1572: CD40, BLK and BANK1 in the Pathogenesis of Immunoglobulin-A Vasculitis

Fernanda Genre¹, Sara Remuzgo-Martinez¹, Veronica Pulito-Cueto¹, JOAO CARLOS BATISTA LIZ², Diana Prieto-Peña¹, Belén Atienza-Mateo¹, Belén Sevilla-Pérez³, Javier Llorca⁴, Norberto Ortego⁵, María Teresa Leonardo⁶, Ana Peñalba⁶, F. Javier Narváez⁷, Luis Martín-Penagos⁸, Emilio Rodrigo⁸, Cristina Gomez-Fernandez⁹, Lara Belmar-Vega⁸, José A. Miranda-Filloy¹⁰, Luis Caminal-Montero¹¹, Paz Collado¹², Pedro Rodriguez-Jimenez¹³, Diego De Argila¹⁴, Patricia Quiroga-Colina¹⁵, Esther Vicente-Rabaneda¹⁶, Enrique Rubio¹⁷, Manuel León Luque¹⁷, Juan María Blanco-Madrigal¹⁸, Eva Galíndez-Agirregoikoa¹⁹, Javier Martín²⁰, Santos Castañeda¹⁶, Ricardo Blanco²¹, Miguel Ángel González-Gay²² and Raquel Lopez Mejias²³, ¹Research Group on Genetic Epidemiology and Atherosclerosis in Systemic Diseases and in Metabolic Bone Diseases of the Musculoskeletal System, IDIVAL; and Department of Rheumatology, Hospital Universitario Marqués de Valdecilla, Santander, Spain, ²Ilerna, Madrid, Spain, ³Division of Pediatrics, Hospital Universitario San Cecilio, Granada, Spain, ⁴Department of Epidemiology and Computational Biology, School of Medicine, University of Cantabria, and CIBER Epidemiología y Salud Pública (CIBERESP), Santander, Spain, ⁵Medicine Department, Universidad de Granada, Granada, Spain, ⁶Division of Pediatrics, Hospital Universitario Marqués de Valdecilla, Santander, Spain, ⁷Rheumatology Department, Hospital Universitario de Bellvitge, Barcelona, Spain, ⁸Division of Nephrology, Hospital Universitario Marqués de Valdecilla, Santander, Spain, ⁹Division of Dermatology, Hospital Universitario Marqués de Valdecilla, Santander, Spain, ¹⁰Division of Rheumatology, Hospital Universitario Lucus Augusti, Lugo, Spain, ¹¹Division of Rheumatology, Hospital Universitario Central de Asturias, Oviedo, Spain, ¹²Division of Rheumatology, Hospital Universitario Severo Ochoa, Madrid, Spain, ¹³Dermatology Department, Hospital Universitario de La Princesa, Madrid, ¹⁴Dermatology Department, Hospital Universitario de La Princesa, Madrid, Spain, ¹⁵Division of Rheumatology, Hospital Universitario de La Princesa, Madrid, Spain, ¹⁶Division of Rheumatology, Hospital Universitario de La Princesa, IIS-Princesa, Madrid, Spain, ¹⁷Division of Rheumatology, Hospital Universitario Virgen del Rocío, Sevilla, Spain, ¹⁸Division of Rheumatology, Hospital Universitario de Basurto, Bilbao, Spain, ¹⁹Basurto University Hospital, Bilbao, Spain, ²⁰Instituto de Parasitología y Biomedicina ‘López-Neyra’, CSIC, PTS Granada, Granada, Spain, ²¹Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain, ²²Department of Medicine and Psychiatry, Universidad de Cantabria; Rheumatology Division, Hospital Universitario Marqués de Valdecilla; Research group on genetic epidemiology and atherosclerosis in systemic diseases and in metabolic diseases of the musculoskeletal system, IDIVAL, Santander, Spain. Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa, ²³IDIVAL, Santander, Spain

Background/Purpose: CD40 is a membrane glycoprotein expressed on B cells surface that activates antigen presenting cells [1]. BLK and BANK1 are components of B cells signalosome [2] implicated in the development as well as in the activation and signalling of B cells, respectively [3, 4]. Previous studies have revealed that CD40, BLK and BANK1 genes are involved in the predisposition to several immune-mediated diseases [1, 2, 5]. Accordingly, we aimed to determine whether CD40, BLK and BANK1 represent novel genetic risk factors for the pathogenesis of Immunoglobulin-A vasculitis (IgAV), a predominantly B cell inflammatory condition.

