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

TY - JOUR

T1 - A decade of research on the 17q12-21 asthma locus

T2 - Piecing together the puzzle

AU - Stein, Michelle M.

AU - Thompson, Emma E.

AU - Schoettler, Nathan

AU - Helling, Britney A.

AU - Magnaye, Kevin M.

AU - Stanhope, Catherine

AU - Igartua, Catherine

AU - Morin, Andréanne

AU - Washington, Charles

AU - Nicolae, Dan

AU - Bønnelykke, Klaus

AU - Ober, Carole

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

KW - gene expression

KW - genome-wide association study

KW - GSDMA

KW - GSDMB

KW - immune cells

KW - lung cells

KW - ORMDL3

KW - PGAP3

KW - Wheezing

U2 - 10.1016/j.jaci.2017.12.974

DO - 10.1016/j.jaci.2017.12.974

M3 - Review

C2 - 29307657

AN - SCOPUS:85041238661

SN - 0091-6749

VL - 142

SP - 749-764.e3

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 3

ER -