HLA-DRB1 alleles associate with hypercalcemia in sarcoidosis.

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.

A Gene-Environment Interaction Between Smoking and Gene polymorphisms Provides a High Risk of Two Subgroups of Sarcoidosis.

The influence and effect of cigarette smoking in sarcoidosis is unclear. Here, we evaluated gene-environment interaction between multiple genetic variants including HLA genes and smoking in sarcoidosis defined by two clinical phenotypes, Löfgren's syndrome (LS) and patients without Löfgren's syndrome (non-LS). To quantify smoking effects in sarcoidosis, we performed a gene-environment interaction study in a Swedish population-based case-control study consisting of 3,713 individuals. Cases and controls were classified according to their cigarette smoking status and genotypes by Immunochip platform. Gene-smoking interactions were quantified by an additive interaction model using a logistic regression adjusted by sex, age and first two principal components. The estimated attributable proportion (AP) was used to quantify the interaction effect. Assessment of smoking effects with inclusion of genetic information revealed 53 (in LS) and 34 (in non-LS) SNP-smoking additive interactions at false discovery rate (FDR) below 5%. The lead signals interacting with smoking were rs12132140 (AP = 0.56, 95% CI = 0.22-0.90), p = 1.28e-03) in FCRL1 for LS and rs61780312 (AP = 0.62, 95% CI = 0.28-0.90), p = 3e-04) in IL23R for non-LS. We further identified 16 genomic loci (in LS) and 13 (in non-LS) that interact with cigarette smoking. These findings suggest that sarcoidosis risk is modulated by smoking due to genetic susceptibility. Therefore, patients having certain gene variants, are at a higher risk for the disease. Consideration of individual's genetic predisposition is crucial to quantify effects of smoking in sarcoidosis.