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Review

Genomic polymorphisms in sickle cell disease: implications for clinical diversity and treatment

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Pages 443-458 | Published online: 10 Jan 2014

References

  • Ingram VM. Gene mutations in human haemoglobin: the chemical difference between normal and sickle cell haemoglobin. Nature180(4581), 326–328 (1957).
  • Nagel RL, Labie D. DNA haplotypes and the bS globin gene. Prog. Clin. Biol. Res.316B, 371–393 (1989).
  • Nagel RL, Steinberg MH. Role of epistatic (modifier) genes in the modulation of the phenotypic diversity of sickle cell anemia. Pediatr. Pathol. Mol. Med.20, 123–136 (2001).
  • Steinberg MH, Adewoye AH. Modifier genes and sickle cell anemia. Curr. Opin. Hematol.13, 131–136 (2006).
  • Steinberg MH. Predicting clinical severity in sickle cell anaemia. Br. J. Haematol.129, 465–481 (2005).
  • Steinberg MH. Genetic etiologies for phenotypic diversity in sickle cell anemia. ScientificWorldJournal18, 46–67 (2009).
  • Steinberg MH. Sickle cell anemia, the first molecular disease: overview of molecular etiology, pathophysiology, and therapeutic approaches. ScientificWorldJournal8, 1295–1324 (2008).
  • Pauling L, Itano HA, Singer SJ, Wells IC. Sickle cell anemia, a molecular disease. Science109, 443 (1949).
  • Platt OS, Orkin SH, Dover G, Beardsley GP, Miller B, Nathan DG. Hydroxyurea enhances fetal hemoglobin production in sickle cell anemia. J. Clin. Invest.74, 652–656 (1984).
  • Charache S, Terrin ML, Moore RD et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N. Engl. J. Med.332, 1317–1322 (1995).
  • International HapMap Consortium. The International HapMap project. Nature426, 789–796 (2003).
  • Sedgewick AE, Timofeev N, Sebastiani P et al. BCL11A is a major HbF quantitative trait locus in three different populations with β-hemoglobinopathies. Blood Cells Mol. Dis.41, 255–258 (2008).
  • Kan YW, Dozy AM. Polymorphism of DNA sequence adjacent to human β-globin structural gene: relationship to sickle mutation. Proc. Natl Acad. Sci. USA75(11), 5631–5635 (1978).
  • Dekker MCJ, van Duijn CM. Prospects of genetic epidemiology in the 21st Century. Eur. J. Epidemiol.18, 607–616 (2003).
  • Freimer N, Sabatti C. The use of pedigree, sib-pair and association studies of common diseases for genetic mapping and epidemiology. Nat. Genet.36, 1045–1051 (2004).
  • Cordell HJ. Detecting gene–gene interactions that underlie human diseases. Nat. Rev. Genet.10, 392–404 (2009).
  • Manolio TA, Collins FS, Cox NJ et al. Finding the missing heritability of complex diseases. Nature461, 747–753 (2009).
  • Teo YY, Small KS, Kwiatkowski DP. Methodological challenges of genome-wide association analysis in Africa. Nat. Rev. Genet.11, 149–160 (2010)
  • Pepke S, Wold B, Mortazavi A. Computation for ChIP-seq and RNA-seq studies. Nat. Methods6(11 Suppl.), S22–S32 (2009).
  • Park PJ. ChIP-seq: advantages and challenges of a maturing technology. Nat. Rev. Genet.10, 669–680 (2009).
  • Gräslund T, Li X, Magnenat L, Popkov M, Barbas CF 3rd. Exploring strategies for the design of artificial transcription factors: targeting sites proximal to known regulatory regions for the induction of γ-globin expression and the treatment of sickle cell disease. J. Biol. Chem.280, 3707–3714 (2005).
  • Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature447, 661–678 (2007).
  • Wellcome Trust Case Control Consortium. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature464, 713–720 (2010).
  • Steinberg MH. Compound heterozygous and other hemoglobinopathies. In: Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management. Steinberg MH, Forget BG, Higgs DR, Nagel RL (Eds). Cambridge University Press, Cambridge, UK 786–810 (2001).
