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Åke Lernmark

Principal investigator

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

Author

  • Samina Asad
  • Pernilla Nikamo
  • Alexandra Gyllenberg
  • Hedvig Bennet
  • Ola Hansson
  • Nils Wierup
  • Annelie Carlsson
  • Gun Forsander
  • Sten Ivarsson
  • Helena Larsson
  • Åke Lernmark
  • Bengt Lindblad
  • Johnny Ludvigsson
  • Claude Marcus
  • Kjersti S. Ronningen
  • Jan Nerup
  • Flemming Pociot
  • Holger Luthman
  • Malin Fex
  • Ingrid Kockum

Summary, in English

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.

Department/s

  • Diabetes and Celiac Unit
  • Paediatrics (Lund)
  • Paediatric Endocrinology
  • Genetics
  • EXODIAB: Excellence in Diabetes Research in Sweden

Publishing year

2012

Language

English

Publication/Series

PLoS ONE

Volume

7

Issue

5

Document type

Journal article

Publisher

Public Library of Science

Topic

  • Pediatrics
  • Endocrinology and Diabetes

Status

Published

Research group

  • Diabetes and Celiac Unit
  • Paediatric Endocrinology
  • Genetics

ISBN/ISSN/Other

  • ISSN: 1932-6203