Cosmopolitan and ethnic-specific replication of genetic risk factors for asthma in 2 Latino populations

Abstract

Background: Although Mexicans and Puerto Ricans are jointly classified as "Hispanic/Latino," there are significant differences in asthma prevalence, severity, and mortality between the 2 groups. We sought to examine the possibility that population-specific genetic risks contribute to this disparity.

Objectives: More than 100 candidate genes have been associated with asthma and replicated in an independent population, and 7 genome-wide association studies in asthma have been performed. We compared the pattern of replication of these associations in Puerto Ricans and Mexicans.

Methods: We genotyped Mexican and Puerto Rican trios using an Affymetrix 6.0 GeneChip and used a family-based analysis to test for genetic associations in 124 genes previously associated with asthma.

Results: We identified 32 single nucleotide polymorphisms (SNPs) in 17 genes associated with asthma in at least 1 of the 2 populations. Twenty-two of these SNPs in 11 genes were significantly associated with asthma in the combined population and showed no significant heterogeneity of association, whereas 5 SNPs were associated in only 1 population and showed statistically significant heterogeneity. In a gene-based approach 2 additional genes were associated with asthma in the combined population, and 3 additional genes displayed ethnic-specific associations with heterogeneity.

Conclusions: Our results show that only a minority of genetic association studies replicate in our population of Mexican and Puerto Rican asthmatic subjects. Among SNPs that were successfully replicated, most showed no significant heterogeneity across populations. However, we identified several population-specific genetic associations.

Figure 1

Process of SNP and gene selection.

Figure 2

Boxplot of individual ancestry estimates of GALA Mexicans and Puerto Ricans. On average Puerto Ricans have higher African and European ancestry than Mexicans while Mexicans have higher Native American ancestry.

Figure 3

SNP based replication showing odds ratio for Mexican, Puerto Rican, and combined samples. The top graph shows the genes that replicated in the combined population with low heterogeneity; the bottom graph shows genes that replicated in one population and had significant heterogeneity.

Figure 3

SNP based replication showing odds ratio for Mexican, Puerto Rican, and combined samples. The top graph shows the genes that replicated in the combined population with low heterogeneity; the bottom graph shows genes that replicated in one population and had significant heterogeneity.

Figure 4

Venn diagram showing the relationships between the replicated genes. An asterisk (*) indicates that there was heterogeneity between ethnicities. Genes within boxes are additional genes identified only in the gene-based replication; the rest of the genes were identified in the SNP-based replication. In three genes, ADRA1B, ORMDL3, and RAD50, different SNPs in the genes fit into the diagram differently so the gene is shown twice.