A genome-wide association study of bronchodilator response in participants of European and African ancestry from six independent cohorts

Introduction Bronchodilator response (BDR) is a measurement of acute bronchodilation in response to short-acting β2-agonists, with a heritability between 10 and 40%. Identifying genetic variants associated with BDR may lead to a better understanding of its complex pathophysiology. Methods We performed a genome-wide association study (GWAS) of BDR in six adult cohorts with participants of European ancestry (EA) and African ancestry (AA) including community cohorts and cohorts ascertained on the basis of obstructive pulmonary disease. Validation analysis was carried out in two paediatric asthma cohorts. Results A total of 10 623 EA and 3597 AA participants were included in the analyses. No single nucleotide polymorphism (SNP) was associated with BDR at the conventional genome-wide significance threshold (p<5×10−8). Performing fine mapping and using a threshold of p<5×10−6 to identify suggestive variants of interest, we identified three SNPs with possible biological relevance: rs35870000 (within FREM1), which may be involved in IgE-and IL5-induced changes in airway smooth muscle cell responsiveness; rs10426116 (within ZNF284), a zinc finger protein, which has been implicated in asthma and BDR previously; and rs4782614 (near ATP2C2), involved in calcium transmembrane transport. Validation in paediatric cohorts yielded no significant SNPs, possibly due to age–genotype interaction effects. Conclusion Ancestry-stratified and ancestry-combined GWAS meta-analyses of over 14 000 participants did not identify genetic variants associated with BDR at the genome-wide significance threshold, although a less stringent threshold identified three variants showing suggestive evidence of association. A common definition and protocol for measuring BDR in research may improve future efforts to identify variants associated with BDR. © The authors 2022.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease

Pathogenesis and treatment of chronic pulmonary disease

Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease

Increased airway responsiveness is linked to lung function decline and mortality in subjects with chronic obstructive pulmonary disease (COPD); however, the genetic contribution to airway responsiveness remains largely unknown. A genome-wide association study (GWAS) was performed using the Illumina (San Diego, CA) Human660W-Quad BeadChip on European Americans with COPD from the Lung Health Study. Linear regression models with correlated meta-analyses, including data from baseline (n = 2,814) and Year 5 (n = 2,657), were used to test for common genetic variants associated with airway responsiveness. Genotypic imputation was performed using reference 1000 Genomes Project data. Expression quantitative trait loci (eQTL) analyses in lung tissues were assessed for the top 10 markers identified, and immunohistochemistry assays assessed protein staining for SGCD and MYH15. Four genes were identified within the top 10 associations with airway responsiveness. Markers on chromosome 9p21.2 flanked by LINGO2 met a predetermined threshold of genome-wide significance (P <9.57x10(-8)). Markers on chromosomes 3q13.1 (flanked by MYH15), 5q33 (SGCD), and 6q21 (PDSS2) yielded suggestive evidence of association (9.57x10(-8) <

Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD

Accelerated lung function decline is a key COPD phenotype; however, its genetic control remains largely unknown. We performed a genome-wide association study using the Illumina Human660W-Quad v.1_A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung function decline over a 5-year period in 4,048 European American Lung Health Study participants with largely mild COPD. Genotype imputation was performed using reference HapMap II data. To validate regions meeting genome-wide significance, replication of top SNPs was attempted in independent cohorts. Three genes (TMEM26, ANK3 and FOXA1) within the regions of interest were selected for tissue expression studies using immunohistochemistry. Two intergenic SNPs (rs10761570, rs7911302) on chromosome 10 and one SNP on chromosome 14 (rs177852) met genome-wide significance after Bonferroni. Further support for the chromosome 10 region was obtained by imputation, the most significantly associated imputed SNPs (rs10761571, rs7896712) being flanked by observed markers rs10761570 and rs7911302. Results were not replicated in four general population cohorts or a smaller cohort of subjects with moderate to severe COPD; however, we show novel expression of genes near regions of significantly associated SNPS, including TMEM26 and FOXA1 in airway epithelium and lung parenchyma, and ANK3 in alveolar macrophages. Levels of expression were associated with lung function and COPD status. We identified two novel regions associated with lung function decline in mild COPD. Genes within these regions were expressed in relevant lung cells and their expression related to airflow limitation suggesting they may represent novel candidate genes for COPD susceptibility

