A Genome-Wide Association Study Suggests the HLA Class II Region As the Major Susceptibility Locus for IgA Vasculitis

Raquel López-Mejías¹, Sara Remuzgo-Martínez¹, Fernanda Genre¹, Francisco David Carmona², Santos Castañeda³, Belén Sevilla Pérez⁴, Norberto Ortego Centeno⁴, Javier Llorca⁵, Begoña Ubilla¹, Veronica Mijares¹, Trinitario Pina⁶, Jose A. Miranda-Filloy⁷, Antonio Navas Parejo⁸, Diego Argila⁹, Maximiliano Aragües¹⁰, Esteban Rubio-Romero¹¹, Manuel Leon Luque¹², Juan María Blanco Madrigal¹³, Eva Galindez-Agirregoikoa¹³, David Jayne¹⁴, Ricardo Blanco¹, Javier Martin¹⁵ and Miguel Angel González-Gay¹⁶, ¹Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, Rheumatology Division, IDIVAL, Santander, Spain, ²Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, PTS-Granada, Departamento de Genética e Instituto de Biotecnología, University of Granada, Granada, Spain, ³Hospital Universitario La Princesa. IIS-IP. Madrid. Spain, Madrid, Spain, ⁴Medicine Department, Hospital Universitario San Cecilio, Granada, Spain, ⁵Department of Epidemiology and Computational Biology, School of Medicine, University of Cantabria, and CIBER Epidemiología y Salud Pública (CIBERESP), IDIVAL, Santander, Spain, ⁶Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, IDIVAL, Santander, Spain, ⁷Rheumatology Division, Hospital Lucus Augusti, Lugo, Spain, ⁸Nephrology Department, Hospital Universitario San Cecilio, Granada, Spain, ⁹Dermatology Department, Hospital Universitario La Princesa, IIS-Princesa, Madrid, Spain, ¹⁰Dermatology Department, Hospital Universitario La Princesa, IIS-Princesa, MAdrid, Spain, ¹¹Hospital Universitario Virgen del Rocío. Sevilla. Spain, Sevilla, Spain, ¹²Rheumatology Department,Hospital Universitario Virgen del Rocío, Sevilla, Spain, ¹³Rheumatology Division, Hospital Universitario de Basurto, Bilbao, Spain, ¹⁴Department of Medicine, University of Cambridge, Cambridge, United Kingdom, ¹⁵Instituto de Parasitología y Biomedicina López-Neyra, Granada, Spain, ¹⁶Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, IDIVAL and School of Medicine, University of Cantabria, Santander, Spain

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: genetics and vasculitis, GWAS

Session Information

Date: Tuesday, November 7, 2017

Title: Pediatric Rheumatology – Pathogenesis and Genetics Poster

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: Immunoglobulin-A (IgA) vasculitis, also known as Henoch-Schöenlein purpura (HSP), is the most common type of primary small-sized blood vessel leukocytoclastic vasculitis in children, although it may also develop in adults [1]. IgA vasculitis has a multifactorial etiology in which both environmental and genetic factors seem to contribute to the predisposition and clinical phenotype of the disease [1,2]. However, the genetic component of this type of vasculitis remains poorly understood, as only a few candidate gene studies have been performed to date [3,4]. Taking these considerations into account, and to increase the current knowledge on the genetic component of this vasculitis, we performed the first genome-wide association study (GWAS) on this condition using the largest series of IgAV patients of European ancestry ever assessed for a genetic study.

Methods: 308 IgA vasculitis patients and 1,018 healthy controls from Spain were genotyped by Illumina HumanCore BeadChips. Imputation of GWAS data was performed using the 1000 Genomes Project Phase III dataset as reference panel [5]. After quality control filters and GWAS imputation, 285 patients and 1,006 controls remained in the datasets and were included in further analysis. Additionally, the human leukocyte antigen (HLA) region was comprehensively studied by imputing classical alleles and polymorphic amino acid positions [6].

Results: A linkage disequilibrium block of polymorphisms located in the HLA class II region surpassed the genome-wide level of significance (odds ratio = 0.56, 95% confidence intervals = 0.46-0.68). Although no polymorphic amino acid positions were associated at the genome-wide level of significance, P-values of potential relevance were observed for the positions 13 and 11 of HLA-DRB1 (P = 6.67E-05, P = 1.88E-05, respectively). Outside the HLA, potential associations were detected, but none of them were close to the statistical significance.

Conclusion: Our study suggests that IgA vasculitis is an archetypal HLA class II disease.

[1] Gonzalez-Gay et al. Rheum Dis Clin North Am 2001, 27:729-49; [2] Wyatt et al. N Engl J Med 2013, 368:2402-14; [3] López-Mejías et al. Arthritis Res Ther 2015,17:102; [4] López-Mejías et al. Arthritis Rheumatol 2014;67:823-7; [5] Howie et al. PLoSGenet 2009;5: e1000529. [6] Carmona et al. Am J Hum Genet 2015;96:565-80.

This study is supported by European Union FEDER funds and “Fondo de Investigaciones Sanitarias” (grant PI12/00193) from ‘Instituto de Salud Carlos III’ (ISCIII, Health Ministry, Spain). RL-M is supported by the Miguel Servet I programme of the Spanish Ministry of Economy and Competitiveness through the grant CP16/00033. SR-M is supported by funds from the RETICS Program (RIER) (RD16/0012/0009). FG is recipient of a Sara Borrell postdoctoral fellowship from the “Instituto Carlos III de Salud” at the Spanish Ministry of Health (Spain) (CD15/00095). FDC is supported by the Ramón y Cajal programme of the Spanish Ministry of Economy and Competitiveness through the grant RYC-2014-16458.

Disclosure: R. López-Mejías, None; S. Remuzgo-Martínez, None; F. Genre, None; F. D. Carmona, None; S. Castañeda, None; B. Sevilla Pérez, None; N. Ortego Centeno, None; J. Llorca, None; B. Ubilla, None; V. Mijares, None; T. Pina, None; J. A. Miranda-Filloy, None; A. Navas Parejo, None; D. Argila, None; M. Aragües, None; E. Rubio-Romero, None; M. Leon Luque, None; J. M. Blanco Madrigal, None; E. Galindez-Agirregoikoa, None; D. Jayne, None; R. Blanco, None; J. Martin, None; M. A. González-Gay, None.

To cite this abstract in AMA style:

López-Mejías R, Remuzgo-Martínez S, Genre F, Carmona FD, Castañeda S, Sevilla Pérez B, Ortego Centeno N, Llorca J, Ubilla B, Mijares V, Pina T, Miranda-Filloy JA, Navas Parejo A, Argila D, Aragües M, Rubio-Romero E, Leon Luque M, Blanco Madrigal JM, Galindez-Agirregoikoa E, Jayne D, Blanco R, Martin J, González-Gay MA. A Genome-Wide Association Study Suggests the HLA Class II Region As the Major Susceptibility Locus for IgA Vasculitis [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/a-genome-wide-association-study-suggests-the-hla-class-ii-region-as-the-major-susceptibility-locus-for-iga-vasculitis/. Accessed .

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