1932-6203
DOI
10.1371/journal.pone.0035439
language
English
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yes
id
bc26dd4b-904b-40a6-87c3-60281e1f2451 (old id 2890848)
date added to LUP
2012-08-01 08:55:08
date last changed
2017-07-23 04:19:46
@article{bc26dd4b-904b-40a6-87c3-60281e1f2451,
  abstract     = {Background: We have previously performed a genome-wide linkage study in Scandinavian Type 1 diabetes (T1D) families. In the Swedish families, we detected suggestive linkage (LOD &lt;= 2.2) to the chromosome 5p13-q13 region. The aim of our study was to investigate the linked region in search for possible T1D susceptibility genes. Methodology/Principal Findings: Microsatellites were genotyped in the Scandinavian families to fine-map the previously linked region. Further, SNPs were genotyped in Swedish and Danish families as well as Swedish sporadic cases. In the Swedish families we detected genome-wide significant linkage to the 5-hydroxytryptamine receptor 1A (HTR1A) gene (LOD 3.98, p&lt;9.8x10(-6)). Markers tagging two separate genes; the ring finger protein 180 (RNF180) and HTR1A showed association to T1D in the Swedish and Danish families (p&lt;0.002, p&lt;0.001 respectively). The association was not confirmed in sporadic cases. Conditional analysis indicates that the primary association was to HTR1A. Quantitative PCR show that transcripts of both HTR1A and RNF180 are present in human islets of Langerhans. Moreover, immunohistochemical analysis confirmed the presence of the 5-HTR1A protein in isolated human islets of Langerhans as well as in sections of human pancreas. Conclusions: We have identified and confirmed the association of both HTR1A and RFN180, two genes in high linkage disequilibrium (LD) to T1D in two separate family materials. As both HTR1A and RFN180 were expressed at the mRNA level and HTR1A as protein in human islets of Langerhans, we suggest that HTR1A may affect T1D susceptibility by modulating the initial autoimmune attack or either islet regeneration, insulin release, or both.},
  author       = {Asad, Samina and Nikamo, Pernilla and Gyllenberg, Alexandra and Bennet, Hedvig and Hansson, Ola and Wierup, Nils and Carlsson, Annelie and Forsander, Gun and Ivarsson, Sten and Larsson, Helena and Lernmark, Åke and Lindblad, Bengt and Ludvigsson, Johnny and Marcus, Claude and Ronningen, Kjersti S. and Nerup, Jan and Pociot, Flemming and Luthman, Holger and Fex, Malin and Kockum, Ingrid},
  issn         = {1932-6203},
  language     = {eng},
  number       = {5},
  publisher    = {Public Library of Science},
  series       = {PLoS ONE},
  title        = {HTR1A a Novel Type 1 Diabetes Susceptibility Gene on Chromosome 5p13-q13},
  url          = {http://dx.doi.org/10.1371/journal.pone.0035439},
  volume       = {7},
  year         = {2012},
}