Influence of the βs haplotype and α-thalassemia on stroke development in a Brazilian population with sickle cell anaemia

Annals of Hematology - Tập 93 - Trang 1123-1129 - 2014
Igor F. Domingos1,2, Diego A. Falcão1, Betania L. Hatzlhofer1,2, Anderson F. Cunha3, Magnun N. Santos4, Dulcinéia M. Albuquerque5, Kleber Y. Fertrin5, Fernando F. Costa5, Renata C. Azevedo2, Cíntia G. Machado2, Aderson S. Araújo2, Antonio R. Lucena-Araujo1, Marcos A. Bezerra1,2
1Department of Genetics, Centre of Biological Sciences, Federal University of Pernambuco, Recife, Brazil
2Haematology and Haemotherapy Foundation of Pernambuco, Recife, Brazil
3Department of Genetics and Evolution, Federal University of São Carlos, São Carlos, Brazil
4Department of Clinical Pathology, School of Medical Sciences, University of Campinas, Campinas, Brazil
5Haematology and Haemotherapy Centre, University of Campinas, São Paulo, Brazil

Tóm tắt

Stroke is a catastrophic complication of sickle cell anaemia (SCA) and is one of the leading causes of death in both adults and children with SCA. Evidence suggests that some genetic polymorphisms could be related to stroke development, but their association remains controversial. Here, we performed genotyping of five published single nucleotide polymorphisms, the α-thalassemia genotype, the G6PD A (−) variant deficiency, and the βS haplotype in a large series of SCA patients with well-defined stroke phenotypes. Of 261 unrelated SCA patients included in the study, 67 (9.5 %) presented a documented, primary stroke event. Markers of haemolysis (red blood cell (RBC) counts, p = 0.023; reticulocyte counts, p = 0.003; haemoglobin (Hb) levels, p < 0.001; indirect bilirubin levels, p = 0.006; lactate dehydrogenase (LDH) levels, p = 0.001) were associated with stroke susceptibility. Genetically, only the βS haplotype (odds ratio (OR) 2.9, 95 % confidence interval (CI) 1.56 to 4.31; p = 0.003) and the α3.7kb-thalassemia genotype (OR 0.31, 95 % CI 0.11 to 0. 83; p = 0.02) were associated with increased and decreased stroke risk, respectively. In multivariate analysis, the βS haplotype was independently associated with stroke development (OR 2.26, 95 % CI 1.16 to 4.4; p = 0.016). Our findings suggest that only the βS haplotypes and the α3.7kb-thalassemia genotype modulate the prevalence of stroke in our SCA population. Genetic heterogeneity among different populations may account for the irreproducibility amongst different studies.