  • Figueiredo MS, Kerbauy J, Gonçalves MS et al. Effect of α-thalassemia and β-globin gene cluster haplotypes on the hematological and clinical features of sickle-cell anemia in Brazil. Am. J. Hematol.53, 72–76 (1996).
  • Kéclard L, Ollendorf V, Berchel C et al. βS haplotypes, α-globin gene status, and hematological data of sickle cell disease patients in Guadeloupe. Hemoglobin20, 63–74 (1996).
  • Steinberg MH, Embury SH. α-thalassemia in blacks: genetic and clinical aspects and interactions with the sickle hemoglobin gene. Blood68, 985–990 (1986).
  • Schroeder WA, Powars DR, Kay LM et al. β-cluster haplotypes, α-gene status, and hematological data from SS, SC, and S-β-thalassemia patients in southern California. Hemoglobin13(4), 325–353 (1989).
  • Mukherjee MB, Colah RB, Ghosh K et al. Milder clinical course of sickle cell disease in patients with α-thalassemia in the Indian subcontinent. Blood89, 732 (1997).
  • Costa FF, Tavella MH, Zago MA. Deletion type α-thalassemia among Brazilian patients with sickle cell anemia. Brazil. J. Genetics12(3), 605–611 (1989).
  • Sonati MF, Farah SB, Ramalho AS, Costa FF. High prevalence of α-thalassemia in a black population of Brazil. Hemoglobin15(4), 309–311 (1991).
  • Noguchi CT, Dover GJ, Rodgers GP et al. α thalassemia changes erythrocyte heterogeneity in sickle cell disease. J. Clin. Invest.75(5), 1632–1637 (1985).
  • Embury SH, Dozy AM, Miller J et al. Concurrent sickle-cell anemia and α-thalassemia. Effect on severity of anemia. N. Engl. J. Med.306, 270 (1982).
  • de Ceulaer D, Higgs DR. Weatherall DJ, Hayes RJ, Serjeant BE, Serjeant GR. α-thalassemia reduces the hemolytic rate in homozygous sickle cell disease. N. Engl. J. Med.309, 189 (1983).
  • Higgs DR, Aldridge BE, Lamb J et al. The interaction of α-thalassemia and homozygous sickle cell disease. N. Engl. Med.306, 1441 (1982).
  • Steinberg MH, Rosenstock W, Coleman MB et al. Effects of thalassemia and microcytosis upon the hematological and vaso-occlusive severity of sickle cell anemia. Blood63, 1353 (1984).
  • Ataga KI, Smith WR, De Castro LM et al. Efficacy and safety of the Gardos channel blocker, senicapoc (ICA-17043), in patients with sickle cell anemia. Blood111(8), 3991–3997 (2008).
  • Penman BS, Pybus OG, Weatherall DJ, Gupta S. Epistatic interactions between genetic disorders of hemoglobin can explain why the sickle-cell gene is uncommon in the Mediterranean. Proc. Natl Acad. Sci. USA106, 21242–21246. (2009).
  • Goldberg MA, Husson MA, Bunn HF. Participation of hemoglobins A and F in polymerization of sickle hemoglobin. J. Biol. Chem.252, 3414–3421 (1977).
  • Sunshine HR, Hofrichter J, Eaton WA. Gelation of sickle cell hemoglobin in mixtures with normal adult and fetal hemoglobins. J. Mol. Biol.133, 435–467 (1979).
  • Charache S. Fetal hemoglobin, sickling, and sickle cell disease. Adv. Pediatr.37, 1–31 (1990).
  • Benesch RE, Edalji R, Benesch R, Kwong S. Solubilization of hemoglobin S by other hemoglobins. Proc. Natl Acad. Sci. USA77, 5130–5134 (1980).
  • Gonçalves MS, Nechtman JF, Figueiredo MS et al. Sickle cell disease in a Brazilian population from São Paulo: a study of the βS haplotypes. Hum. Hered.44, 322–327 (1994).
  • Ballas SK, Talacki CA, Adachi K, Schwartz E, Surrey S, Rappaport E. The Xmn I site (-158, C–T) 5´ to the G γ gene: correlation with the Senegalese haplotype and G γ globin expression. Hemoglobin15(5), 393–405 (1991).
