title: HTR1A a novel type 1 diabetes susceptibility gene on chromosome 5p13-q13.
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.
  
  
  RESULTS
  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<9.8×10(-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.
authors.affiliation: Neuroimmunology Unit, Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Samina
authors.initials: S
authors.lastname: Asad
authors.forename: Pernilla
authors.initials: P
authors.lastname: Nikamo
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gyllenberg
authors.forename: Hedvig
authors.initials: H
authors.lastname: Bennet
authors.forename: Ola
authors.initials: O
authors.lastname: Hansson
authors.forename: Nils
authors.initials: N
authors.lastname: Wierup
authors.forename: Annelie
authors.initials: A
authors.lastname: Carlsson
authors.forename: Gun
authors.initials: G
authors.lastname: Forsander
authors.forename: Sten-Anders
authors.initials: SA
authors.lastname: Ivarsson
authors.forename: Helena
authors.initials: H
authors.lastname: Larsson
authors.forename: Åke
authors.initials: Å
authors.lastname: Lernmark
authors.forename: Bengt
authors.initials: B
authors.lastname: Lindblad
authors.forename: Johnny
authors.initials: J
authors.lastname: Ludvigsson
authors.forename: Claude
authors.initials: C
authors.lastname: Marcus
authors.forename: Kjersti S
authors.initials: KS
authors.lastname: Rønningen
authors.forename: Jan
authors.initials: J
authors.lastname: Nerup
authors.forename: Flemming
authors.initials: F
authors.lastname: Pociot
authors.forename: Holger
authors.initials: H
authors.lastname: Luthman
authors.forename: Malin
authors.initials: M
authors.lastname: Fex
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kockum
mesh_terms: D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D003718:Denmark; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000378:metabolism; D005192:Family Health; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000378:metabolism; D015810:Linkage Disequilibrium; D008126:Lod Score; D020799:Pancrelipase; D020641:Polymorphism, Single Nucleotide; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013548:Sweden; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: D044282:Receptor, Serotonin, 5-HT1A; D020799:Pancrelipase; C571330:RNF180 protein, human; D044767:Ubiquitin-Protein Ligases