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HLA-DRB1 alleles associate with hypercalcemia in sarcoidosis
Joanna Werner1, Natalia Rivera2, Johan Grunewald1
1Department of Respiratory Medicine, Theme Inflammation and Infection, Karolinska University Hospital, 171 76, Stockholm, Sweden; Department of Medicine Solna, Respiratory Medicine Division, Karolinska Institutet, 171 77, Stockholm, Sweden.
Insights
Sarcoidosis-associated hypercalcemia (SAHC) is linked to a more severe disease, especially in patients with the HLA-DRB1*04 allele. Identifying this genetic marker can help predict and monitor SAHC risk.
Area of Science:
- Immunogenetics
- Nephrology
- Endocrinology
Background:
- Sarcoidosis-associated hypercalcemia (SAHC) mechanisms and risk factors remain unclear.
- Human leukocyte antigen (HLA) alleles are known to influence sarcoidosis phenotypes.
- Understanding HLA associations may elucidate SAHC mechanisms and identify at-risk patients.
Purpose of the Study:
- To investigate the association between HLA alleles and SAHC.
- To define the clinical and phenotypic characteristics of patients with SAHC.
Main Methods:
- Retrospective analysis of 66 SAHC patients and 150 controls.
- Data collected included HLA-DRB1 alleles, ACE levels, creatinine, extrapulmonary manifestations (EPM), and disease duration.
Main Results:
- The HLA-DRB1*04 allele was significantly more prevalent in SAHC patients, particularly those with severe hypercalcemia (p < 0.01).
- SAHC patients exhibited higher rates of renal insufficiency, elevated ACE, EPM, and non-resolving disease.
- The average time from sarcoidosis diagnosis to SAHC detection was 1.39 years.
Conclusions:
- SAHC is associated with a more severe sarcoidosis phenotype.
- Carriage of the HLA-DRB1*04 allele increases the risk of developing SAHC.
- HLA-DRB1*04 assessment may aid in identifying patients at risk for SAHC, guiding future mechanistic studies.
Background:
The mechanisms behind and which patients are at risk of developing sarcoidosis associated hypercalcemia (SAHC) have not been addressed. Different human leukocyte antigen (HLA) alleles associate with disease phenotypes in sarcoidosis. Insights into associations between HLA alleles, clinical phenotype and calcium levels may provide clues to mechanisms behind SAHC and help monitoring patients at risk for SAHC.
Aims And Objectives:
To identify any HLA-association with SAHC, and to phenotypically characterize this patient group.
Methods:
66 patients with SAHC (s-Ca2+>1.33 mmol/L) and 150 normocalcemic patients as controls were identified in a cohort of sarcoidosis patients. Data on HLA-DRB1 alleles, sex, angiotensin-converting enzyme (ACE), creatinine, extrapulmonary manifestations (EPM), age at sarcoidosis diagnosis, and how long after diagnosis SAHC emerged, were retrieved.
Results:
HLA-DRB1*04 was more common in patients with SAHC and the proportion of patients with HLA-DRB1*04 increased the more pronounced hypercalcemia. In patients with s-Ca2+>1.4 mmol/L, 20 out of 30 carried the HLA-DRB1*04 allele (67%, p < 0.01). Patients with SAHC more often disclosed renal insufficiency, elevated ACE, EPM, and a non-resolving disease than controls. The mean duration between sarcoidosis diagnosis and detection of SAHC was 1.39 years.
Conclusions:
SAHC is associated with a more severe disease phenotype, particularly patients carrying the HLA-DRB1*04 allele are at higher risk for SAHC. HLA-assessment in the clinic can be a way to identify these patients. The results provide a basis for future studies on the connection between HLA-DRB1*04 and SAHC mechanisms.
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