  • el-Hazmi MA, Bahakim HM, Warsy AS. DNA polymorphism in the β-globin gene cluster in Saudi Arabs: relation to severity of sickle cell anaemia. Acta Haematol.88(2–3), 61–66 (1992).
  • Lapoumeroulie C, Dunda O, Ducrocq R et al. A novel sickle gene of yet another origin in Africa: the Cameroon type. Hum. Genet.89, 333–337 (1989).
  • Gilman JG, Huisman THJ. DNA sequence variation associated with elevated foetal Gγ globin production. Blood66, 783–787 (1985).
  • Steinberg MH, Lu ZH, Barton FB, Terrin ML, Charache S, Dover GJ. Fetal hemoglobin in sickle cell anemia: determinants of response to hydroxyurea. Multicenter Study of Hydroxyurea. Blood89, 1078–1088 (1997).
  • Lu ZH, Steinberg MH. Fetal hemoglobin in sickle cell anemia: relation to regulatory sequences cis to the β-globin gene. Blood87, 1604–1611 (1996).
  • Ofori-Acquah SF, Lalloz MRA, Layton DM. Localisation of cis-active determinants of fetal hemoglobin level in sickle cell anemia. Blood88, 493a (1996).
  • Chang YPC, Maier-Redelsperger M, Smith KD et al. The relative importance of the X-linked FCP locus and β-globin haplotypes in determining hemoglobin F levels: a study of SS patients homozygous for βS haplotypes. Br. J. Haematol.96, 806–814 (1997).
  • Dover GJ, Smith KD, Chang YC et al. Fetal hemoglobin levels in sickle cell disease and normal individuals are partially controlled by an X-linked gene located at Xp22.2. Blood80, 816–824 (1992).
  • Thein SL, Weatherall DJ. A non-deletion hereditary persistence of foetal hemoglobin (HPFH) determinant not linked to the β-globin gene complex. In: Hemoglobin Switching, Part B: Cellular and Molecular Mechanisms. Stamatoyannopoulos G, Nienhuis AW (Eds). Alan R Liss Inc., NY, USA 97–111 (1989).
  • Garner C, Mitchell J, Hatzis T, Reittie J, Farrall M, Thein SL. Haplotype mapping of a major quantitative-trait locus for fetal hemoglobin production, on chromosome 6q23. Am. J. Hum. Genet.62, 1468–1474 (1998).
  • Craig JE, Rochette J, Fisher CA et al. Dissecting the loci controlling fetal haemoglobin production on chromosomes 11p and 6q by the regressive approach. Nat. Genet.12, 58–64 (1996).
  • Creary LE, Ulug P, Menzel S et al. Genetic variation on chromosome 6 influences F cell levels in healthy individuals of African descent and HbF levels in sickle cell patients. PLoS One4, e4218 (2009).
  • Garner C, Menzel S, Martin C et al. Interaction between two quantitative trait loci affects fetal haemoglobin expression. Ann. Hum. Genet.69,707–714 (2005).
  • Sebastiani P, Wang L, Nolan VG et al. Fetal hemoglobin in sickle cell anemia: Bayesian modeling of genetic associations. Am. J. Hematol.83,189–195 (2008)
  • Lettre G, Sankaran VG, Bezerra MA et al. DNA polymorphisms at the BCL11A, HBS1L-MYB, and β-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease. Proc. Natl Acad. Sci. USA105(33), 11869–11874 (2008).
  • Solovieff N, Milton JN, Hartley SW et al. Fetal hemoglobin in sickle cell anemia: genome-wide association studies suggest a regulatory region in the 5´ olfactory receptor gene cluster. Blood115(9), 1815–1822 (2010).
  • Ma Q, Wyszynski DF, Farrell JJ et al. Fetal hemoglobin in sickle cell anemia: genetic determinants of response to hydroxyurea. Pharmacogenomics J.7, 386–394 (2007).
  • Kumkhaek C, Zhu J, Taylor JG et al. Variation in the small guanosine triphosphate (GTP)-binding protein, secretion-associated and RAS-related (SAR1A) gene and response to hydroxyurea treatment in sickle cell disease. Blood110, 3392 (2007).