Methods: 8 genetic variants, previously related to several immune-mediated diseases [1, 2, 5], were genotyped in the largest series of Caucasian patients diagnosed with IgAV ever assessed for genetic studies (n=382) and in 955 ethically matched healthy controls. In particular, 3 polymorphisms within CD40 (rs1883832, rs1535045, rs4813003) and BLK (rs2254546, rs2736340, rs2618476) as well as 2 genetic variants within BANK1 (rs10516487, rs3733197) were genotyped in this study.

Results: No genotypes or alleles differences were observed between IgAV patients and controls when CD40, BLK and BANK1 genetic variants were analyzed independently. Likewise, no statistically significant differences were found in the genotype and allele frequencies of CD40, BLK and BANK1 when IgAV patients were stratified according to the age at disease onset or to the presence/absence of gastrointestinal (GI) or renal manifestations. Similar results were disclosed when CD40, BLK and BANK1 haplotypes were compared between IgAV patients and controls and between IgAV patients stratified according to the age at disease onset or to the presence/absence of GI or renal manifestations.

Conclusion: Our results suggest that CD40, BLK and BANK1 does not contribute to the genetic network underlying IgAV.

References: [1] PLoS One. 2012;7:e49214; [2] Front Genet. 2020;11:58; [3] J Immunol. 1999;163:5453-61; [4] Nat Genet. 2008;40:484; [5] Curr Opin Rheumatol. 2015;27:10-7.

This study was supported by European Union FEDER funds and “Fondo de Investigaciones Sanitarias” (grants PI18/00042 and PI21/00042) from ‘Instituto de Salud Carlos III’ (ISCIII, Health Ministry, Spain). DP-P is a recipient of a Río Hortega programme fellowship from the ISCIII, co-funded by the European Social Fund (ESF, `Investing in your future´) [grant number CM20/00006]; SR-M and VP-C are supported by funds of the RETICS Program co-funded by the European Regional Development Fund (ERDF) [grant number RD16/0012/0009]; FG is supported by funds of the RICORS Program from ISCIII, co-funded by the European Union [grant number RD21/0002/0025]; RL-M is a recipient of a Miguel Servet type II programme fellowship from the ISCIII, co-funded by the European Social Fund (ESF, `Investing in your future´) [grant number CPII21/00004].

Table 1. Genotype and allele frequencies of CD40, BLK and BANK1 genes in patients with IgAV and healthy controls
Disclosures: F. Genre, None; S. Remuzgo-Martinez, None; V. Pulito-Cueto, None; J. BATISTA LIZ, None; D. Prieto-Peña, UCB, Roche, Pfizer, Amgen, Janssen, AbbVie/Abbott, Novartis, Eli Lilly; B. Atienza-Mateo, AbbVie/Abbott, Roche, Pfizer, Celgene, Novartis, Janssen, UCB, Eli Lilly; B. Sevilla-Pérez, None; J. Llorca, None; N. Ortego, None; M. Leonardo, None; A. Peñalba, None; F. Narváez, None; L. Martín-Penagos, None; E. Rodrigo, None; C. Gomez-Fernandez, None; L. Belmar-Vega, None; J. Miranda-Filloy, None; L. Caminal-Montero, None; P. Collado, None; P. Rodriguez-Jimenez, None; D. De Argila, None; P. Quiroga-Colina, None; E. Vicente-Rabaneda, None; E. Rubio, None; M. León Luque, None; J. Blanco-Madrigal, None; E. Galíndez-Agirregoikoa, None; J. Martín, None; S. Castañeda, Roche; R. Blanco, Eli Lilly, Pfizer, Roche, Janssen, MSD, AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Galapagos, Novartis, Sanofi; M. González-Gay, AbbVie/Abbott, Merck/MSD, Janssen, Roche, AbbVie/Abbott, Roche, Sanofi, Eli Lilly, Celgene, Sobi, Merck/MSD; R. Lopez Mejias, None.