title: Sickle Cell Disease in the Post Genomic Era: A Monogenic Disease with a Polygenic Phenotype.
abstract: More than half a century after the discovery of the molecular basis of Sickle Cell Disease (SCD), the causes of the phenotypic heterogeneity of the disease remain unclear. This heterogeneity manifests with different clinical outcomes such as stroke, vaso-occlusive episodes, acute chest syndrome, avascular necrosis, leg ulcers, priapism and retinopathy. These outcomes cannot be explained by the single mutation in the beta-globin gene alone but may be attributed to genetic modifiers and environmental effects. Recent advances in the post human genome sequence era have opened the door for the identification of novel genetic modifiers in SCD. Studies are showing that phenotypes of SCD seem to be modulated by polymorphisms in genes that are involved in inflammation, cell-cell interaction and modulators of oxidant injury and nitric oxide biology. The discovery of genes implicated in different phenotypes will help understanding of the physiopathology of the disease and aid in establishing targeted cures. However, caution is needed in asserting that genetic modifiers are the cause of all SCD phenotypes, because there are other factors such as genetic background of the population, environmental components, socio-economics and psychology that can play significant roles in the clinical heterogeneity.
authors.affiliation: Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, Georgia, USA.
authors.forename: A
authors.initials: A
authors.lastname: Driss
authors.forename: K O
authors.initials: KO
authors.lastname: Asare
authors.forename: J M
authors.initials: JM
authors.lastname: Hibbert
authors.forename: B E
authors.initials: BE
authors.lastname: Gee
authors.forename: T V
authors.initials: TV
authors.lastname: Adamkiewicz
authors.forename: J K
authors.initials: JK
authors.lastname: Stiles
references.citation: Blood. 2005 Jan 15;105(2):545-7
references.pmid: 15454485
references.citation: Blood. 1992 Aug 1;80(3):816-24
references.pmid: 1379090
references.citation: BMC Genomics. 2004 May 31;5(1):33
references.pmid: 15169551
references.citation: Curr Opin Hematol. 1995 Mar;2(2):103-8
references.pmid: 9371979
references.citation: Lancet Neurol. 2007 May;6(5):414-20
references.pmid: 17434096
references.citation: Am J Hematol. 2008 Mar;83(3):189-95
references.pmid: 17918249
references.citation: Lancet. 2003 Nov 1;362(9394):1450-5
references.pmid: 14602439
references.citation: Am J Hematol. 1998 Dec;59(4):267-72
references.pmid: 9840906
references.citation: Hum Immunol. 2002 Mar;63(3):194-9
references.pmid: 11872237
references.citation: Blood. 2005 Feb 1;105(3):968-72
references.pmid: 15388579
references.citation: Blood. 2003 Apr 15;101(8):3281-7
references.pmid: 12506027
references.citation: Blood. 1990 Jan 1;75(1):266-70
references.pmid: 2294990
references.citation: Hemoglobin. 2001 May;25(2):213-7
references.pmid: 11480782
references.citation: Afr J Med Med Sci. 1991 Mar;20(1):11-4
references.pmid: 1905464
references.citation: Lancet. 2002 Apr 13;359(9314):1311-2
references.pmid: 11965279
references.citation: J Cogn Neurosci. 2000 Jul;12(4):622-34
references.pmid: 10936915
references.citation: Br J Haematol. 1991 Mar;77(3):382-5
references.pmid: 1707292
references.citation: Ann Trop Med Parasitol. 1983 Aug;77(4):411-9
references.pmid: 6639186
references.citation: Blood. 1988 Mar;71(3):748-52
references.pmid: 3345344
references.citation: Am J Med Sci. 1996 Oct;312(4):166-74
references.pmid: 8853065
references.citation: Am J Hematol. 1997 Jan;54(1):12-5
references.pmid: 8980255
references.citation: Am J Hematol. 1985 Oct;20(2):195-9
references.pmid: 3898822
references.citation: Br J Haematol. 2007 May;137(3):262-7