  • Dworkis D, Sebastiani P, Melista E et al. Fetal hemoglobin in sickle cell anemia: a novel method for high-resolution discovery of associated genomic copy number variations. Blood112, 2491 (2008).
  • Timofeev N, Sebastiani P, Hartley SH et al. Fetal hemoglobin in sickle cell anemia: a genome-wide association study of the response to hydroxyurea. Blood112, 2471 (2008).
  • McDade J, Flanagan JM, Mortier N et al. Genetic predictors of hydroxyurea response in children with sickle cell disease. Blood114, 820 (2009).
  • Timofeev N, Milton JN, Hartley SW et al. Genome-wide studies in sickle cell anemia show associations between SNPs in the olfactory receptor gene cluster and fetal hemoglobin concentration. Blood114, 821 (2009).
  • Xiu J, Sankaran VG, Fujiwara Y et al. Control of hemoglobin switching by BCL11A. Blood114, 5 (2009).
  • Platt OS, Thorington BD, Brambilla DJ et al. Pain in sickle cell disease. Rates and risk factors. N. Engl. J. Med.325(1), 11–16 (1991).
  • Ballas SK, Larner J, Smith ED, Surrey S, Schwartz E, Rappaport EF. Rheologic predictors of the severity of the painful sickle cell crisis. Blood72(4), 1216–1223 (1988).
  • Billett HH, Nagel RL, Fabry ME. Paradoxical increase of painful crises in sickle cell patients with α-thalassemia. Blood86(11), 4382 (1995).
  • Brousseau DC, McCarver DG, Drendel AL, Divakaran K, Panepinto JA. The effect of CYP2D6 polymorphisms on the response to pain treatment for pediatric sickle cell pain crisis . J. Pediatr.150(6), 623–626 (2007).
  • Shord SS, Cavallari LH, Gao W et al. The pharmacokinetics of codeine and its metabolites in Blacks with sickle cell disease. Eur. J. Clin. Pharmacol.65, 651–658 (2009).
  • Darbari DS, van Schaik RHN, Capparelli EV, Rana S, McCarter R, van den Anker J. UGT2B7 promoter variant -840G>A contributes to the variability in hepatic clearance of morphine in patients with sickle cell disease. Am. J. Hematol.83, 200–202 (2008).
  • Taylor JG, Belfer I, Desai K et al. A GCH1 haplotype associated with susceptibility to vasoocclusive pain and impaired vascular function in sickle cell anemia. Blood114, 575 (2009).
  • Oliveira MC, Mendonça TF, Vasconcelos LR et al. Association of the MBL2 gene EXON1 polymorphism and vasoocclusive crisis in patients with sickle cell anemia. Acta Haematol.121(4), 212–215 (2009).
  • Mendonça TF, Oliveira MC, Vasconcelos LR et al. Association of variant alleles of MBL2 gene with vasoocclusive crisis in children with sickle cell anemia. Blood Cells Mol. Dis. DOI: 10.1016/j.bcmd.2010.02.004 (2010) (Epub ahead of print).
  • Martinez-Castaldi C, Nolan VG, Baldwin CT et al. Association of genetic polymorphisms in the TGF-β pathway with the acute chest syndrome of sickle cell anemia. Blood118, 666a (2007).
  • Saito Y, Yamagishi T, Nakamura T et al. Klotho protein protects against endothelial dysfunction. Biochem. Biophys. Res. Commun.248, 324–329 (1998).
  • Sharan K, Surrey S, Ballas S et al. Association of T-786C eNOS gene polymorphism with increased susceptibility to acute chest syndrome in females with sickle cell disease. Br. J. Haematol.124(2), 240–243 (2004).
  • Kutlar A, Kutlar F, Turker I, Tural C. The methylene tetrahydrofolate reductase (C677T) mutation as a potential risk factor for avascular necrosis in sickle cell disease. Hemoglobin25(2), 213–217 (2001).
