Citations

Abstract Background Asthma exacerbations are a serious public health concern due to high healthcare resource utilization, work/school productivity loss, impact on quality of life, and risk of mortality. The genetic basis of asthma exacerbations has been studied in several populations, but no prior study has performed a multi‐ancestry meta‐analysis of genome‐wide association studies (meta‐GWAS) for this trait. We aimed to identify common genetic loci associated with asthma exacerbations across diverse populations and to assess their functional role in regulating DNA methylation and gene expression. Methods A meta‐GWAS of asthma exacerbations in 4989 Europeans, 2181 Hispanics/Latinos, 1250 Singaporean Chinese, and 972 African Americans analyzed 9.6 million genetic variants. Suggestively associated variants ( p ≤ 5 × 10 −5 ) were assessed for replication in 36,477 European and 1078 non‐European asthma patients. Functional effects on DNA methylation were assessed in 595 Hispanic/Latino and African American asthma patients and in publicly available databases. The effect on gene expression was evaluated in silico. Results One hundred and twenty‐six independent variants were suggestively associated with asthma exacerbations in the discovery phase. Two variants independently replicated: rs12091010 located at vascular cell adhesion molecule‐1/exostosin like glycosyltransferase‐2 ( VCAM1 / EXTL2 ) (discovery: odds ratio (OR T allele ) = 0.82, p = 9.05 × 10 −6 and replication: OR T allele = 0.89, p = 5.35 × 10 −3 ) and rs943126 from pantothenate kinase 1 ( PANK1 ) (discovery: OR C allele = 0.85, p = 3.10 × 10 −5 and replication: OR C allele = 0.89, p = 1.30 × 10 −2 ). Both variants regulate gene expression of genes where they locate and DNA methylation levels of nearby genes in whole blood. Conclusions This multi‐ancestry study revealed novel suggestive regulatory loci for asthma exacerbations located in genomic regions participating in inflammation and host defense.

P10 Coronary artery calcification (CAC), quantified by electron beam computed tomography, provides a measure of extent of coronary atherosclerosis in asymptomatic and symptomatic individuals. It is well recognized that coronary artery disease and CAC are complex processes that are influenced by many genetic and environmental factors. Several aspects of CAC quantity make genetic studies of it particularly challenging. These include the non-normality of CAC frequency distributions and the strong age- and sex-dependence of CAC levels. To search for regions that may contain genes influencing CAC quantity, a genome-wide scan was conducted on a sample enriched for hypertension from the Epidemiology of Coronary Artery Calcification Study. The genome-wide linkage scan was based on 370 anonymous markers spanning the 22 autosomal chromosomes in 29 families. The analysis sample consisted of 20 affected sib-pairs, 8 affected sib-trios and 1 family with 6 affected siblings. Here, affection status was defined as being above the 70th sex- and age-specific percentile based on a reference population. Mode-of-inheritance-free qualitative linkage analysis was used to analyze sib-pair data. Maximum multipoint lod scores were calculated using the computer software Genehunter-2. Weighted analyses were conducted using Holmans “possible triangle” constraint. The overall maximum lod scores were observed on chromosomes 6 (lod=2.22) and 10 (lod=3.24). Additional lod scores greater than 1.0 were observed on chromosomes 2, 14, 15 and 17. These results identify regions that may harbor genes involved in high sex- and age-specific levels of CAC (supported by HL46292).