Tài liệu tham khảo

Cajado C, Cerqueira BA, Couto FD, Moura-Neto JP, Vilas-Boas W, Dorea MJ et al (2011) TNF-alpha and IL-8: serum levels and gene polymorphisms (-308G>A and -251A>T) are associated with classical biomarkers and medical history in children with sickle cell anemia. Cytokine 56:312–317 Steinberg MH (2009) Genetic etiologies for phenotypic diversity in sickle cell anemia. Sci World J 9:46–67 Stuart MJ, Nagel RL (2004) Sickle-cell disease. Lancet 364:1343–1360 Ohene-Frempong K, Weiner SJ, Sleeper LA, Miller ST, Embury S, Moohr JW et al (1998) Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood 91:288–294 Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH et al (1994) Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 330:1639–1644 Taylor JG, Nolan VG, Mendelsohn L, Kato GJ, Gladwin MT, Steinberg MH (2008) Chronic hyper-hemolysis in sickle cell anemia: association of vascular complications and mortality with less frequent vasoocclusive pain. PLoS One 3:e2095 Solovey A, Lin Y, Browne P, Choong S, Wayner E, Hebbel RP (1997) Circulating activated endothelial cells in sickle cell anemia. N Engl J Med 337:1584–1590 Chiang EY, Frenette PS (2005) Sickle cell vaso-occlusion. Hematol Oncol Clin North Am 19:771–784, v Conran N, Franco-Penteado CF, Costa FF (2009) Newer aspects of the pathophysiology of sickle cell disease vaso-occlusion. Hemoglobin 33:1–16 Balkaran B, Char G, Morris JS, Thomas PW, Serjeant BE, Serjeant GR (1992) Stroke in a cohort of patients with homozygous sickle cell disease. J Pediatr 120:360–366 Wang WC, Langston JW, Steen RG, Wynn LW, Mulhern RK, Wilimas JA et al (1998) Abnormalities of the central nervous system in very young children with sickle cell anemia. J Pediatr 132:994–998 Leikin SL, Gallagher D, Kinney TR, Sloane D, Klug P, Rida W (1989) Mortality in children and adolescents with sickle cell disease. Cooperative study of sickle cell disease. Pediatrics 84:500–508 Stockman JA, Nigro MA, Mishkin MM, Oski FA (1972) Occlusion of large cerebral vessels in sickle-cell anemia. N Engl J Med 287:846–849 Hoppe C, Klitz W, D’Harlingue K, Cheng S, Grow M, Steiner L et al (2007) Confirmation of an association between the TNF(−308) promoter polymorphism and stroke risk in children with sickle cell anemia. Stroke 38:2241–2246 Adams RJ (2005) TCD in sickle cell disease: an important and useful test. Pediatr Radiol 35:229–234 Hoppe C, Klitz W, Cheng S, Apple R, Steiner L, Robles L et al (2004) Gene interactions and stroke risk in children with sickle cell anemia. Blood 103:2391–2396 Sebastiani P, Ramoni MF, Nolan V, Baldwin CT, Steinberg MH (2005) Genetic dissection and prognostic modeling of overt stroke in sickle cell anemia. Nat Genet 37:435–440 Voetsch B, Jin RC, Bierl C, Benke KS, Kenet G, Simioni P et al (2007) Promoter polymorphisms in the plasma glutathione peroxidase (GPx-3) gene: a novel risk factor for arterial ischemic stroke among young adults and children. Stroke 38:41–49 Flanagan JM, Frohlich DM, Howard TA, Schultz WH, Driscoll C, Nagasubramanian R et al (2011) Genetic predictors for stroke in children with sickle cell anemia. Blood 117:6681–6684 Driscoll MC, Hurlet A, Styles L, McKie V, Files B, Olivieri N et al (2003) Stroke risk in siblings with sickle cell anemia. Blood 101:2401–2404 Kwiatkowski JL, Hunter JV, Smith-Whitley K, Katz ML, Shults J, Ohene-Frempong K (2003) Transcranial Doppler ultrasonography in siblings with sickle cell disease. Br J Haematol 121:932–937 Poggi V, Town M, Foulkes NS, Luzzatto L (1990) Identification of a single base change in a new human mutant glucose-6-phosphate dehydrogenase gene by polymerase-chain-reaction amplification of the entire coding region from genomic DNA. Biochem J 271:157–160 Powars DR (1991) Beta s-gene-cluster haplotypes in sickle cell anemia. Clinical and hematologic features. Hematol Oncol Clin North Am 5:475–493 Dode C, Krishnamoorthy R, Lamb J, Rochette J (1993) Rapid analysis of -α3.7 thalassaemia and αααanti 3.7 triplication by enzymatic amplification analysis. Br J Haematol 83:105–111 Arruda VR, Annichino-Bizzacchi JM, Costa FF, Reitsma PH (1995) Factor V Leiden (FVQ 506) is common in a Brazilian population. Am J Hematol 49:242–243 Data SA, Roltsch MH, Hand B, Ferrell RE, Park JJ, Brown MD (2003) eNOS T-786C genotype, physical activity, and peak forearm blood flow in females. Med Sci Sports Exerc 35:1991–1997 Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG et al (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10:111–113 Poort SR, Rosendaal FR, Reitsma PH, Bertina RM (1996) A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 88:3698–3703 Bandeira FM, Santos MN, Bezerra MA, Gomes YM, Araujo AS, Braga MC et al (2008) Family screening for HBB*S gene and detection of new cases of sickle cell trait in Northeastern Brazil. Rev Saude Publica 42:234–241 Bezerra MA, Santos