  • Andrade FL, Annichino-Bizzacchi JM, Saad ST, Costa FF, Arruda VR. Prothrombin mutant, Factor V Leiden, and thermolabile variant of methylenetetrahydrofolate reductase among patients with sickle cell disease in Brazil. Am. J. Hematol.59(1), 46–50 (1998).
  • Moreira Neto F, Lourenço DM, Noguti MAE et al. The clinical impact of MTHFR polymorphism on the vascular complications of sickle cell disease. Braz. J. Med. Biol. Res.39, 1291–1295 (2006).
  • DeCastro L, Rinder HM, Howe JG, Smith BR. Thrombophilic genotypes do not adversely affect the course of sickle cell disease (SCD). Blood92, 161a (1998).
  • Zimmerman SA, Ware RE. Inherited DNA mutations contributing to thrombotic complications in patients with sickle cell disease. Am. J. Hematol.59(4), 267–272 (1998).
  • Castro V, Alberto FL, Costa RN et al. Polymorphism of the human platelet antigen-5 system is a risk factor for occlusive vascular complications in patients with sickle cell anemia. Vox Sanguinis87, 118–123 (2004).
  • Al-Subaie AM, Fawaz NA, Mahdi N et al. Human platelet alloantigens (HPA) 1, HPA2, HPA3, HPA4, and HPA5 polymorphisms in sickle cell anemia patients with vaso-occlusive crisis. Eur. J. Haematol.83(6), 579–585 (2009).
  • Ballas SK, Talacki CA, Rao VM, Steiner RM. The prevalence of avascular necrosis in sickle cell anemia: correlation with α-thalassemia. Hemoglobin13(7–8), 649–655 (1989).
  • Milner PF, Kraus AP, Sebes JI et al. Sickle cell disease as a cause of osteonecrosis of the femoral head. N. Engl. J. Med.325(21), 1476–1481 (1991).
  • Baldwin C, Nolan VG, Wyszynski DF et al. Association of klotho, bone morphogenic protein 6 and annexin A2 polymorphisms with sickle cell osteonecrosis. Blood106(1), 372–375 (2005).
  • Tsujikawa H, Kurotaki Y, Fujimori T, Fukuda K, Nabeshima Y. Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system. Mol. Endocrinol.17, 2393–2403 (2003).
  • Ulug P, Vasavda N, Awogbade M, Cunningham J, Menzel S, Thein SL. Association of sickle avascular necrosis with bone morphogenic protein 6. Ann. Hematol.88, 803–805 (2009).
  • Steinberg MH, Nolan VG, Baldwin CT et al. Association of polymorphisms in genes of the transforming growth factor-β pathway with sickle cell osteonecrosis. Blood102, 262a–263a (2003).
  • Norris CF, Surrey S, Bunin GR, Schwartz E, Buchanan GR, McKenzie SE. Relationship between Fc receptor IIA polymorphism and infection in children with sickle cell disease. J. Pediatr.128(6), 813–819 (1996).
  • Tamouza R, Neonato M, Busson M et al. Infectious complications in sickle cell disease are influenced by HLA class II alleles. Hum. Immunol.63, 194–199 (2002).
  • Tamouza R, Busson M, Fortier C et al. HLA-E*0101 allele in homozygous state favors severe bacterial infections in sickle cell anemia. Hum. Immunol.68, 849–853 (2007).
  • Al-Ola K, Mahdi N, Al-Subaie AM, Ali ME, Al-Absi IK, Almawi WY. Evidence for HLA class II susceptible and protective haplotypes for osteomyelitis in pediatric patients with sickle cell anemia. Tissue Antigens71(5), 453–457 (2008).
  • Cordero EA, Veit TD, da Silva MA, Jacques SM, Silla LM, Chies JÁ. HLA-G polymorphism influences the susceptibility to HCV infection in sickle cell disease patients. Tissue Antigens74(4), 308–313 (2009).
  • Neonato MG, Lu CY, Guilloud-Bataille M et al. Genetic polymorphism of the mannose-binding protein gene in children with sickle cell disease: identification of three new variant alleles and relationship to infections. Eur. J. Hum. Genet.7, 679–686 (1999).
