Extensive admixture in Brazilian sickle cell patients: implications for the mapping of genetic modifiers

To the editor:

Genome-wide association studies (GWASs) of sickle cell disease (SCD) patients are a promising tool for identifying genetic modifiers of clinically relevant traits.^1,2  In such a study, Solovieff et al²  have uncovered a set of SNPs associated with fetal hemoglobin (HbF) concentration, the major modulator of the clinical course of this disease.

After the introduction of the SCD mutations into the Americas by African slaves, African descendants mixed with individuals of Native American and European origin to various extents across the continent. In Latin America, individuals tend to be more admixed than in African-American populations.^3,4  Studying different phenotypes, Solovieff et al²  did not find an association between fetal hemoglobin concentration and European ancestry, while Creary et al⁵  have reported an association between European ancestry and the proportion of erythrocytes containing HbF.

The level of admixture of SCD patients has implications for the design of association studies aimed at identifying new genetic modifiers of SCD clinical manifestations, particularly if these outcomes are associated with ancestry. If both genetic variants and clinical manifestations are associated with ancestry, there are 2 important issues to address. First, an observed association may be spurious if ancestry is not controlled for.⁶  Second, the admixture mapping strategy⁷  may be used: Thousands of ancestry-informative markers may be genotyped across the genome, and the local ancestry along chromosomes can be inferred. The genetic modifier alleles are expected to be located in genomic regions with an excess of ancestry of the population associated with the more common clinical outcome.

The risk of spurious association and the power of admixture mapping increase both with the level of admixture. However, estimates of ancestry are rare in SCD patients. Excluding GWASs, association studies between SNPs and SCD subphenotypes seldom control for ancestry.

We estimated admixture in 200 patients with SCD and in 291 healthy blood donors; all from the State of Minas Gerais (approximately 20 million inhabitants in South Eastern Brazil). We genotyped 54 SNPs/INDELs validated for admixture studies.^3,8,9  The ancestry of the healthy blood donors, who represent the general population reasonably well, was 33.8% African, 57.7% European and 3.5% Amerindian; whereas SCD patients showed 47.3%, 39.7% and 13.0% of African, European and Amerindian ancestry, respectively (estimated following Dupanloup and Bertorelle,¹⁰  see supplemental Table 1, available on the Blood Web site; see the supplemental Materials link at the top of the online article). Considering individual admixture (Figure 1), only 11.05% of SCD patients had > 85% African ancestry. Most of the patients (73.37%) had intermediate levels of admixture (15%-85%), and interestingly, 13.8% had predominant European ancestry (> 85%, and for 13.0%, the lower limit of the 90% credibility interval of European ancestry was > 0.60). Therefore, the prevalence of European ancestry is high, and the individual admixture is very heterogeneous in SCD patients from Brazil. Our results suggest that: (1) despite the association of SCD with African ancestry, the label “ethnic/racial” disease seems inappropriate in this population, (2) in association studies with SCD patients, controlling for ancestry is important to avoid spurious association, and (3) Latin American populations of SCD patients are promising targets for admixture mapping of genetic modifiers of ancestry-associated SCD clinical manifestations.