MN, Araujo AS, Gomes YM, Abath FG, Bandeira FM (2007) Molecular variations linked to the grouping of beta- and alpha-globin genes in neonatal patients with sickle cell disease in the state of Pernambuco, Brazil. Hemoglobin 31:83–88 Lyra IM, Goncalves MS, Braga JA, Gesteira MF, Carvalho MH, Saad ST et al (2005) Clinical, hematological, and molecular characterization of sickle cell anemia pediatric patients from two different cities in Brazil. Cad Saude Publica 21:1287–1290 Sarnaik SA, Ballas SK (2001) Molecular characteristics of pediatric patients with sickle cell anemia and stroke. Am J Hematol 67:179–182 Sebastiani P, Solovieff N, Hartley SW, Milton JN, Riva A, Dworkis DA et al (2010) Genetic modifiers of the severity of sickle cell anemia identified through a genome-wide association study. Am J Hematol 85:29–35 Adams RJ, Kutlar A, McKie V, Carl E, Nichols FT, Liu JC et al (1994) Alpha thalassemia and stroke risk in sickle cell anemia. Am J Hematol 45:279–282 Belisario AR, Rodrigues CV, Martins ML, Silva CM, Viana MB (2010) Coinheritance of alpha-thalassemia decreases the risk of cerebrovascular disease in a cohort of children with sickle cell anemia. Hemoglobin 34:516–529 Hsu LL, Miller ST, Wright E, Kutlar A, McKie V, Wang W et al (2003) Alpha thalassemia is associated with decreased risk of abnormal transcranial Doppler ultrasonography in children with sickle cell anemia. J Pediatr Hematol Oncol 25:622–628 Rusanova I, Cossio G, Moreno B, Javier PF, De Borace RG, Perea M et al (2011) β-Globin gene cluster haplotypes in sickle cell patients from Panama. Am J Hum Biol 23:377–380 da Silva Filho IL, Leite AC, Moura PG, Ribeiro GS, Cavalcante AC, de Azevedo FC et al (2012) Reply: genetic polymorphisms and cerebrovascular disease in children with sickle cell anemia from Rio de Janeiro. Brazil Arq Neuropsiquiatr 70:648–649 Brawley OW, Cornelius LJ, Edwards LR, Gamble VN, Green BL, Inturrisi C et al (2008) National Institutes of Health Consensus Development Conference statement: hydroxyurea treatment for sickle cell disease. Ann Intern Med 148:932–938 Lanzkron S, Strouse JJ, Wilson R, Beach MC, Haywood C, Park H et al (2008) Systematic review: hydroxyurea for the treatment of adults with sickle cell disease. Ann Intern Med 148:939–955 Steinberg MH, Barton F, Castro O, Pegelow CH, Ballas SK, Kutlar A et al (2003) Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. JAMA 289:1645–1651 Steinberg MH (2005) Predicting clinical severity in sickle cell anaemia. Br J Haematol 129:465–481 Lezcano NE, Odo N, Kutlar A, Brambilla D, Adams RJ (2006) Regular transfusion lowers plasma free hemoglobin in children with sickle-cell disease at risk for stroke. Stroke 37:1424–1426 Steinberg MH, McCarthy WF, Castro O, Ballas SK, Armstrong FD, Smith W et al (2010) The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: a 17.5-year follow-up. Am J Hematol 85:403–408 Ariyaratnam R, Casas JP, Whittaker J, Smeeth L, Hingorani AD, Sharma P (2007) Genetics of ischaemic stroke among persons of non-European descent: a meta-analysis of eight genes involving approximately 32,500 individuals. PLoS Med 4:e131 Banerjee I, Gupta V, Ganesh S (2007) Association of gene polymorphism with genetic susceptibility to stroke in Asian populations: a meta-analysis. J Hum Genet 52:205–219 Casas JP, Hingorani AD, Bautista LE, Sharma P (2004) Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls. Arch Neurol 61:1652–1661 Bernaudin F, Verlhac S, Chevret S, Torres M, Coic L, Arnaud C et al (2008) G6PD deficiency, absence of alpha-thalassemia, and hemolytic rate at baseline are significant independent risk factors for abnormally high cerebral velocities in patients with sickle cell anemia. Blood 112:4314–4317 Pereira TV, Rudnicki M, Franco RF, Pereira AC, Krieger JE (2007) Effect of the G-308A polymorphism of the tumor necrosis factor alpha gene on the risk of ischemic heart disease and ischemic stroke: a meta-analysis. Am Heart J 153:821–830 Rubattu S, Speranza R, Ferrari M, Evangelista A, Beccia M, Stanzione R et al (2005) A role of TNF-alpha gene variant on juvenile ischemic stroke: a case-control study. Eur J Neurol 12:989–993 Niu PP, Yang G, Zheng BK, Guo ZN, Jin H, Yang Y (2013) Relationship between endothelial nitric oxide synthase gene polymorphisms and ischemic stroke: a meta-analysis. Acta Neurol Scand 128:202–212 Li P, Qin C (2013) Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and susceptibility to ischemic stroke: a meta-analysis. Gene 535:359–64 Wang M, Jiang X, Wu W, Zhang D (2013) Endothelial NO synthase gene polymorphisms and risk of ischemic stroke in Asian population: a meta-analysis. PLoS One 8:e60472 Katusic ZS, Austin SA (2014) Endothelial nitric oxide: protector of a healthy mind. Eur Heart J (in press) Kato GJ, Gladwin MT, Steinberg MH (2007) Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Rev 21:37–47