Fcγ Receptor IIIb (CD16b) Polymorphisms are Associated with Susceptibility to Idiopathic Pulmonary Fibrosis

An excess of neutrophils in the alveoli and lung interstitium has been described in idiopathic pulmonary fibrosis (IPF). Engagement of neutrophil Fc gamma receptors with IgG complexes may contribute to the pathogenesis of IPF. The neutrophil Fc gamma RIIIb receptor occurs in two codominantly expressed allelic variants, NA1 and NA2, which exhibit different binding affinities for IgG1 and IgG3 subclasses. The aim of this study was to investigate whether Fc gamma RIIIb genotype is associated with IPF susceptibility or disease progression. In a case-control study we compared the distribution of Fc gamma RIIIb NA1/2 polymorphisms in 142 patients with IPF and in 218 controls using allele-specific PCR amplification. Significant skewing in the distribution of Fc gamma RIIIb genotypes was observed between patients with IPF and control subjects. In the IPF cohort, there was higher frequency of the NA1/NA1 genotype (0.19 vs. 0.07), and lower NA2/NA2 frequency (0.31 vs. 0.50; chi(2) = 17.71, df = 2, P < 0.001). The overall frequency of the NA1 allele was increased in IPF patients compared to controls (0.44 vs. 0.29; P < 0.0001, odds ratio [OR] = 1.93, 95% confidence interval [CI] = 1.42-2.64). Heterozygotes and homozygotes of the NA1 allele were at higher risk of developing IPF (OR = 2.19, 95% CI = 1.40-3.41, P = 0.0005), whereas the NA2 allele was protective against IPF (OR = 0.34, 95% CI = 0.17-0.65, P = 0.0014). There was no association of Fc gamma RIIIb genotype with disease progression as assessed by serial lung function measurements. Fc gamma RIIIb NA1/2 polymorphisms are associated with IPF disease susceptibility. These results support a role for immunological mechanisms contributing to IPF pathogenesis.