A Genome Wide Approach to Identify Genetic Determinants of Asthma Traits Related to Airway Function in Two Populations of African Descent

Abstract

RATIONALE: Asthma is a complex disease with a strong genetic component characterized by intermittent airway inflammation, often resulting in irreversible airway remodeling and airflow limitation. Asthma morbidity and mortality are disproportionately high among African Americans, but few genetic studies have focused on this particularly vulnerable group. The genome-wide association study is a cutting-edge approach to identify novel genes for potential therapeutic targets and improved diagnostics.METHODS: Using the Illumina HumanHap650Y BeadChip, we genotyped 655,352 single nucleotide polymorphisms (SNPs) on two asthmatic populations of African ancestry: 998 case-controls in Baltimore-Washington D.C. and 977 family based subjects in Barbados, among whom 131 and 215 asthmatics, respectively, had complete lung function data. Genotypic tests of association for FEV1 (%predicted) as a quantitative trait in a linear regression model were calculated with PLINK in the Baltimore-DC population, with SNPs at (P < 0.05) selected for replication in the Barbados group using FBAT.RESULTS: Two SNPs were associated with FEV1 (% predicted) at the P = 10-7 level, plus one SNP at P = 10-6 and 55 SNPs at P = 10-5. Two of the strongest signals (combined P = 3.9 X 10-7 and 1.8 X 10-5) localize to CUL5, encoding a calcium-mobilizing receptor involved in intracellular signal transduction, on chromosome 11q22. This gene has not been previously studied in asthma or related traits.CONCLUSIONS: The genome-wide association study can effectively identify novel genetic determinants in complex traits, including asthma. Replication of findings in independent populations is ongoing. RATIONALE: Asthma is a complex disease with a strong genetic component characterized by intermittent airway inflammation, often resulting in irreversible airway remodeling and airflow limitation. Asthma morbidity and mortality are disproportionately high among African Americans, but few genetic studies have focused on this particularly vulnerable group. The genome-wide association study is a cutting-edge approach to identify novel genes for potential therapeutic targets and improved diagnostics. METHODS: Using the Illumina HumanHap650Y BeadChip, we genotyped 655,352 single nucleotide polymorphisms (SNPs) on two asthmatic populations of African ancestry: 998 case-controls in Baltimore-Washington D.C. and 977 family based subjects in Barbados, among whom 131 and 215 asthmatics, respectively, had complete lung function data. Genotypic tests of association for FEV1 (%predicted) as a quantitative trait in a linear regression model were calculated with PLINK in the Baltimore-DC population, with SNPs at (P < 0.05) selected for replication in the Barbados group using FBAT. RESULTS: Two SNPs were associated with FEV1 (% predicted) at the P = 10-7 level, plus one SNP at P = 10-6 and 55 SNPs at P = 10-5. Two of the strongest signals (combined P = 3.9 X 10-7 and 1.8 X 10-5) localize to CUL5, encoding a calcium-mobilizing receptor involved in intracellular signal transduction, on chromosome 11q22. This gene has not been previously studied in asthma or related traits. CONCLUSIONS: The genome-wide association study can effectively identify novel genetic determinants in complex traits, including asthma. Replication of findings in independent populations is ongoing.