6533b7d3fe1ef96bd1260c22
RESEARCH PRODUCT
Common variants in the HLA-DQ region confer susceptibility to idiopathic achalasia
Luigi LaghiJens U. MarquardtLude FrankeHarm-jan WestraRalf KiesslichCisca WijmengaJulio Perez De La SernaRosario CuomoJan TackPeter R. GalleInes GockelHenning G. SchulzGiovanni SarnelliDaniel DrescherJessica BeckerStefan NiebischElisabeth MangoldAnna LatianoPaul I.w. De BakkerV. AnneseUberto FumagalliAntonio Ruiz De LeónMichael T. HenekaAlexander J. EckardtPer HoffmannMira M. WoutersHans Dieter AllescherJulian ZimmermannTimo HessWerner KneistElena UrcelayAna G. VigoHauke LangMarkus M. NöthenGosia TrynkaHenning R. GockelBurkhard H.a. Von RahdenVinod KumarKarl-peter HopfnerKarl-peter HopfnerDavid RamonetStefan HermsStefanie HeilmannMichael KnappMichaela MüllerGuy E. BoeckxstaensJohannes SchumacherManuel Mattheisensubject
MaleModels MolecularAchalasiaImmunogeneticsBiologyMajor histocompatibility complexPolymorphism Single Nucleotidedigestive systemHLA-DQ alpha-ChainsHLA-DQ AntigensHLA-DQotorhinolaryngologic diseasesGeneticsmedicineHLA-DQ beta-ChainsHumansGenetic Predisposition to DiseaseEsophagusAllelesGenetic Association StudiesGenetic associationGeneticsAchalasiaMotility disorderASSOCIATIONmedicine.diseasedigestive system diseasesEsophageal AchalasiaINSIGHTSLogistic Modelsmedicine.anatomical_structureAmino Acid SubstitutionHaplotypesCase-Control StudiesImmunologybiology.proteinFemaleIdiopathic achalasiageneticMHCdescription
Idiopathic achalasia is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus(1,2). This ultimately leads to massive dilatation and an irreversibly impaired megaesophagus. We performed a genetic association study in 1,068 achalasia cases and 4,242 controls and fine-mapped a strong MHC association signal by imputing classical HLA haplotypes and amino acid polymorphisms. An eight-residue insertion at position 227-234 in the cytoplasmic tail of HLA-DQ beta 1 (encoded by HLA-DQB1*05:03 and HLA-DQB1*06:01) confers the strongest risk for achalasia (P = 1.73 x 10(-19)). In addition, two amino acid substitutions in the. extracellular domain of HLA-DQ alpha 1 at position 41 (lysine encoded by HLA-DQA1*01:03; P = 5.60 x 10(-10)) and of HLA-DQ beta 1 at position 45 (glutamic acid encoded by HLA-DQB1*03:01 and HLA-DQB1*03:04; P = 1.20 x 10(-9)) independently confer achalasia risk. Our study implies that immune-mediated processes are involved in the pathophysiology of achalasia.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2014-08-01 | Nature Genetics |