Genetics and genomics of longitudinal lung function patterns in individuals with asthma

Michael J. McGeachie, Katherine P. Yates, Xiaobo Zhou, Feng Guo, Alice L. Sternberg, Mark L. Van Natta, Robert A. Wise, Stanley J. Szefler, Sunita Sharma, Alvin T. Kho, Michael H. Cho, Damien C. Croteau-Chonka, Peter J. Castaldi, Gaurav Jain, Amartya Sanyal, Ye Zhan, Bryan R. Lajoie, Job Dekker, John Stamatoyannopoulos, Ronina A. CovarRobert S. Zeiger, N. Franklin Adkinson, Paul V. Williams, H. William Kelly, Hartmut Grasemann, Judith M. Vonk, Gerard H. Koppelman, Dirkje S. Postma, Benjamin A. Raby, Isaac Houston, Quan Lu, Anne L. Fuhlbrigge, Kelan G. Tantisira, Edwin K. Silverman, James Tonascia, Robert C. Strunk, Scott T. Weiss

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


Rationale: Patterns of longitudinal lung function growth and decline in childhood asthma have been shown to be important in determining risk for future respiratory ailments including chronic airway obstruction and chronic obstructive pulmonary disease. Objectives: To determine the genetic underpinnings of lung function patterns in subjects with childhood asthma. Methods: We performed a genome-wide association study of 581 non-Hispanic white individuals with asthma that were previously classified by patterns of lung function growth and decline (normal growth, normal growth with early decline, reduced growth, and reduced growth with early decline). The strongest association was also measured in two additional cohorts: a small asthma cohort and a large chronic obstructive pulmonary disease metaanalysis cohort. Interaction between the genomic region encompassing the most strongly associated single-nucleotide polymorphismand nearby genes was assessed by two chromosome conformation capture assays. Measurements and Main Results: An intergenic singlenucleotide polymorphism(rs4445257) on chromosome 8was strongly associatedwith thenormal growthwithearly decline patterncompared with all other pattern groups (P = 6.7×10-9; odds ratio, 2.8; 95% confidence interval, 2.0-4.0); replication analysis suggested this variant had opposite effects in normal growth with early decline and reduced growth with early decline pattern groups. Chromosome conformation capture experiments indicated a chromatin interaction between rs4445257 and the promoter of the distal CSMD3 gene. Conclusions: Early decline in lung function after normal growth is associated with a genetic polymorphism that may also protect against early decline in reduced growth groups.

Original languageEnglish (US)
Pages (from-to)1465-1474
Number of pages10
JournalAmerican journal of respiratory and critical care medicine
Issue number12
StatePublished - Dec 15 2016


  • Asthma
  • CSMD3
  • Chronic obstructive pulmonary disease
  • Genome-wide association studies
  • Longitudinal lung function patterns

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine


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