Clinical outcome in anti-neutrophil cytoplasmic antibody–associated vasculitis and gene variants of 11β-hydroxysteroid dehydrogenase type 1 and the glucocorticoid receptor

• Published in: Rheumatology (Oxford, England) Vol. 58; no. 3; pp. 447 - 454
• Main Authors: Hessels, Arno C, Tuin, Janneke, Sanders, Jan Stephan F, Huitema, Minke G, van Rossum, Elisabeth F C, Koper, Jan W, van Beek, André P, Stegeman, Coen A, Rutgers, Abraham
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.03.2019; Oxford Publishing Limited (England)
• Subjects: 11-beta-Hydroxysteroid Dehydrogenase Type 1 - genetics; 11β-Hydroxysteroid dehydrogenase; Adult; Aged; Alleles; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - drug therapy; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - genetics; Antineutrophil cytoplasmic antibodies; Dehydrogenases; Disease-Free Survival; Dyslipidemia; End-stage renal disease; Female; Gene Frequency; Gene polymorphism; Genotype; Genotyping; Glucocorticoid receptors; Glucocorticoids; Glucocorticoids - therapeutic use; Haplotypes; Humans; Inflammation; Kidney diseases; Male; Metabolism; Middle Aged; Mortality; Pharmacogenetics; Polymorphism; Polymorphism, Single Nucleotide; Prednisolone - therapeutic use; Receptors, Glucocorticoid - genetics; Remission Induction; Single-nucleotide polymorphism; Treatment Outcome; Vasculitis; epidemiology; genetics; inflammation; microscopic polyangiitis; vasculitis; biomarkers; Wegener’s granulomatosis; anti-neutrophil cytoplasm antibody; metabolic disease
• ISSN: 1462-0324; 1462-0332
• DOI: 10.1093/rheumatology/key319

Abstract Objectives We aimed to investigate whether five potential functional haplotypes of the glucocorticoid receptor (GR) gene and a single-nucleotide polymorphism of 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) are associated with clinical outcome in ANCA-associated vasculitis. Methods Patients diagnosed with ANCA-associated vasculitis (n = 241) were genotyped for five polymorphisms of the GR gene and one polymorphism of the HSD11B1 gene. GR gene haplotypes were predicted based on genotyping results. Relapse-free survival, mortality, renal survival, metabolic adverse events and infections were compared between carriers and non-carriers of GR haplotypes and the HSD11B1 genotype. Results Carriers of haplotype 4 (ER22/23EK + 9β+TthIII1) of GR had a significantly higher 5-year mortality risk [hazard ratio (HR) 4.5 (95% CI 1.6, 12.8)] and had a higher risk of developing end-stage renal disease [HR 7.4 (95% CI 1.9, 28.7)]. Carriers of a minor variant of HSD11B1 more frequently experienced relapse [HR 2.5 (95% CI 1.5, 4.1)] except if they also carried haplotype 1 (BclI) of GR. Homozygous carriers of haplotype 1 had a higher risk of developing dyslipidaemia [HR 4.1 (95% CI 1.8, 9.6)]. The occurrence of infections did not differ between GR haplotypes and HSD11B1 genotypes. Conclusion Haplotypes 1 and 4 of GR and a polymorphism of the HSD11B1 gene were associated with clinically relevant inflammatory and metabolic outcomes in ANCA-associated vasculitis.