Avaliação nutricional de estratégias de suplementação para bovinos de corte durante a estação da seca Nutritional evaluation of supplementation strategies for beef cattle during the dry season

Objetivou-se avaliar o efeito da frequência de oferta de suplementos proteicos sobre as características nutricionais de bovinos de corte em pastejo durante o período de seca. Utilizaram-se cinco novilhos mestiços Nelore nãocastrados, com peso médio inicial de 290 kg, fistulados no esôfago e rúmen e distribuídos em delineamento quadrado latino 5 &#215; 5. A área experimental foi composta de cinco piquetes de Brachiaria decumbens, cada um com 0,40 hectare. O experimento foi composto de cinco períodos experimentais de 15 dias, com os sete primeiros dias destinados à adaptação dos animais. As estratégias estudadas foram autocontrole de consumo e oferta de suplementos (1,0 kg/dia) em três frequências: 3 vezes/semana (às segundas, quartas e sextas-feiras), 5 vezes/semana (de segunda a sexta-feira), 6 vezes/semana (de segunda a sábado) e diariamente. Não houve efeito das frequencias de suplementação sobre os consumos expressos em kg/dia ou % PV. A frequência de suplementação teve efeito nas digestibilidades aparentes total e ruminal da MS e da PB, que foram maiores nos animais do grupo autocontrole. Os valores médios de pH observados no dia em que os animais não receberam suplemento foram de: 6,54±0,13; 6,48 ± 0,15 e 6,61 ± 0,07, respectivamente, para as frequências 3 vezes/semana, 5 vezes/semana e 6 vezes/semana. A concentração do NH3 foi 14,65 ± 5,78; 13,57 ± 5,30 e 15,30 ± 4,98 mg/dL de líquido ruminal, respectivamente, para as frequências 3 vezes/semana, 5 vezes/semana e 6 vezes/semana nos dias em que os animais não receberam suplemento. As eficiências microbianas e as concentrações de nitrogênio na urina e no soro sanguíneo são afetadas pelas estratégias estudadas e maiores nos animais alimentados com suplemento autocontrole.<br>The objective of this study was to evaluate the effect of the frequency of protein supplementation on the nutritional characteristics of beef cattle during the dry season. Five Nellore crossbred steer were used 290.0 kg LW, fistulated in the rumen and esophagus, distributed in a 5 &#215; 5 Latin square design. The experimental area consisted of five 0.40 ha Brachiaria decumbens paddocks. The experiment consisted of five 15-day experimental periods, with the first seven days for the animals to adapt. The strategies studied were: self-feed supplementation and supplementation (1.0 kg/animal/day) offered at three frequencies: three times/week (Monday, Wednesday and Friday), five times/week (Monday to Friday) and six times/week (Monday to Saturday) and daily. There were no effects of the different strategies on the intake expressed in kg/day or LW percentage. The supplementation frequency affected the total DM apparent digestibility and ruminal crude protein apparent digestibility that were higher in the self-feed supplementation group. The mean pH values, observed on the day when the animals were not supplemented were: 6.54 ± 0.13; 6.48 ± 0.15 and 6.61 ± 0.07, respectively for, the frequencies 3 times/week, 5 times/ week and 6 times/week. The NH3 concentration was: 14.65 ± 5.78; 13.57 ± 5.30 and 15.30 ± 4.98 mg/dL ruminal liquid, respectively, for the frequencies 3 times/week, 5 times/week and 6 times/week, on days without supplementation. The microbial efficiency and nitrogen concentrations in the urine and serum are affected by the strategies studied and are higher in the animals fed self feed supplementation