Major minors only?

Comment on Oh et al, page 1408

Is race important after all? In this issue of Blood, Oh and colleagues describe the association between ethnicity and the incidence of graft-versus-host disease (GVHD) following HLA-identical sibling bone marrow transplantation.

Arelatively uniform group of patients with leukemia from 3 island populations (Japan, Scandinavia, Ireland) were compared with white Americans and African Americans. White Americans or Americans of African origins and Irish patients had a higher risk of developing acute GVHD, and white Americans and African Americans had a higher risk of early treatment-related mortality (TRM) compared with the other ethnic groups. There were no differences in the incidence of chronic GVHD, relapse, or overall survival. This study encompasses a large number of patients and the comprehensive analyses provide important insights.

These observations confirm previous findings,¹  but, as with many important papers, the data raise more questions. Undoubtedly, there are genetic polymorphisms that differ among ethnic groups. These polymorphisms are expressed in the HLA phenotype and the multiple minor histocompatibility antigens: the more homogeneous the population, the more limited the variation among these genes. The limited variability potentially leads to better matching and thus less GVHD. However, other polymorphisms do matter. Cytokine polymorphisms have been described as being predictive of GVHD.²  Yet, the association of acute GVHD with ethnicity did not correlate to differences in chronic GHVD, relapse, and overall survival: end points that historically have been associated with acute GVHD. Moreover, white Americans and African Americans had higher TRM, yet overall survival was similar.

Why is this important? Variations in drug metabolism is one area that is just starting to be studied. For example, we have observed marked differences in the rate of high-dose cyclophosphamide metabolism based on differences in cytochrome P450 polymorphism, which in turn are determined by the genetic background. A more rapid conversion of cyclophosphamide to its active metabolites would result in a higher area-under-the-curve (AUC) and thus higher drug exposure and toxicity (or efficacy). Moreover, recent drug studies that have targeted African Americans in the treatment of heart failure demonstrate significant improvement in survival.³  With rare exceptions, the US population is composed of immigrants from various homelands and spanning several generations. Thus, the designation of white American or African American is clearly too simple. These designations do not capture the heterogeneity and genetic diversity, and this manuscript reflects that diversity. Thus, race is a crude undefined marker. It is necessary to understand the genetic makeup of an individual, the unique genetic material that, while influenced by parents, is potentially derived from many different ethnic groups. In the end, the ability to tease out the important components that contribute to the overall outcome is what is important rather than one's race.

Last, group differences in outcome may not be related to genetics. There are social, societal, economic, and environmental factors that could contribute to the observed differences. For example, could lower incidence of cytomegalovirus (CMV), longer stays in the inpatient wards, and better social/family networks for posttransplantation care all contribute to the observed differences? ▪