Genome-wide screen for asthma in Puerto Ricans: evidence for association with 5q23 region.

While the number of success stories for mapping genes associated with complex diseases using genome-wide association approaches is growing, there is still much work to be done in developing methods for such studies when the samples are collected from a population, which may not be homogeneous. Here we report the first genome-wide association study to identify genes associated with asthma in an admixed population. We genotyped 96 Puerto Rican moderate to severe asthma cases and 88 controls as well as 109 samples representing Puerto Rico's founding populations using the Affymetrix GeneChip Human Mapping 100K array sets. The data from samples representing Puerto Rico's founding populations was used to identify ancestry informative markers for admixture mapping analyses. In addition, a genome-wide association analysis using logistic regression was performed on the data. Although neither admixture mapping nor regression analysis gave any significant association with asthma after correction for multiple testing, an overlap analysis using the top scoring SNPs from different methods suggested chromosomal regions 5q23.3 and 13q13.3 as potential regions harboring genes for asthma in Puerto Ricans. The validation analysis of these two regions in 284 Puerto Rican asthma trios gave significant association for the 5q23.3 region. Our results provide strong evidence that the previously linked 5q23 region is associated with asthma in Puerto Ricans. The detection of causative variants in this region will require fine mapping and functional validation.

Ancestry-environment interactions and asthma risk among Puerto Ricans.

BACKGROUND: Puerto Ricans, an admixed population of African, European, and Native American ancestries, have the highest asthma prevalence, morbidity, and mortality rates of any United States' population. Although socioeconomic status (SES) is negatively correlated with asthma incidence in most populations, no such relationship has been identified among Puerto Ricans. We hypothesized that, in this admixed population, the association between SES and asthma may interact with genetic ancestry. METHODS: We analyzed 135 Puerto Rican subjects with asthma and 156 control subjects recruited from six different recruitment centers in Puerto Rico. Individual ancestry for each subject was estimated using 44 ancestry informative markers. SES was assigned using the census tracts' median family income. Analyses of SES were based on the SES of the clinic site from which the subjects were recruited and on a subset of individuals on whom home address-based SES was available. RESULTS: In the two (independent) analyses, we found a significant interaction between SES, ancestry, and asthma disease status. At lower SES, European ancestry was associated with increased risk of asthma, whereas African ancestry was associated with decreased risk. The opposite was true for their higher SES counterparts. CONCLUSIONS: The observed interaction may help to explain the unique pattern of risk for asthma in Puerto Ricans and the lack of association with SES observed in previous studies when not accounting for varying proportions of ancestry.

Genetic admixture and asthma-related phenotypes in Mexican American and Puerto Rican asthmatics.

Genetic association studies in admixed populations may be biased if individual ancestry varies within the population and the phenotype of interest is associated with ancestry. However, recently admixed populations also offer potential benefits in association studies since markers informative for ancestry may be in linkage disequilibrium across large distances. In particular, the enhanced LD in admixed populations may be used to identify alleles that underlie a genetically determined difference in a phenotype between two ancestral populations. Asthma is known to have different prevalence and severity among ancestrally distinct populations. We investigated several asthma-related phenotypes in two ancestrally admixed populations: Mexican Americans and Puerto Ricans. We used ancestry informative markers to estimate the individual ancestry of 181 Mexican American asthmatics and 181 Puerto Rican asthmatics and tested whether individual ancestry is associated with any of these phenotypes independently of known environmental factors. We found an association between higher European ancestry and more severe asthma as measured by both forced expiratory volume at 1 second (r=-0.21, p=0.005) and by a clinical assessment of severity among Mexican Americans (OR: 1.55; 95% CI 1.25 to 1.93). We found no significant associations between ancestry and severity or drug responsiveness among Puerto Ricans. These results suggest that asthma severity may be influenced by genetic factors differentiating Europeans and Native Americans in Mexican Americans, although differing results for Puerto Ricans require further investigation.