Variants at the Interleukin 1 Gene Locus and Pericarditis.

Importance: Recurrent pericarditis is a treatment challenge and often a debilitating condition. Drugs inhibiting interleukin 1 cytokines are a promising new treatment option, but their use is based on scarce biological evidence and clinical trials of modest sizes, and the contributions of innate and adaptive immune processes to the pathophysiology are incompletely understood. Objective: To use human genomics, transcriptomics, and proteomics to shed light on the pathogenesis of pericarditis. Design, Setting, and Participants: This was a meta-analysis of genome-wide association studies of pericarditis from 5 countries. Associations were examined between the pericarditis-associated variants and pericarditis subtypes (including recurrent pericarditis) and secondary phenotypes. To explore mechanisms, associations with messenger RNA expression (cis-eQTL), plasma protein levels (pQTL), and CpG methylation of DNA (ASM-QTL) were assessed. Data from Iceland (deCODE genetics, 1983-2020), Denmark (Copenhagen Hospital Biobank/Danish Blood Donor Study, 1977-2022), the UK (UK Biobank, 1953-2021), the US (Intermountain, 1996-2022), and Finland (FinnGen, 1970-2022) were included. Data were analyzed from September 2022 to August 2023. Exposure: Genotype. Main Outcomes and Measures: Pericarditis. Results: In this genome-wide association study of 4894 individuals with pericarditis (mean [SD] age at diagnosis, 51.4 [17.9] years, 2734 [67.6%] male, excluding the FinnGen cohort), associations were identified with 2 independent common intergenic variants at the interleukin 1 locus on chromosome 2q14. The lead variant was rs12992780 (T) (effect allele frequency [EAF], 31%-40%; odds ratio [OR], 0.83; 95% CI, 0.79-0.87; P = 6.67 × 10-16), downstream of IL1B and the secondary variant rs7575402 (A or T) (EAF, 45%-55%; adjusted OR, 0.89; 95% CI, 0.85-0.93; adjusted P = 9.6 × 10-8). The lead variant rs12992780 had a smaller odds ratio for recurrent pericarditis (0.76) than the acute form (0.86) (P for heterogeneity = .03) and rs7575402 was associated with CpG methylation overlapping binding sites of 4 transcription factors known to regulate interleukin 1 production: PU.1 (encoded by SPI1), STAT1, STAT3, and CCAAT/enhancer-binding protein ß (encoded by CEBPB). Conclusions and Relevance: This study found an association between pericarditis and 2 independent sequence variants at the interleukin 1 gene locus. This finding has the potential to contribute to development of more targeted and personalized therapy of pericarditis with interleukin 1-blocking drugs.

Severe weight loss in a hypothyroid patient as an acute presentation of autoimmune polyglandular syndrome type II.

BACKGROUND: Autoimmune disease, including autoimmune thyroid disease, with uncharacteristic symptoms can be due to additional severe disease. We report a life-threatening debut of autoimmune polyglandular syndrome type II (APS II) defined as Addison's disease combined with autoimmune diabetes and/or thyroid disease. PATIENT FINDINGS: A 33-year-old male with newly diagnosed hypothyroidism was referred to a tertiary center due to fatigue and 20-kg rapid weight loss. Malignancy was excluded. After a gastroscopy, he developed Addison's crisis; he was admitted to our hospital and stabilized. Final diagnoses included Hashimoto's thyroiditis, Addison's disease, vitiligo, and pernicious anemia. Whole genome sequencing found no genetic variants associated with component diseases. Human leukocyte antigen typing revealed DR3/DR4 and DQ8/DQ2 heterozygosity associated with APS II. A patient with Hashimoto's thyroiditis and weight loss presented with Addison's crisis and was diagnosed with APS II. CONCLUSIONS: Awareness of potential polyautoimmunity in clinical evaluation of patients with thyroid disease improves diagnosis and can be lifesaving.