  • Costa RNP, Conran N, Albuquerque DM, Soares PH, Saad STO, Costa FF. Association of the G-463A myeloperoxidase polymorphism with infection in sickle cell anemia. Haematologica90, 977–979 (2005).
  • Adewoye AH, Nolan VG, Ma Q et al. Association of polymorphisms of IGF1R and genes in the transforming growth factor-β/bone morphogenetic protein pathway with bacteremia in sickle cell anemia. Clin. Infect. Dis.43, 593–598 (2006).
  • Dossou-Yovo OP, Zaccaria I, Benkerrou M et al. Effects of RANTES and MBL2 gene polymorphisms in sickle cell disease clinical outcomes: association of the g.In1.1T>C RANTES variant with protection against infections. Am. J. Hematol.84(6), 378–380 (2009).
  • Vargas AE, da Silva MA, Silla L, Chies JA. Polymorphisms of chemokine receptors and eNOS in Brazilian patients with sickle cell disease. Tissue Antigens66, 683–690 (2005).
  • Hoppe C. Defining stroke risk in children with sickle cell anaemia. Br. J. Haematol.128(6), 751–766 (2005).
  • Adams GT, Snieder H, McKie VC et al. Genetic risk factors for cerebrovascular disease in children with sickle cell disease: design of a case–control association study and genomewide screen. BMC Medical Genet.4, 6 (2003).
  • Neonato MG, Guilloud-Bataille M, Beauvais P et al. Acute clinical events in 299 homozygous sickle cell patients living in France. French Study Group on Sickle Cell Disease. Eur. J. Haematol.65, 155–164 (2000).
  • Hsu LL, Miller ST, Wright E et al. α-thalassemia is associated with decreased risk of abnormal transcranial Doppler ultrasonography in children with sickle cell anemia. J. Ped. Hematol/Oncol.25, 622–628 (2003).
  • Ohene-Frempong K, Weiner SJ, Sleeper LA et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood91, 288–294 (1998).
  • Miller ST, Macklin EA, Pegelow CH et al. Silent infarction as a risk factor for overt stroke in children with sickle cell anemia: a report from the Cooperative Study of Sickle Cell Disease. J. Pediatr.139, 385–390 (2001).
  • Balkaran B, Char G, Morris J, Thomas P, Serjeant B, Serjeant G. Stroke in a cohort of patients with homozygous sickle cell disease. J. Pediatr.120, 360–366 (1992).
  • Styles LA, Hoppe C, Klitz W et al. Evidence for HLA-related susceptibility for stroke in children with sickle cell disease. Blood95(11), 3562–3567 (2000).
  • Taylor JG, Tang DC, Savage SA et al. Variants in the VCAM1 gene and risk for symptomatic stroke in sickle cell disease. Blood100(13), 4303–4309 (2002).
  • Hoppe C, Klitz W, Cheng S et al. Gene interactions and stroke risk in children with sickle cell anemia. Blood103(6), 2391–2396 (2004).
  • Hoppe C, Klitz W, Noble J et al. Distinct HLA associations by stroke subtype in children with sickle cell anemia. Blood101(7), 2865–2869 (2003).
  • Hoppe C, Klitz W, D’Harlingue K et al. Confirmation of an association between the TNF(-308) promoter polymorphism and stroke risk in children with sickle cell anemia. Stroke38, 2241–2246 (2007).
  • Barber LA, Ashley-Koch AE, Garrett ME et al. Polymorphisms in TNFα are associated with cerebrovascular events in sickle cell disease. Blood114, 1540 (2009).
  • Sebastiani P, Ramoni MF, Nolan V, Baldwin CT, Steinberg MH. Genetic dissection and prognostic modeling of overt stroke in sickle cell anemia. Nat. Genet.37, 435–440 (2005).
  • Steinberg MH, Baldwin CT, Wyszynski DF et al. Stroke in sickle cell anemia: association with single nucleotide polymorphisms in genes affecting vascular function. Blood102, 926 (2003).
  • Sebastiani P, Milton JN, Timofeev N et al. Genome-wide association study of stroke in sickle cell anemia. Blood114, 1528 (2009).
  • Barrett-Connor E. Cholelithiasis in sickle cell anemia. Am. J. Med.45, 889–898 (1968).
