title: FCGR3A and FCGR3B copy number variations are risk factors for sarcoidosis.
abstract: Sarcoidosis is a multisystem granulomatous disorder that causes significant morbidity. Genetic factors contribute to sarcoidosis risks. In this study, we investigated whether copy number variations (CNVs) of FCGR3A (coding for FcγRIIIA) and FCGR3B (coding for FcγRIIIB) genes are associated with sarcoidosis susceptibility and whether the expressions of FcγRIIIA on NK cells and FcγRIIIB on neutrophils are altered in sarcoidosis patients. TaqMan real-time PCR assays were used to analyze the CNV of FCGR3A and FCGR3B genes. FCGR3A and FCGR3B CNV genotypes were compared between 671 biopsy-proven sarcoidosis patients and the same number of healthy controls matched with age, sex, race, and geographic area from the ACCESS (A Case Control Etiologic Study of Sarcoidosis) cohort. Flow cytometry analyses were used to determine expressions of FcγRIIIA on NK cells and FcγRIIIB on neutrophils in phenotype analyses. We found that FCGR3A CNVs were significantly associated with sarcoidosis in females (CN = 1 vs. CN = 2 logistic regression adjusted for sex and race, OR 4.0156, SE = 2.2784, P = 0.0143; CN = 3 vs. CN = 2 logistic regression adjusted for sex and race, OR 2.8044, SE = 1.1065, P = 0.0090), suggesting that FCGR3A gene abnormality influences sarcoidosis development in a gender-specific manner. Furthermore, FcγRIIIA expressions were significantly decreased on NK cells from sarcoidosis patients compared to those from healthy controls (P = 0.0007). Additionally, low FCGR3B CN was associated with sarcoidosis (CN <2 vs. CN = 2 logistic regression adjusted for sex and race, OR 1.5025, SE = 0.2682, P = 0.0226), indicating that the functions of FCGR3B gene may also contribute to the pathogenesis of sarcoidosis. We conclude that FCGR3A CNVs are a major risk factor for female sarcoidosis and FCGR3B CNVs may also affect the development of sarcoidosis.
authors.affiliation: Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, 235B AnSc/VetMed Bldg., 1988 Fitch Avenue, St. Paul, MN, 55108, USA. jmwu@umn.edu.
authors.forename: Jianming
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, 235B AnSc/VetMed Bldg., 1988 Fitch Avenue, St. Paul, MN, 55108, USA.
authors.forename: Yunfang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, USA.
authors.forename: Weihua
authors.initials: W
authors.lastname: Guan
authors.affiliation: Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, School of Medicine, University of Minnesota, Minneapolis, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Viken
authors.affiliation: Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, School of Medicine, University of Minnesota, Minneapolis, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Perlman
authors.affiliation: Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, School of Medicine, University of Minnesota, Minneapolis, USA.
authors.forename: Maneesh
authors.initials: M
authors.lastname: Bhargava
mesh_terms: D000328:Adult; D000368:Aged; D056915:DNA Copy Number Variations; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D017452:Receptors, IgG / Q000235:genetics*; D012307:Risk Factors; D012507:Sarcoidosis / Q000235:genetics* / Q000473:pathology; D012727:Sex Characteristics
chemical_list: C496124:FCGR3A protein, human; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D017452:Receptors, IgG