HLA‐DQB1*0601 is primarily associated with the susceptibility to cardiac sarcoidosis

Abstract

Cardiac sarcoidosis occurs in 1-5% of sarcoidosis patients. We previously reported a significant increase of the uncommon TNFA (tumor necrosis factor alpha) allele, TNFA2 with cardiac sarcoidosis in Japanese. In order to precisely localize the susceptible locus for cardiac sarcoidosis within the HLA region, genetic polymorphisms of classical HLA genes, non-classical HLA class II genes such as HLA-DMA and -DMB genes and several genes involved in the class I-mediated antigen presentation pathway (TAP1, TAP2, LMP2 and LMP7) were investigated. Further, association analyses using four polymorphic microsatellite markers located around the TAP1 and TNFA genes were also carried out. As a result, HLA-DQB1*0601 was found to be the most significantly associated allele, being more significantly increased than TNFA2. No significant increase of the DR52-associated DRB1 alleles (DRB1*03, 05, 06 and 08), which was suggested to be primarily associated with lung sarcoidosis, was observed in cardiac sarcoidosis. A primary role of DQB1*0601 in determination of the susceptibility to cardiac sarcoidosis was supported by association analysis using four polymorphic microsatellite markers, in which only the TAP1 microsatellite locus, the nearest marker to the DQB1 gene among the microsatellites tested, displayed a significant positive association with cardiac sarcoidosis. On the other hand, the HLA-DQB1*0501-DQA1*0101-DRB1*0101-B7 haplotype showed a negative association with the disease, as similarly observed in lung sarcoidosis. Thus, molecular mechanism for controlling the development of the disease related to HLA molecules are different between cardiac and lung sarcoidosis, whereas those for conferring a resistant trait may be similar to each other.

Sarcoidosis and the heart: A review of the literature

“…Genetically predisposed individuals are likely to develop granulomas after exposure to antigens that trigger an exaggerated cellular immune response (8). The presence of HLA-DQB1*0601 and the allele TNFA2 in Japanese female patients with CS also indicates a genetic etiology (23,24).…”

“…sulfonamide or methotrexate) can induce granuloma formation in genetically-predisposed individuals with abnormal immune responses (8,(18)(19)(20)(21)(22). The variability of disease presentation (pattern of disease, severity, and prognosis) among different races and in individuals with specific HLA sub-types and the presence of some familial clusters indicate a genetic susceptibility for sarcoidosis (5,23,24). First-degree relatives of patients with sarcoidosis were found to have a relative risk of sarcoidosis five times that of control subjects (1,25).…”

Genetik der Sarkoidose: Ein Schlüssel zum Verständnis ihrer Pathogenese

“…Bei schwedischen Patienten ist die Chro− nifizierung mit HLA−DRB1*14 und *15 [42] und bei irischen Pa− tienten nur mit HLA−DRB1*15 [44] assoziiert. In Deutschland findet sich eine Assoziation der Chronifizierung mit HLA− DRB1*09, *11, *14 und *15 [31,45] und in Japan mit *11 und *14 [46]. Darüber hinaus konnte eine Assoziation unterschiedlichs− ter MHC−Varianten oder ganzer Haplotypen mit unterschiedli− chen radiologischen Befunden, Schweregraden der Erkrankung und klinischen Phänotypen beobachtet werden [47 ± 49].…”

“…Neben Assoziationen mit HLA−DR wurden auch starke Assozia− tionen mit HLA−DQ−Allelen beobachtet. So tragen die HLA− DQB1−Allele*0601 bei Japanern, *0201/0202 bei Schweden, Eng− ländern und Holländern und *0603/0604 bei Deutschen zur Empfänglichkeit bei [42,45,46,50]. [54].…”

Sequence Analysis of Major Histocompatibility Complex Class-II DQB1 (Patr-DQB1) Alleles in Chimpanzees by Polymerase Chain Reaction–Based Methods

“…Knowledge of allele groups and specific alleles at the human MHC human leukocyte antigen (HLA) is implicated in organ and stemcell transplantation and disease susceptibility [7][8][9][10]. In particular, the HLA-DQB1 gene has been reported to be associated with infectious diseases and autoimmune disorders such as cardiac sarcoidosis, sleepwalking disorder, insulin-dependent diabetes mellitus (IDDM), Helicobacter pylori infection, and tuberculosis [11][12][13][14][15]. Therefore, analysis of the HLA-DQB1 allele has progressed actively, and about 70 alleles have been identified at present (ImMunoGeneTics (IMGT)/HLA database).…”