  • del Giudice EM, Perrotta S, Nobili B, Specchia C, d’Urzo G, Iolascon A. Coinheritance of Gilbert syndrome increases the risk for developing gallstones in patients with hereditary spherocytosis. Blood94, 2259–2262 (1999).
  • Bosma PJ, Chowdhury JR, Bakker C et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosultransferase 1 in Gilbert’s syndrome. N. Engl. J. Med.333, 1171–1175 (1995).
  • Carpenter SL, Lieff S, Howard TA, Eggleston B, Ware RE. UGT1A1 promoter polymorphisms and the development of hyperbilirubinemia and gallbladder disease in children with sickle cell anemia. Am. J. Hematol.83(10), 800–803 (2008).
  • Chaar V, Keclard L, Diara JP et al. Association of UGT1A1 polymorphism with prevalence and age at onset of cholelithiasis in sickle cell anemia. Haematologica90, 188–199 (2005).
  • Haverfield EV, McKenzie CA, Forrester T et al. UGT1A1 variation and gallstone formation in sickle cell disease. Blood105, 968–972 (2004).
  • Fertrin KY, Melo MB, Assis AM, Saad ST, Costa FF. UDP-glucuronosyltransferase 1 gene promoter polymorphism is associated with increased serum bilirubin levels and cholecystectomy in patients with sickle cell anemia. Clin. Genet.64, 160–162 (2003).
  • Passon RG, Howard TA, Zimmerman SA, Schultz WH, Ware RE. Influence of bilirubin uridine diphosphate-glucuronosyltransferase 1A promoter polymorphisms on serum bilirubin levels and cholelithiasis in children with sickle cell anemia. J. Pediatr. Hematol. Oncol.23, 448–451 (2001).
  • Martins R, Morais A, Dias A et al. Early modification of sickle cell disease clinical course by UDP-glucuronosyltransferase 1A1 gene promoter polymorphism. Hum. Genet.53, 524–528 (2008).
  • Chaar V, Keclard L, Etienne-Julan M et al. UGT1A1 polymorphism outweighs the modest effect of deletional (-α 3.7kb) α-thalassemia on cholelithogenesis in sickle cell anemia. Am. J. Hematol.81, 377–379 (2006).
  • Vasavda N, Menzel S, Kondaveeti S et al. The linear effects of α-thalassaemia, the UGT1A1 and HMOX1 polymorphisms on cholelithiasis in sickle cell disease. Br. J. Haematol.138, 263–270 (2007).
  • Serjeant GR. Sickle Cell Disease. Oxford University Press, Oxford, UK 261–281 (1992).
  • Pham PT, Pham PC, Wilkinson AH, Lew SQ. Renal abnormalities in sickle cell disease. Kidney Int.57(1), 1–8 (2000).
  • Ataga KI, Orringer EP. Renal abnormalities in sickle cell disease. Am. J. Hematol.63, 205–211 (2000).
  • Gupta AK, Kirchner KA, Nicholson R et al. Effects of α-thalassemia and sickle polymerization tendency on the urine-concentrating defect of individuals with sickle cell trait. J. Clin. Invest.88, 1963–1968 (1991).
  • Powars DR, Elliott M, Chan L. Chronic renal failure in sickle cell disease: risk factors, clinical course and mortality. Ann. Int. Med.115, 614–620 (1991).
  • Nolan VG, Ma Q, Cohen HT et al. Estimated glomerular filtration rate in sickle cell anemia is associated with polymorphisms of bone morphogenetic protein receptor 1B. Am. J. Hematol.82, 179–184 (2007).
  • Koshy M, Entsuah R, Koranda A et al. Leg ulcers in patients with sickle cell disease. Blood74, 1403–1408 (1989).
  • Nolan VG, Adewoye A, Baldwin C et al. Sickle cell leg ulcers: associations with haemolysis and SNPs in Klotho, TEK and genes of the TGF-β/BMP pathway. Br. J. Haematol.133, 570–578 (2006).
  • Peters KG, Kontos CD, Lin PC et al. Functional significance of Tie2 signaling in the adult vasculature. Recent Prog. Horm. Res.59, 51–71 (2004).
