HLA‐alleles associated with increased risk for extra‐pulmonary involvement in sarcoidosis

Abstract

Genetic factors influence the risk for disease as well as the clinical picture seen in sarcoidosis and especially the genes localized to the human leukocyte antigen (HLA) region on chromosome 6 are of importance. The aim of this study was to further investigate associations between HLA-DRB1 alleles and the risk for extra-pulmonary manifestations (EPMs), i.e. engagement of the skin, superficial lymph nodes, eyes, nervous system, kidneys, hypercalcemia, parotid and salivary glands, heart, liver, spleen and bone marrow in Scandinavian sarcoidosis patients. One thousand patients with together with a group of 2000 healthy individuals, matched for sex and age. HLA-DRB1 alleles were determined for all patients and controls. Excluding erythema nodosum and ankle arthritis, we found 288 of 1000 patients to have EPMs. There were 383 patients with Löfgren's syndrome (LS), and among them EPM were relatively uncommon and diagnosed in only 31 (8.1%) of the patients. In contrast, among the 617 non-LS patients, 257 (41.6%) had EPM (P < 0.0001). In LS patients, the absence of HLA-DRB1*03 substantially increased the risk factor for EPM (erythema nodosum and ankle arthritis excluded) (P < 0.0001). A distinct HLA allele combination, HLA-DRB1*04/*15, was identified as a risk factor for EPM in all patients (25 of 50 with DRB1*04/15 had EPM). In conclusion, EPM are common in non-LS sarcoidosis. Furthermore, HLA-typing of sarcoidosis patients can be used in the clinic to identify patients with an increased risk for EPM.

Etiologies of Sarcoidosis

“…The extended haplotype HLA-DQB1*0201-DRB1*0301 is associated with remitting sarcoidosis, whereas DQB1*0602-DRB1*150101 is associated with chronic active disease and severe manifestations including neurological and cardiac involvement in Japanese patients. The absence of DRB1*0301 among Scandinavian patients with Löfgren syndrome was associated with higher risk of extra-pulmonary manifestations, supporting the association of this allele with favorable outcomes in sarcoidosis [22].…”

Cardiac sarcoidosis: diagnosis and management

“…Class II human leucocyte antigen (HLA) links with individual phenotypes further support a genetic association 24. Extrapulmonary involvement occurs in combination with the alleles (DRB1*04/*15),22 and an occupational exposure to insecticides is reported for HLA DRB1*1101 and cardiac sarcoidosis 25. Japanese women with cardiac sarcoidosis show an association with HLA DQB*0601,26 and with the allele Tumour Necrosis Factor (TNF)A2 27.…”

“…Familial clustering19 20 and racial phenotypes18 21 22 indicate a strong genetic element in sarcoidosis 23. Class II human leucocyte antigen (HLA) links with individual phenotypes further support a genetic association 24.…”

Specific antigen(s) in sarcoidosis: a link to autoimmunity?

“…It is of interest that the HLA-DRB1*03 allele is associated with good prognosis in sarcoidosis, i.e. a low rate of extrapulmonary manifestations and a remission within 2 years [17]. Although this allele is regarded as protective, seemingly in conjunction with Vα2.3 + /Vβ22…”