Genetic ancestry modifies pharmacogenetic gene-gene interaction for asthma

A recent admixture mapping analysis identified interleukin 6 (IL6) and IL6 receptor (IL6R) as candidate genes for inflammatory diseases. In the airways during allergic inflammation, IL6 signaling controls the production of proinflammatory and anti-inflammatory factors. In addition, albuterol, a commonly prescribed asthma therapy, has been shown to influence IL6 gene expression. Therefore, we reasoned that interactions between the IL6 and IL6R genes might be associated with bronchodilator drug responsiveness to albuterol in asthmatic patients.

Four functional IL6 single nucleotide polymorphisms (SNPs) and a nonsynonymous IL6R SNP were genotyped in 700 Mexican and Puerto Rican asthma families and in 443 African-American asthma cases and controls. Both family-based association tests and linear regression models were used to assess the association between individual SNPs and haplotypes with bronchodilator response. Gene-gene interactions were tested by using multiple linear regression analyses.

No single SNP was consistently associated with drug response in all the three populations. However, on the gene level, we found a consistent IL6 and IL6R pharmacogenetic interaction in the three populations. This pharmacogenetic gene-gene interaction was contextual and dependent upon ancestry (racial background). This interaction resulted in higher drug response to albuterol in Latinos, but lower drug response in African-Americans. Herein, we show that there is an effect modification by ancestry on bronchodilator responsiveness to albuterol.

Genetic variants in the IL6 and IL6R genes act synergistically to modify the bronchodilator drug responsiveness in asthma and this pharmacogenetic interaction is modified by the genetic ancestry.