Nahm, Moon H.

Abstract Rationale: We have previously shown reduced total IgG, IgG subclasses, and levels/function of pneumococcal-specific antibodies are associated with increased risk for exacerbations of COPD (ECOPD). The binding of IgG to its receptor, the Fc receptor for IgG (FcγR) on immune cells, has a critical role in determining antibody levels and function. In addition to our research demonstrating that IgG heavy chain gene (IGHG) variants are associated with ECOPD, single nucleotide variants (SNVs) in genes encoding FcγR (FCGR1-3, which encode receptor subtypes FcγRI, FcγRIIa/b/c, and FcγRIIIa/b) may also result in antibody deficiency and increased exacerbation risk. Due to technical challenges in accurately identifying SNVs in FCGR, this region has not been well-characterized. The limited data that exist are from people of European descent, and prior studies have not included African American participants. We therefore sought to investigate the hypothesis that distinct SNVs in genes encoding FcγR are associated with disease severity and history of exacerbations in African American people with COPD. Methods: We developed a novel pipeline to identify SNVs in the coding (CDS) regions of chromosome 1 using short-read whole genome sequence data. The pipeline was benchmarked using paired long-read samples from Genome in a Bottle. SNVs were called within CDS regions and analyzed in a meta-analysis of self-reported African American participants in SPIROMICS and COPDGene (n=3063). Genetic variants were tested for association with COPD severity (GOLD spirometry stage 1-2 vs 3-4) as well as COPD exacerbations, adjusting for age, sex and principal components controlling for population structure. Results: Eight SNVs were significantly associated with frequent ECOPD (≥2 in one year) in the meta-analysis of African American COPDGene and SPIROMICS participants (Table). Seven of these 8 SNVs were found in FCGR3; 4 in the activating FCGR3A subtype, and 3 in FCGR3B. Seven of 11 SNVs associated with COPD severity were in FCGR3 (4 in FCGR3A; 3 in FCGR3B). One SNV (rs371849) was associated with both frequent exacerbations (P=0.002) and COPD severity (P=0.044). Conclusions: We used a cutting-edge variant calling pipeline to identify multiple SNVs in FCGR, primarily involving FcγRIII receptor subtypes, associated with COPD severity and exacerbations in African American participants in SPIROMICS and COPDGene. FcγRIII variants are known to cause impaired antibody levels and function in people of European descent. The structural and functional importance of newly recognized variants in African American cohorts require further study, as they may represent immunogenetic risk factors for antibody deficiency and exacerbations.

Abstract Rationale Debate exists about the immunogenicity and protective efficacy of antibodies produced by the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in chronic obstructive pulmonary disease (COPD). The 7-valent diphtheria-conjugated pneumococcal polysaccharide vaccine (PCV7) induces a more robust immune response than PPSV23 in healthy elderly adults. Objectives We hypothesized that serotype-specific IgG antibody concentration and functional antibody activity would be superior after PCV7 vaccination compared with PPSV23 in moderate to severe COPD. We also posited that older age and prior PPSV23 vaccination would be associated with reduced vaccine responsiveness. Methods One hundred twenty patients with COPD were randomized to PPSV23 (63 subjects) or PCV7 (57 subjects). IgG concentrations were determined by ELISA; functional antibody activity was assayed with a standardized opsonophagocytosis assay and reported as an opsonization killing index (OPK). Increases in serotype-specific IgG and OPK at 1 month post vaccination were compared within and between vaccine groups. Measurements and Main Results Both vaccines were well tolerated. Within each study group, postvaccination IgG and OPK were higher than baseline (P < 0.01) for all serotypes. Adjusted for baseline levels, postvaccination IgG was higher in the PCV7 group than the PPSV23 group for all seven serotypes, reaching statistical significance for five (P < 0.05). PCV7 resulted in a higher OPK for six of seven serotypes (statistically greater for four) compared with PPSV23. In multivariate analyses, younger age, vaccine naivety, and receipt of PCV7 were associated with increased OPK responses. Conclusions PCV7 induces a superior immune response at 1 month post vaccination compared with PPSV23 in COPD. Older age and prior PPSV23 reduce vaccine responsiveness. Clinical trial registered with www.clinicaltrials.gov (NCT00457977).