Wu Jianming, Li Yunfang, Guan Weihua, Viken Kevin, Perlman David M, Bhargava Maneesh
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.
Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, USA.
Hum Genet. 2016 Jul;135(7):715-25. doi: 10.1007/s00439-016-1669-3. Epub 2016 Apr 8.
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.
结节病是一种多系统肉芽肿性疾病，可导致严重的发病率。遗传因素会增加患结节病的风险。在本研究中，我们调查了FCGR3A基因（编码FcγRIIIA）和FCGR3B基因（编码FcγRIIIB）的拷贝数变异（CNV）是否与结节病易感性相关，以及结节病患者自然杀伤细胞（NK细胞）上的FcγRIIIA和中性粒细胞上的FcγRIIIB表达是否发生改变。采用TaqMan实时荧光定量PCR检测法分析FCGR3A和FCGR3B基因的CNV。比较了671例经活检证实的结节病患者与ACCESS（结节病病例对照病因学研究）队列中年龄、性别、种族和地理区域相匹配的相同数量健康对照者的FCGR3A和FCGR3B CNV基因型。在表型分析中，采用流式细胞术分析确定NK细胞上FcγRIIIA和中性粒细胞上FcγRIIIB的表达。我们发现，FCGR3A的CNV与女性结节病显著相关（CN = 1与CN = 2，经性别和种族调整的逻辑回归分析，OR = 4.0156，SE = 2.2784，P = 0.0143；CN = 3与CN = 2，经性别和种族调整的逻辑回归分析，OR = 2.8044，SE = 1.1065，P = 0.0090），这表明FCGR3A基因异常以性别特异性方式影响结节病的发展。此外，与健康对照者相比，结节病患者NK细胞上的FcγRIIIA表达显著降低（P = 0.0007）。此外，低FCGR3B拷贝数与结节病相关（CN <2与CN = 2，经性别和种族调整的逻辑回归分析，OR = 1.5025，SE = 0.2682，P = 0.0226），这表明FCGR3B基因的功能也可能参与结节病的发病机制。我们得出结论，FCGR3A的CNV是女性结节病的主要危险因素，FCGR3B的CNV也可能影响结节病的发展。
