A Single Amino Acid In The β1 Chain Of HLA-DR Explains The Majority Of The HLA Association With Giant Cell Arteriti

Javier Martin¹, F. David Carmona², Jose Ezequiel Martin³, Aurora Serrano¹, Lara Bossini-Castillo⁴, Roser Solans⁵, Jose A. Miranda-Filloy⁶, Santos Castañeda⁷, Maria C. Cid⁸, Jose A. Hernandez⁹, Inmaculada C. Morado¹⁰, Javier Narvaez¹¹, Ricardo Blanco¹², Bernardo Sopeña¹³, M. Jesus García-Villanueva¹⁴, Jordi Monfort¹⁵, Norberto Ortego-Centeno¹⁶, Ainhoa Unzurrunzaga¹⁷, Begoña Marí-Alfonso¹⁸, Cesar Magro¹⁹, Ana Hidalgo-Conde²⁰, Marta Conde-Jaldon²¹, María F. González-Escribano²¹, Paul de Bakker²², Bobby P.C. Koeleman²³ and Miguel A. González-Gay²⁴, ¹Instituto de Parasitologia y Biomedicina Lopez-Neyra (IPBLN-CSIC), Granada, Spain, ²Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Armilla (Granada), Spain, ³Immunology, Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Armilla (Granada), Spain, ⁴Immunology, Instituto de Parasitologia y Biomedicina Lopez-Neyra (IPBLN-CSIC), Granada, Spain, ⁵Department of Internal Medicine, Hospital Vall d'Hebron, Barcelona, Spain, ⁶Rheumatology, Division of Rheumatology, Hospital Lucus Augusti, Lugo, Spain, ⁷Rheumatology, Hospital Universitario de La Princesa, IIS Princesa, Madrid, Spain, ⁸Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, ⁹Hospital Clinic. University of Barcelona, IDIBAPS,, Barcelona, Spain, ¹⁰Rheumatology, Hospital Clínico San Carlos, Madrid, Spain, ¹¹Rheumatology, Hospital Universitario de Bellvitge, Barcelona, Spain, ¹²Rheumatology, Hospital Universitario Marqués de Valdecilla, IFIMAV, Santander, Spain, ¹³Thrombosis and Vasculitis Unit-Internal Medicine, Complejo Hospitalario Universitario de Vigo (CHUVI), Vigo, Spain, ¹⁴Rheumatology, Hospital Ramón y Cajal, Madrid, Spain, ¹⁵Reumatologia, Hospital del Mar, Barcelona, Spain, ¹⁶Internal Medicine, Hospital Clínico San Cecilio, Granada, Spain, ¹⁷Internal Medicine, Hospital de Galdakano, Vizcaya, Spain, ¹⁸Internal Medicine, Corporació Sanitaria Parc Taulí, Instituto Universitario Parc Taulí, UAB, Sabadell, Spain, ¹⁹Rheumatology, Hospital Clínico San Cecilio, Granada, Spain, ²⁰Internal Medicine, Hospital Universitario Virgen de la Victoria, Málaga, Spain, ²¹Immunology, Hospital Universitario Virgen del Rocío, Sevilla, Spain, ²²Medical Genetics, University Medical Center Utrecht, Utrecht, Netherlands, ²³Department of Medical Genetics, University Medical Center Utrecht, Utrecht, Netherlands, ²⁴Rheumatology, Hospital Universitario Marqués de Valdecilla. IDIVAL. Santander. Spain, Santander, Spain

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: genetics, giant cell arteritis and human leukocyte antigens (HLA)

Session Information

Title: Vasculitis I

Session Type: Abstract Submissions (ACR)

Background/Purpose: Giant cell arteritis (GCA) is a polygenic inflammatory disease affecting medium- and large-sized blood vessels in people elder than 50-years old. Although it is clear that GCA has an important genetic component, very little is known about the genetic susceptibility to this vasculitis. In order to better understand the genetic association of the HLA region with this disease, we aimed to carried out for the first time a comprehensive fine-mapping of this genomic region to identify the causative variants and/or amino acids responsible for the GCA predisposition.

Methods: 556 biopsy-proven GCA patients and 1,951 controls from Spanish Caucasian ancestry were genotyped using the Illumina Infinium Immunochip genotyping platform. Subsequently, we isolated the genotyping data from the extended major histocompatibility complex (xMHC) region, located in chromosome 6, and used a previously validated imputation method to analyze the variation within the xMHC region of single-nucleotide polymorphisms (SNPs), classical HLA alleles and variable amino acids. For the imputation, we used the Beagle software and a reference panel comprised of 5,225 individuals of European origin with genotyping data of about 8,961 common SNPs and insertion-deletion polymorphisms across the xMHC region, and four digits genotyping data of the HLA class I and II molecules. Control quality filters were performed with the Eigensoft and Plink software.

Results: The accuracy reached after comparing 4 digit types with the corresponding imputed data was >90% for HLA-DQA1, HLA-DRB1 and HLA-B. As expected, one of the highest association peaks was HLA-DRB1*0404 (P=1.97×10-11, OR=2.91, CI 95%=2.13-3.98), but HLA-DQA1*0301 was also firmly associated (P=4.81×10-09, OR=1.70, CI 95%=1.42-2.03). Consequently, different amino acid positions of both DRβ1 and DQα1 chains were strongly associated with disease predisposition (P<5x10-8). However, the presence of a histidine in the position 13 of the DRβ1 molecule defined almost all the association of the HLA region with GCA. Only the addition of an arginine amino acid at position 56 of the HLA-DQα1 chain improved marginally the model (likelihood-P=0.018). Both amino acids are located in the binding pocket of their corresponding molecule and, therefore, may interact with the antigen.

Conclusion: Our results show that one amino acid located at the binding pocket of the HLA-DRβ1 chain is responsible for almost all the HLA association with GCA.

Disclosure:

J. Martin,
None;

F. D. Carmona,
None;

J. E. Martin,
None;

A. Serrano,
None;

L. Bossini-Castillo,
None;

R. Solans,
None;

J. A. Miranda-Filloy,
None;

S. Castañeda,
None;

M. C. Cid,
None;

J. A. Hernandez,
None;

I. C. Morado,
None;

J. Narvaez,
None;

R. Blanco,
None;

B. Sopeña,
None;

M. J. García-Villanueva,
None;

J. Monfort,
None;

N. Ortego-Centeno,
None;

A. Unzurrunzaga,
None;

B. Marí-Alfonso,
None;

C. Magro,
None;

A. Hidalgo-Conde,
None;

M. Conde-Jaldon,
None;

M. F. González-Escribano,
None;

P. de Bakker,
None;

B. P. C. Koeleman,
None;

M. A. González-Gay,
None.

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