A genome-wide analysis of the response to inhaled ß2-agonists in chronic obstructive pulmonary disease.

Short-acting ß2-agonist bronchodilators are the most common medications used in treating chronic obstructive pulmonary disease (COPD). Genetic variants determining bronchodilator responsiveness (BDR) in COPD have not been identified. We performed a genome-wide association study (GWAS) of BDR in 5789 current or former smokers with COPD in one African-American and four white populations. BDR was defined as the quantitative spirometric response to inhaled ß2-agonists. We combined results in a meta-analysis. In the meta-analysis, single-nucleotide polymorphisms (SNPs) in the genes KCNK1 (P=2.02 × 10(-7)) and KCNJ2 (P=1.79 × 10(-7)) were the top associations with BDR. Among African Americans, SNPs in CDH13 were significantly associated with BDR (P=5.1 × 10(-9)). A nominal association with CDH13 was identified in a gene-based analysis in all subjects. We identified suggestive association with BDR among COPD subjects for variants near two potassium channel genes (KCNK1 and KCNJ2). SNPs in CDH13 were significantly associated with BDR in African Americans.The Pharmacogenomics Journal advance online publication, 27 October 2015; doi:10.1038/tpj.2015.65.

Joint fluid antioxidants are decreased in osteoarthritic joints compared to joints with macroscopically intact cartilage and subacute injury.

OBJECTIVE: Excess reactive oxygen species and oxidative damage have been associated with the pathogenesis of osteoarthritis (OA). Extracellular superoxide dismutase (EC-SOD or SOD3) scavenges superoxide is the major catalytic antioxidant in joint fluid and is decreased in OA cartilage. We studied human joint fluid samples to test whether there is an association between OA and EC-SOD or other low molecular antioxidants in the joint fluid. METHODS: Joint fluid samples were obtained from 28 subjects with severe OA undergoing arthrocentesis or knee joint replacement and compared to joint fluid from 12 subjects undergoing knee arthroscopy for chronic knee pain, meniscal tears or anterior cruciate ligament reconstruction. EC-SOD protein was assayed by enzyme-linked immunosorbent assay (ELISA). Ascorbate and urate were measured with high performance liquid chromatography (HPLC) and total nitrates by the Greiss reaction. Glutathione (GSH) and oxidized glutathione were measured using a colorimetric method. Interleukin-6 (IL-6) and transforming growth factor-beta (TGF-beta) were both measured with ELISA. RESULTS: Human joint fluid contains significant amounts of the extracellular, catalytic antioxidant EC-SOD. Joint fluid from OA subjects is characterized by significantly decreased EC-SOD levels and significant decreases in GSH, and ascorbate compared to the reference group of knee joints with pain or subacute injury but macroscopically intact cartilage. GSH and ascorbate show only an age effect with no effect from disease state on regression modeling. Urate is present in joint fluid but does not show a significant difference between groups. IL-6 and TGF-beta both show non-significant trends to increases in the arthritic subjects. There was no correlation of EC-SOD levels with IL-6 as a marker of inflammation in either the comparison group or the OA group. CONCLUSIONS: EC-SOD, the major scavenger of reactive oxygen species (ROS) in extracellular spaces and fluids, is decreased in late stage OA joint fluid compared to fluid from injured/painful joints with intact cartilage. Injured joints may be able to increase or maintain secretion of EC-SOD but it appears that late stage OA joints fail to do so in spite of increased oxidative stress seen in the disease. Associated age related declines in GSH and ascorbate might also contribute to the development of severe OA. The net effect of these changes in joint fluid antioxidants is likely to accelerate the damaging oxidant effects on extracellular matrix stability in cartilage tissue.