We hypothesize that the enhanced asthma risk following infant RSV exposure is due to two non-mutually exclusive factors: (1) a genetic predisposition common to both diseases and (2) infant RSV infection acting as a causal agent in asthma development. We will use genetic epidemiological methods to determine the extent to which infant RSV infection plays a causal role in the development of asthma or if it merely serves as a marker of shared genetic risk with asthma. This study leverages multiple existing US based cohorts, including the Infant Susceptibility to Pulmonary Infections and Asthma Following RSV Exposure (INSPIRE; Hartert, PI), the Tennessee Children's Respiratory Initiative (TCRI; Hartert, PI), RSV Bronchiolitis in Early Life (RBEL I and II; Castro, PI), and Childhood Origins of Asthma (COAST; Lemanske, PI). This revised grant improves power for genetic studies and builds infrastructure to understand infant RSV infection and its respiratory sequelae by collaborating with longitudinal cohorts that have well-characterized respiratory infections in infants during the first year of life followed through to early childhood wheezing/asthma outcomes. We will first identify the genes associated with response to RSV infection (Aim 1) and then determine the genetic bases of shared RSV infection and recurrent wheezing/ early asthma susceptibility (Aim 2). This would be the first GWAS of RSV infection in infancy and its respiratory sequelae of recurrent wheezing/asthma.

We would like to use existing GWAS data from ALSPAC for replication of our primary findings.

Specific Aim 1a:

1a) We will identify the genetic determinants of the severity of RSV infection in the first year of life among ~2000 infants from multiple US cohorts with confirmed RSV exposure or infection. For GWAS genotyping, we will use the Illumina HumanCore + Exome BeadChip in European-Americans (EAs) and the Illumina Omni 2.5M + Exome BeadChip in African-Americans (AAs) and Hispanic-Americans (HAs).

Specific Aim 1b) We will perform a pathway analysis of genome-wide data that addresses limitations of SNP analyses to identify genes or pathways that are associated with severity of RSV infection during infancy.

Specific Aim 2: We will identify the specific genetic variants that lead to the shared genetic risk of severity of RSV infection and early childhood recurrent wheezing/asthma.

This proposed collaboration will address an important gap in understanding how severe infant RSV infection increases the risk of recurrent wheezing/asthma. The results will provide novel insights into both the timing and mechanism for developing primary prevention strategies.

Based on two papers from the ALSPAC cohort, both involving collaborator John Henderson, there are 284 infants hospitalized with infant bronchiolitis. The ALSPAC cohort has well characterized wheezing and asthma outcomes. Using this existing data, we would like to replicate our SNPs predicting severe infant bronchiolitis, measured as hospitalization (y/n). We would also like to replicate SNPs that examine risk of wheezing/asthma after hospitalization for bronchiolitis. We propose in Specific Aim 1b and in exploratory analyses for asthma outcomes to conduct pathway analyses. We would like to use existing ALSPAC data to conduct a replication of our pathway analysis. This will entail the analysis of existing GWAS data.

If the sample size for hospitalization with bronchiolitis followed to to wheezing / asthma outcomes includes enough children with DNA available, we would like to consider using your genetics lab for replication of 480 SNPS from Aim 1 and 480 SNPs from Aim 2 using cases a set of matched controls. At this point we do not know whether our primary SNPs will exist in your data set. We also do not know whether there will be enough children from the case group with DNA.