Idiopathic achalasia is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus1,2. 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-DQβ1 (encoded by HLA-DQB1*05:03 and HLA-DQB1*06:01) confers the strongest risk for achalasia (P = 1.73 × 10−19). In addition, two amino acid substitutions in the extracellular domain of HLA-DQα1 at position 41 (lysine encoded by HLA-DQA1*01:03; P = 5.60 × 10−10) and of HLA-DQβ1 at position 45 (glutamic acid encoded by HLA-DQB1*03:01 and HLA-DQB1*03:04; P = 1.20 × 10−9) independently confer achalasia risk. Our study implies that immune-mediated processes are involved in the pathophysiology of achalasia.
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We thank all subjects for participating to this study. We acknowledge our collaborating clinical partners, all colleagues who contributed to patient recruitment, and our laboratory technicians and colleagues responsible for database management (for a complete list of all individuals, see the Supplementary Note). I.G., M.K. and J.S. received support for this work from the Deutsche Forschungsgemeinschaft (DFG), individual grants GO 1795/1-1, KN 378/2-1 and SCHU 1596/5-1. M.M.N. received support for this work from the Alfried Krupp von Bohlen und Halbach-Stiftung. M.M.N. is a member of the DFG-funded Excellence Cluster ImmunoSensation. The Heinz Nixdorf Recall cohort was established with the generous support of the Heinz Nixdorf Foundation, Germany. We thank B. Pötzsch (University of Bonn) for help with collecting DNA samples from anonymous blood donors. In addition, we thank the Type I Diabetes Genetics Consortium (T1DGC) for data access and J. Sauter (German Bone Marrow Donor Center (DKMS), Tübingen) for help differentiating HLA-DQA1 alleles. P.I.W.d.B. is the recipient of a Vernieuwingsimpuls VIDI Award from the Netherlands Organization for Scientific Research (NWO project 016.126.354). M.M.W. is supported by a postdoctoral fellowship of the Fund for Scientific Research (FWO) Flanders, Belgium. G.E.B. is supported by a grant from the Research Foundation–Flanders (FWO) (Odysseus program). K.-P.H. is supported by DFG SFB 684 and the Center for Integrated Protein Sciences Munich.
The authors declare no competing financial interests.
Integrated supplementary information
(a) The strongest genetic determinant of achalasia risk represents an 8-residue insertion at position 227–234 in HLA-DQβ1. (b) Subsequent conditional analysis controlling for this insertion as well as for amino acid changes at position 41/130 in HLA-DQα1 and position 45 in HLA-DQβ1 revealed no further independent association within the MHC region (P > 1 × 10−6).
This figure shows the comparison of the disease risk predicted by a full logistic regression model in which each HLA-DQ allele confers its own unique risk (y axis) with the disease risk predicted by a simpler logistic regression model in which risk is defined by HLA-DQβ1 positions 227–234 and 45 as well as HLA-DQα1 position 41/130 (x axis). Patients are represented in red, and controls are represented in blue.
Representation of our study sample and HapMap individuals for the first two dimensions obtained by multidimensional scaling analysis of a matrix of pairwise IBS (identical-by-state) distance values between samples.
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Gockel, I., Becker, J., Wouters, M. et al. Common variants in the HLA-DQ region confer susceptibility to idiopathic achalasia. Nat Genet 46, 901–904 (2014). https://doi.org/10.1038/ng.3029
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