6533b824fe1ef96bd12813ec
RESEARCH PRODUCT
Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene
Lj DavisonC WallaceJd CooperNf CopeNk WilsonDj SmythJm HowsonN SalehA Al-jefferyKl AngusHe StevensS NutlandS DuleyRm CoulsonNm WalkerOs BurrenCm RiceF CambienT ZellerT MunzelK LacknerS BlakenbergP FraserB GottgensJa ToddT AttwoodS BelzP BraundF CambienJ CooperA Crisp-hihnP DiemertP DeloukasN FoadJ ErdmannAh GoodallJ GraceyE GrayRg WilliamsS HeimerlC HengstenbergJ JolleyU KrishnanH Lloyd-jonesI LugauerP LundmarkS MaoucheJs MooreD MuirE MurrayCp NelsonJ NeudertD NiblettK O'learyWh OuwehandH PollardA RankinCm RiceH SagerNj SamaniJ SambrookG SchmitzM ScholzL SchroederH SchunkertAc SyvannenS TennstedtC Wallacesubject
Candidate geneQuantitative Trait LociSingle-nucleotide polymorphismBiologyPolymerase Chain ReactionPolymorphism Single NucleotideMonocytesAutoimmune Diseases03 medical and health sciences0302 clinical medicineGeneticsHumansEnhancerMolecular BiologyGeneGenetics (clinical)030304 developmental biologyGenetics0303 health sciencesIntronMembrane ProteinsPromoterGeneral MedicineArticlesDNADNA-Binding ProteinsRegulatory sequenceCandidate Disease Gene030217 neurology & neurosurgeryChromosomes Human Pair 16description
The chromosome 16p13 region has been associated with several autoimmune diseases, including type 1 diabetes (T1D) and multiple sclerosis (MS). CLEC16A has been reported as the most likely candidate gene in the region, since it contains the most disease-associated single-nucleotide polymorphisms (SNPs), as well as an imunoreceptor tyrosine-based activation motif. However, here we report that intron 19 of CLEC16A, containing the most autoimmune disease-associated SNPs, appears to behave as a regulatory sequence, affecting the expression of a neighbouring gene, DEXI. The CLEC16A alleles that are protective from T1D and MS are associated with increased expression of DEXI, and no other genes in the region, in two independent monocyte gene expression data sets. Critically, using chromosome conformation capture (3C), we identified physical proximity between the DEXI promoter region and intron 19 of CLEC16A, separated by a loop of >150 kb. In reciprocal experiments, a 20 kb fragment of intron 19 of CLEC16A, containing SNPs associated with T1D and MS, as well as with DEXI expression, interacted with the promotor region of DEXI but not with candidate DNA fragments containing other potential causal genes in the region, including CLEC16A. Intron 19 of CLEC16A is highly enriched for transcription-factor-binding events and markers associated with enhancer activity. Taken together, these data indicate that although the causal variants in the 16p13 region lie within CLEC16A, DEXI is an unappreciated autoimmune disease candidate gene, and illustrate the power of the 3C approach in progressing from genome-wide association studies results to candidate causal genes.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2011-10-11 | Human Molecular Genetics |