Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide(1). We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 x 10(-6)) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples(2-7), while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis(8,9) (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity(10). We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases

Objective-Severe alcohol consumption can cause serious morbidity and death. Because the serotonin transporter (5-HTT) is an important regulator of neuronal 5-HT function, allelic differences at that gene may modulate the severity of alcohol consumption and predict therapeutic response to the 5-HT 3 receptor antagonist, ondansetron.Method-We randomized 283 alcoholics by genotype in the 5′-regulatory region of the 5-HTT gene (LL/LS/SS), with additional genotyping for another functional single nucleotide polymorphism (T/G), rs1042173, in the 3′-untranslated region, in a controlled double-blind trial. Subjects received ondansetron (4 μg/kg twice daily) or placebo for 11 weeks, plus standardized cognitive behavioral therapy.Results-LL subjects who received ondansetron vs. placebo had fewer mean drinks per drinking day (DDD) and a higher percentage of days abstinent (PDA) (−1.62; p=0.007 and 11.27%; p=0.023). Within ondansetron recipients, DDD was lower and PDA higher in LL vs. LS/SS subjects (−1.53; p=0.005 and 9.73%; p=0.03). Ondansetron LL subjects also had fewer DDD and greater PDA than all other genotype and treatment groups combined (−1.45; p=0.002 and 9.65%; p=0.013). For both DDD and PDA, 5′-HTTLPR and rs1042173 variants interacted significantly (p=0.023 and 0.009). Ondansetron LL/TT had fewer DDD and a greater PDA than all other genotype and treatment groups combined (−2.63; p<0.0001 and 16.99%; p=0.002). Conclusions-We propose a new pharmacogenetic approach using ondansetron to reduce the severity of alcohol consumption and improve abstinence in alcoholics.

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR-129-2/HSD17B12, PRDM11, WWOX, and KCNJ2. Two (GSTCD and PTCH1) loci previously associated with spirometric measures were related to FVC. Newly implicated regions were followed-up in samples of African American, Korean, Chinese, and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and pathogenesis of restrictive lung disease.

Contrast echocardiography can rapidly and accurately provide short-, intermediate-, and long-term prognostic information in patients presenting to the ED with suspected cardiac CP even before serum cardiac markers are known. Integrating contrast echocardiography into the ED evaluation of CP may improve the risk stratification of such patients.

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.