Population stratification confounds genetic association studies among Latinos.

In the United States, asthma prevalence and mortality are the highest among Puerto Ricans and the lowest among Mexicans. Case-control association studies are a powerful strategy for identifying genes of modest effect in complex diseases. However, studies of complex disorders in admixed populations such as Latinos may be confounded by population stratification. We used ancestry informative markers (AIMs) to identify and correct for population stratification among Mexican and Puerto Rican subjects participating in case-control studies of asthma. Three hundred and sixty-two subjects with asthma (Mexican: 181, Puerto Rican: 181) and 359 ethnically matched controls (Mexican: 181, Puerto Rican: 178) were genotyped for 44 AIMs. We observed a greater than expected degree of association between pairs of AIMs on different chromosomes in Mexicans (P < 0.00001) and Puerto Ricans (P < 0.00002) providing evidence for population substructure and/or recent admixture. To assess the effect of population stratification on association studies of asthma, we measured differences in genetic background of cases and controls by comparing allele frequencies of the 44 AIMs. Among Puerto Ricans but not in Mexicans, we observed a significant overall difference in allele frequencies between cases and controls (P = 0.0002); of 44 AIMs tested, 8 (18%) were significantly associated with asthma. However, after adjustment for individual ancestry, only two of these markers remained significantly associated with the disease. Our findings suggest that empirical assessment of the effects of stratification is critical to appropriately interpret the results of case-control studies in admixed populations.

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.

ADAM33 is not associated with asthma in Puerto Rican or Mexican populations.

A recent study identified the ADAM33 gene as a promising candidate contributing to asthma. In Puerto Rican and Mexican populations, we have genotyped six single nucleotide polymorphisms (SNPs) that were used in the Genetics of Asthma in Latino Americans Study. We chose to study these two populations because in the United States, Puerto Ricans have the highest asthma prevalence, morbidity, and mortality and Mexicans the lowest. We used the transmission disequilibrium test to analyze associations between the ADAM33 gene variants and asthma, asthma severity, bronchodilator responsiveness, and total IgE levels using single SNPs, two to six SNP combinations, and specific haplotypes in 583 trios (proband with asthma and both biological parents). We also genotyped matched control samples to allow case-control analyses. None of the transmission disequilibrium test or case-control results showed significant association in either population. We found no evidence for association of single SNPs with asthma severity, bronchodilator response, or IgE levels in Mexicans or in the combined population. Two SNPs showed a modest association in Puerto Ricans, insignificant when the number of comparisons was taken into account. We conclude that the ADAM33 gene is not an important risk factor for asthma or for asthma-associated phenotypes in Mexicans or in Puerto Ricans.