The Role of NFKB1 and NFKBIA in Immunoglobulin A Vasculitis

Joao Carlos Batista Liz^1*María Sebastián Mora-Gil¹Mónica Renuncio García²María Teresa Leonardo³Ana Peñalba³Ligia Gabrie^3,4Rafael Gálvez^3,4Luis Martín-Penagos⁵Javier Narvaez⁶Belén Sevilla Pérez⁷Raquel Ríos Fernandez⁸Jose Luis Callejas-Rubio⁸Luis Caminal-Montero⁹Paz Collado¹⁰Jose Javier Pérez Venegas¹¹María José Rodríguez Valls¹²Diego De Árgila¹³Patricia Quiroga Colina¹⁴Esther Francisca Vicente Rabaneda^14,15Esteban Rubio¹⁶Manuel León Luque¹⁶Juan María Blanco Madrigal¹⁷Eva Galíndez Agirregoikoa¹⁷Javier Gonzalo Ocejo-Vinyals¹⁸Ricardo Blanco^19,4Verónica Pulito-Cueto^19*Raquel Lopez-Mejías^19*

• ¹Immunopathology, Marqués de Valdecilla Health Research Institute (IDIVAL), Santander, Spain
• ²Immunology, Complejo Asistencial Universitario de Leon, León, Spain
• ³Paediatrics, Hospital Universitario Marques de Valdecilla, Santander, Spain
• ⁴Hospital Universitario Marques de Valdecilla Servicio de Reumatologia, Santander, Spain
• ⁵Nephrology, Hospital Universitario Marques de Valdecilla, Santander, Spain
• ⁶Rheumatology, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Spain
• ⁷Rheumatology, Hospital Universitario San Cecilio, Granada, Spain
• ⁸Systemic Autoimmune Disease Unit, Hospital Universitario San Cecilio, Granada, Spain
• ⁹Hospital Universitario Central de Asturias Servicio de Medicina Interna, Oviedo, Spain
• ¹⁰Rhaumatology, Hospital Universitario Severo Ochoa, Leganés, Spain
• ¹¹Rheumatology, Hospital Universitario de Jerez de la Frontera, Jerez de la Frontera, Spain
• ¹²Rhaumatology, Hospital Universitario de Jerez de la Frontera, Jerez de la Frontera, Spain
• ¹³Hospital Universitario de la Princesa Servicio de Dermatologia, Madrid, Spain
• ¹⁴Rheumatology, Hospital Universitario de la Princesa, Madrid, Spain
• ¹⁵Universidad Autonoma de Madrid, Madrid, Spain
• ¹⁶Rheumatology, Hospital Universitario Virgen del Rocio, Seville, Spain
• ¹⁷Rheumatology, Hospital Universitario Basurto, Bilbao, Spain
• ¹⁸Immunology, Hospital Universitario Marques de Valdecilla, Santander, Spain
• ¹⁹Immunopathology, Instituto de Investigacion Marques de Valdecilla, Santander, Spain

Abstract Objectives: Immunoglobulin A Vasculitis (IgAV) is an inflammatory disease mediated by B-cells. NF-kappa B (NF-kB) is essential for the development and maturation of B cells and plays a key role in autoimmunity and inflammation. In particular, the NF-kB canonical activation pathway genes NFKB1 (gene encoding NF-kB1) and NFKBIA (gene encoding the NF-kB Inhibitor Alpha) are described as risk loci for several immune-mediated diseases, but their role in IgAV is still unclear. Accordingly, we aimed to determine whether NFKB1 and NFKBIA represent novel genetic risk factors for IgAV pathogenesis. Methods: The NFKB1 promoter variant -94 ins/del ATTG (rs28362491), six tag NFKB1 polymorphisms (rs77830930, rs1598856, rs7340881, rs4648055, rs4648090, and rs230547), and seven tag NFKBIA variants (rs3138055, rs696, rs1022714, rs2233419, rs2233415, rs1050851, and rs1957106) were genotyped in 343 Caucasian IgAV patients and 764 healthy ethnically matched controls using TaqMan Probes. Patients were also stratified according to age at disease onset and the presence or absence of renal, articular, and gastrointestinal manifestations, and genotype, allele, and haplotype frequencies were compared between patients and controls as well as across clinical subgroups. Results: When comparing the genotype and allele frequencies of NFKB1 and NFKBIA between IgAV patients and healthy controls, no statistically significant differences were found. Likewise, similar NFKB1 and NFKBIA haplotype frequencies were observed in both these groups.