Evaluation of oxidative stress-related genetic variants for predicting stroke in patients with sickle cell anemia.

Overt stroke in adults with sickle cell anemia (SCA) continues to be a major cause of morbidity and mortality, while no evidence-based strategy for prevention has been reached so far. Although transcranial Doppler ultrasonography represents the most important tool for identifying young patients with SCA at risk of primary stroke, strategies for stroke prediction in adulthood remain challenging. Emerging data suggest that oxidative stress may exert a pivotal role in the pathogenesis of ischemic brain injury. Combining these pieces of evidences with the well-known genetic contribution to the development of stroke in SCA, we hypothesized that genetic variants related to the biology of oxidative stress could be used to identify adult patients at higher risk of stroke. Overall, 499 unrelated patients with SCA aged >18 years were genotyped for SOD2 Val16Ala (rs4880), GPX3 T-568C (rs8177404), GPX3 T-518C (rs8177406), GPX3 T-65C (rs8177412), and CAT01 C-262 T (rs1001179) polymorphisms, along with α-thalassemia status and ß-globin gene haplotypes. Of these, only the SOD2 Val16Ala polymorphism was associated with stroke. SOD2 Val16Ala polymorphism was independently associated with risk of stroke (odds ratio: 1.98; 95% confidence interval [CI]: 1.18-3.32; P = .009) and with the long-term cumulative incidence of stroke (hazard ratio: 2.24, 95% CI: 1.3-3.9; P = .004). In summary, we provide evidence that oxidative stress-related genetic variants, in particular, the SOD2 Val16Ala polymorphism, may represent a simple and inexpensive alternative for identifying patients at risk of stroke.

Genetic comparison of sickle cell anaemia cohorts from Brazil and the United States reveals high levels of divergence.

Genetic analysis of admixed populations raises special concerns with regard to study design and data processing, particularly to avoid population stratification biases. The point mutation responsible for sickle cell anaemia codes for a variant hemoglobin, sickle hemoglobin or HbS, whose presence drives the pathophysiology of disease. Here we propose to explore ancestry and population structure in a genome-wide study with particular emphasis on chromosome 11 in two SCA admixed cohorts obtained from urban populations of Brazil (Pernambuco and São Paulo) and the United States (Pennsylvania). Ancestry inference showed different proportions of European, African and American backgrounds in the composition of our samples. Brazilians were more admixed, had a lower African background (43% vs. 78% on the genomic level and 44% vs. 76% on chromosome 11) and presented a signature of positive selection and Iberian introgression in the HbS region, driving a high differentiation of this locus between the two cohorts. The genetic structures of the SCA cohorts from Brazil and US differ considerably on the genome-wide, chromosome 11 and HbS mutation locus levels.