Format

Send to

Choose Destination
J Allergy Clin Immunol. 2018 Sep;142(3):749-764.e3. doi: 10.1016/j.jaci.2017.12.974. Epub 2018 Jan 4.

A decade of research on the 17q12-21 asthma locus: Piecing together the puzzle.

Author information

1
Department of Human Genetics, University of Chicago, Chicago, Ill.
2
Department of Human Genetics, University of Chicago, Chicago, Ill; Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Ill.
3
Department of Human Genetics, University of Chicago, Chicago, Ill; Department of Statistics and Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Ill.
4
COPSAC, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
5
Department of Human Genetics, University of Chicago, Chicago, Ill. Electronic address: c-ober@genetics.uchicago.edu.

Abstract

Chromosome 17q12-21 remains the most highly replicated and significant asthma locus. Genotypes in the core region defined by the first genome-wide association study correlate with expression of 2 genes, ORM1-like 3 (ORMDL3) and gasdermin B (GSDMB), making these prime candidate asthma genes, although recent studies have implicated gasdermin A (GSDMA) distal to and post-GPI attachment to proteins 3 (PGAP3) proximal to the core region as independent loci. We review 10 years of studies on the 17q12-21 locus and suggest that genotype-specific risks for asthma at the proximal and distal loci are not specific to early-onset asthma and mediated by PGAP3, ORMDL3, and/or GSDMA expression. We propose that the weak and inconsistent associations of 17q single nucleotide polymorphisms with asthma in African Americans is due to the high frequency of some 17q alleles, the breakdown of linkage disequilibrium on African-derived chromosomes, and possibly different early-life asthma endotypes in these children. Finally, the inconsistent association between asthma and gene expression levels in blood or lung cells from older children and adults suggests that genotype effects may mediate asthma risk or protection during critical developmental windows and/or in response to relevant exposures in early life. Thus studies of young children and ethnically diverse populations are required to fully understand the relationship between genotype and asthma phenotype and the gene regulatory architecture at this locus.

KEYWORDS:

GSDMA; GSDMB; ORMDL3; PGAP3; Wheezing; gene expression; genome-wide association study; immune cells; lung cells

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center