Ancestry, ancestry-informative markers, asthma, and the quest for personalized medicine

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Conventional wisdom regarding the ultimate utility of human genome discoveries in common complex diseases such as asthma is that with the discovery of genetic polymorphisms that track with specific clinical traits, genetic profiling for personalized medicine will eventually be realized and lead to improvements in the prognosis and prediction of disease in the clinical setting. Acknowledging that few such discoveries have resulted in reliably predictive tests thus far, beyond some of the Mendelian disorders (ie, Huntington disease and phenylketonuria) and perhaps a handful of common diseases (ie, hypertriglyceridemia and age-related macular degeneration), genome-based prediction of common diseases like asthma is nevertheless anticipated in the long-term. The tremendous investment committed to the field of asthma genetics over the past 2 decades, spanning from the early linkage and candidate gene studies in the early 1990s and into the 21st century to the dozen or so asthma genome-wide association studies performed in just the past few years, is testimony to our confidence in the ‘‘gene hunters.’’ It is well established and has been demonstrated year after year in survey after survey that asthmatic subjects of African descent have greater asthmamorbidity andmortality than white subjects, but the extent to which genetic variation contributes to these profound racial and ethnic disparities has not been so clear. Reports of increases in the prevalence and severity of asthma according to African ancestry outside of the United States further support a role for a genetic contribution that is dictated, at least in part, by one’s biogeography. Although race and ethnicity are undeniably social constructs reflective of an individual’s self-ascribed sociocultural, psychological, behavioral, and biological identity, the striking racial and ethnic disparities in disease prevalence and severity for common complex disorders, such as asthma, cannot be explained entirely by ‘‘nongenetic’’ factors. Indeed, however one chooses (or chooses not) to define the biological construct of race, in the case of asthma, substantial variation in frequencies of high-risk genetic variants according to ancestry has been well established. This has been of special interest in the field of pharmacogenetics, in which genetic variation in response to treatment according to self-reported race/ethnicity is suspected.