A genome-wide association study in Hispanics/Latinos identifies novel signals for lung function: the Hispanic Community Health Study/Study of Latinos

Rationale:: Lung function and chronic obstructive pulmonary disease (COPD) are heritable traits. Genome-wide association studies (GWAS) have identified numerous pulmonary function and COPD loci, primarily in cohorts of European ancestry. Objectives: Perform a GWAS of COPD-phenotypes in Hispanic/Latino populations to identify loci not previously detected in European populations. Methods: :GWAS of lung function and COPD in Hispanic/Latino participants from a population-based cohort. We performed replication studies of novel loci in independent studies. Measurements and Main Results: Among 11,822 Hispanic/Latino participants, we identified eight novel signals; three replicated in independent populations of European Ancestry. A novel locus for forced expiratory volume in one second (FEV1) in ZSWIM7 (rs4791658; p=4.99×10-9) replicated. A rare variant (MAF=0.002) in HAL (rs145174011) was associated with FEV1 to forced vital capacity (FEV1/FVC) (p=9.59×10-9) in a region previously identified for COPD-related phenotypes; it remained significant in conditional analyses but did not replicate. Admixture mapping identified a novel region, with a variant in AGMO (rs41331850), associated with Amerindian ancestry and FEV1, which replicated. A novel locus for FEV1 identified among ever smokers (rs291231; p=1.92×10-8) approached statistical significance for replication in admixed populations of African ancestry and a novel SNP for COPD in PDZD2 (rs7709630; p=1.56×10-8) regionally replicated. Additionally, loci previously identified for lung function in European samples were associated in Hispanic/Latino participants in HCHS/SOL at the genome-wide significance level. Conclusions: We identified novel signals for lung function and COPD in a Hispanic/Latino cohort. Including admixed populations when performing genetic studies may identify variants contributing togenetic etiologies of COPD

Community Poverty and Trends in Racial/Ethnic Survival Disparities Among People Diagnosed With AIDS in Florida, 1993–2004

Objectives. We described the racial/ethnic disparities in survival among people diagnosed with AIDS in Florida from 1993 to 2004, as the availability of highly active antiretroviral therapy (HAART) became widespread. We determined whether these disparities decreased after controlling for measures of community-level socioeconomic status. Methods. We compared survival from all causes between non-Hispanic Blacks and non-Hispanic Whites vis-a-vis survival curves and Cox proportional hazards models controlling for demographic, clinical, and area-level poverty factors. Results. Racial/ethnic disparities in survival peaked for those diagnosed during the early implementation of HAART (1996–1998) with a Black-to-White hazard ratio (HR) of 1.72 (95% confidence interval [CI] = 1.62, 1.83) for males and 1.40 (95% CI = 1.24, 1.59) for females. These HRs declined significantly to 1.48 (95% CI = 1.35, 1.64) for males and nonsignificantly to 1.25 (95% CI = 1.05, 1.48) for females in the 2002 to 2004 diagnosis cohort. Disparities decreased significantly for males but not females when controlling for baseline demographic factors and CD4 count and percentage, and became nonsignificant in the 2002 to 2004 cohort after controlling for area poverty. Conclusions. Area poverty appears to play a role in racial/ethnic disparities even after controlling for demographic factors and CD4 count and percentage

Protein tyrosine phosphatase 1B negatively regulates S100A9-mediated lung damage during respiratory syncytial virus exacerbations

Protein tyrosine phosphatase 1B (PTP1B) has anti-inflammatory potential but PTP1B responses are desensitized in the lung by prolonged cigarette smoke exposure. Here we investigate whether PTP1B expression impacts lung disease severity during respiratory syncytial viral (RSV) exacerbations of chronic obstructive pulmonary disease (COPD). Ptp1b(-/-) mice infected with RSV exhibit exaggerated immune cell infiltration, damaged epithelial cell barriers, cytokine production and increased apoptosis. Elevated expression of S100A9, a damage-associated molecular pattern molecule, was observed in the lungs of Ptp1b(-/-) mice during RSV infection. Utilizing a neutralizing anti-S100A9 IgG antibody, it was determined that extracellular S100A9 signaling significantly impacts lung damage during RSV infection. Pre-exposure to cigarette smoke desensitized PTP1B activity, which coincided with enhanced S100A9 secretion and inflammation in wild type animals during RSV infection. S100A9 levels in human bronchoalveolar lavage fluid had an inverse relationship with lung function in healthy subjects, smokers and COPD subjects. Fully differentiated human bronchial epithelial cells isolated from COPD donors cultured at the air liquid interface secreted more S100A9 than cells from healthy donors or smokers following RSV infection. Together, these findings show that reduced PTP1B responses contribute to disease symptoms in part by enhancing S100A9 expression during viral-associated COPD exacerbations