  • Gladwin MT, Sachdev V, Jison ML et al. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N. Engl. J. Med.350(9), 886–895 (2004).
  • Taylor JG 6th, Ackah D, Cobb C et al. Mutations and polymorphisms in hemoglobin genes and the risk of pulmonary hypertension and death in sickle cell disease. Am. J. Hematol.83(1), 6–14 (2008).
  • Roberts KE, McElroy JJ, Wong WP et al. BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease. Eur. Respir. J.24, 371–374 (2004).
  • Trembath RC, Thomson JR, Machado RD et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N. Engl. J. Med.345, 325–334 (2001).
  • Ashley-Koch AE, Elliott L, Kail ME et al. Identification of genetic polymorphisms associated with risk for pulmonary hypertension in sickle cell disease. Blood111(12), 5721–5726 (2008).
  • Klings ES, Dworkis DA, Sedgewick A et al. Genetic polymorphisms in NEDD4L are associated with pulmonary hypertension of sickle cell anemia. Blood114, 2562 (2009).
  • Nouraie M, Reading NS, Campbell A et al. Cytochrome b5 reductase T116S mutation and hemolysis in sickle cell disease. Blood114, 903 (2009)
  • Fowler Jr JE, Koshy M, Strub M, Chinn SK. Priapism associated with the sickle cell hemoglobinopathies: prevalence, natural history and sequelae. J. Urol.145, 65–68 (1991).
  • Hamre MR, Harmon EP, Kirkpatrick DV, Stern MJ, Humbert JR. Priapism as a complication of sickle cell disease. J. Urol.145, 1–5 (1991).
  • Elliott L, Ashley-Koch AE, De Castro L et al. Genetic polymorphisms associated with priapism in sickle cell disease. Br. J. Haematol.137(3), 262–267 (2007).
  • Nolan VG, Baldwin C, Ma Q et al. Association of single nucleotide polymorphisms in klotho with priapism in sickle cell anaemia. Br. J. Haematol.128(2), 266–272 (2005).
  • Brown CB, Boyer AS, Runyan RB, Barnett JV. Requirement of type III TGF-β receptor for endocardial cell transformation in the heart. Science283, 2080–2082 (1999).
  • Blanc L, Liu J, Vidal M, Chasis JA, An X, Mohandas N. The water channel aquaporin-1 partitions into exosomes during reticulocyte maturation: implication for the regulation of cell volume. Blood114(18), 3928–3934 (2009).
  • Endeward V, Musa-Aziz R, Cooper GJ et al. Evidence that aquaporin 1 is a major pathway for CO2 transport across the human erythrocyte membrane. FASEB J.20(12), 1974–1981 (2006).
  • Friedlander M, Brooks PC, Shaffer RW, Kincaid CM, Varner JA, Cheresh DA. Definition of two angiogenic pathways by distinct αv integrins. Science270(5241), 1500–1502 (1995).
  • Pruissen DM, Slooter AJ, Rosendaal FR, van der Graaf Y, Algra A. Coagulation factor XIII gene variation, oral contraceptives, and risk of ischemic stroke. Blood111(3), 1282–1286 (2008).
  • Jeng MR, Adams-Graves P, Howard TA, Whorton MR, Li CS, Ware RE. Identification of hemochromatosis gene polymorphisms in chronically transfused patients with sickle cell disease. Am. J. Hematol.74(4), 243–248 (2003).
  • Aygun B, Padmanabhan S, Paley C, Chandrasekaran V. Clinical significance of RBC alloantibodies and autoantibodies in sickle cell patients who received transfusions. Transfusion42(1), 37–43 (2002).
  • Tatari-Calderone Z, Minniti CP, Kratovil T et al. rs660 polymorphism in Ro52 (SSA1; TRIM21) is a marker for age-dependent tolerance induction and efficiency of alloimmunization in sickle cell disease. Mol. Immunol.47(1), 64–70 (2009).
  • Sebastiani P, Solovieff N, Hartley SW et al. Genetic modifiers of the severity of sickle cell anemia identified through a genome-wide association study. Am. J. Hematol.85(1), 29–35 (2010).

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