Comprehensive testing of positionally cloned asthma genes in two populations

Abstract

Rationale: Replication of gene-disease associations has become a requirement in complex trait genetics.

Objectives: In studies of childhood asthma from two different ethnic groups, we attempted to replicate associations with five potential asthma susceptibility genes previously identified by positional cloning.

Methods: We analyzed two family-based samples ascertained through an asthmatic proband: 497 European-American children from the Childhood Asthma Management Program and 439 Hispanic children from the Central Valley of Costa Rica. We genotyped 98 linkage disequilibrium-tagging single-nucleotide polymorphisms (SNPs) in five genes: ADAM33, DPP10, GPR154 (HUGO name: NPSR1), HLA-G, and the PHF11 locus (includes genes SETDB2 and RCBTB1). SNPs were tested for association with asthma and two intermediate phenotypes: airway hyperresponsiveness and total serum immunoglobulin E levels.

Measurements and main results: Despite differing ancestries, linkage disequilibrium patterns were similar in both cohorts. Of the five evaluated genes, SNP-level replication was found only for GPR154 (NPSR1). In this gene, three SNPs were associated with asthma in both cohorts, although the opposite alleles were associated in either study. Weak evidence for locus-level replication with asthma was found in the PHF11 locus, although there was no overlap in the associated SNP across the two cohorts. No consistent associations were observed for the three other genes.

Conclusions: These results provide some further support for the role of genetic variation in GPR154 (NPSR1) and PHF11 in asthma susceptibility and also highlight the challenges of replicating genetic associations in complex traits such as asthma, even for genes identified by linkage analysis.

Figure 1.

Correlation of pairwise r² values between all pairs of single-nucleotide polymorphisms (SNPs) in four of five studied asthma genes in the Costa Rica and Childhood Asthma Management Program (CAMP) studies. Because only two SNPs were genotyped, data for HLA-G are not shown.

Figure 2.

(A–D) Comparison of linkage disequilibrium (LD) patterns in four of five studied asthma genes across the Costa Rica and Childhood Asthma Management Program (CAMP) studies. LD is measured as D′, with darker red colors indicating higher values. Because only two SNPs were genotyped, data for HLA-G are not shown.

Figure 2.

(A–D) Comparison of linkage disequilibrium (LD) patterns in four of five studied asthma genes across the Costa Rica and Childhood Asthma Management Program (CAMP) studies. LD is measured as D′, with darker red colors indicating higher values. Because only two SNPs were genotyped, data for HLA-G are not shown.

Figure 2.

(A–D) Comparison of linkage disequilibrium (LD) patterns in four of five studied asthma genes across the Costa Rica and Childhood Asthma Management Program (CAMP) studies. LD is measured as D′, with darker red colors indicating higher values. Because only two SNPs were genotyped, data for HLA-G are not shown.

Figure 2.

(A–D) Comparison of linkage disequilibrium (LD) patterns in four of five studied asthma genes across the Costa Rica and Childhood Asthma Management Program (CAMP) studies. LD is measured as D′, with darker red colors indicating higher values. Because only two SNPs were genotyped, data for HLA-G are not shown.