references.pmid: 17408468
references.citation: Proc Natl Acad Sci U S A. 1985 Apr;82(7):2111-4
references.pmid: 2580306
references.citation: Brain. 2000 Sep;123 ( Pt 9):1784-812
references.pmid: 10960044
references.citation: Lancet. 2001 Mar 3;357(9257):680-3
references.pmid: 11247552
references.citation: Blood. 1987 Jan;69(1):341-4
references.pmid: 2431731
references.citation: Bull World Health Organ. 1995;73(3):375-86
references.pmid: 7614670
references.citation: Lancet. 1979 Jan;1(8107):104
references.pmid: 84107
references.citation: Clin Lab Haematol. 2005 Dec;27(6):384-90
references.pmid: 16307540
references.citation: Blood. 2002 Dec 15;100(13):4303-9
references.pmid: 12393616
references.citation: Gastroenterology. 2005 Aug;129(2):718-34
references.pmid: 16083725
references.citation: Blood. 2007 Oct 1;110(7):2708-17
references.pmid: 17609430
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1620-5
references.pmid: 18245381
references.citation: PLoS One. 2007 Apr 11;2(4):e362
references.pmid: 17426810
references.citation: Neurology. 2001 Apr 24;56(8):997-1008
references.pmid: 11339244
references.citation: Bull World Health Organ. 2001;79(8):704-12
references.pmid: 11545326
references.citation: J Clin Invest. 1985 May;75(5):1632-7
references.pmid: 2581999
references.citation: Blood. 2004 Dec 1;104(12):3774-81
references.pmid: 15308566
references.citation: Blood. 2005 Jul 1;106(1):372-5
references.pmid: 15784727
references.citation: Nat Clin Pract Gastroenterol Hepatol. 2005 Sep;2(9):423-33
references.pmid: 16265433
references.citation: J Pediatr Hematol Oncol. 2001 Oct;23(7):448-51
references.pmid: 11878580
references.citation: Arch Intern Med. 2007 Apr 9;167(7):701-8
references.pmid: 17420429
references.citation: Curr Opin Microbiol. 2006 Aug;9(4):388-94
references.pmid: 16815736
references.citation: Br J Haematol. 2004 Jul;126(1):160; author reply 161
references.pmid: 15198747
references.citation: Br J Haematol. 1998 Dec;103(4):1037-44
references.pmid: 9886316
references.citation: Hemoglobin. 2001 May;25(2):195-211
references.pmid: 11480781
references.citation: Br Med J (Clin Res Ed). 1982 Aug 28-Sep 4;285(6342):633-5
references.pmid: 6819042
references.citation: Cell Mol Biol (Noisy-le-grand). 2004 Feb;50(1):23-33
references.pmid: 15040424
references.citation: Br J Haematol. 2004 Jan;124(2):240-3
references.pmid: 14687036
references.citation: Tex Rep Biol Med. 1980-1981;40:43-54
references.pmid: 6172872
references.citation: N Engl J Med. 1999 Apr 1;340(13):1021-30
references.pmid: 10099145
references.citation: Br J Haematol. 2008 Apr;141(1):105-8
references.pmid: 18324973
references.citation: J Lab Clin Med. 2003 Apr;141(4):279-82
references.pmid: 12677174
references.citation: Blood. 2000 Nov 1;96(9):3276-8
references.pmid: 11050014
references.citation: Blood. 2000 Jan 1;95(1):342-6
references.pmid: 10607722
references.citation: Malar J. 2008 Jan 14;7:13
references.pmid: 18194515
references.citation: J Pediatr Hematol Oncol. 2007 Mar;29(3):140-4
references.pmid: 17356390
references.citation: Am J Respir Crit Care Med. 1999 May;159(5 Pt 1):1368-76
references.pmid: 10228097
references.citation: N Engl J Med. 1994 Jun 9;330(23):1639-44
references.pmid: 7993409
references.citation: N Engl J Med. 1995 Nov 2;333(18):1171-5
references.pmid: 7565971
references.citation: JAMA. 2005 Apr 6;293(13):1653-62
references.pmid: 15811985
references.citation: N Engl J Med. 1997 Sep 11;337(11):762-9
references.pmid: 9287233
references.citation: Br J Haematol. 2005 Jan;128(2):266-72
references.pmid: 15638863
references.citation: Blood. 1995 Nov 15;86(10):3997-8
references.pmid: 7579371
references.citation: Lancet. 1996 Mar 2;347(9001):578-81
references.pmid: 8596320
references.citation: Haematologica. 2005 Feb;90(2):188-99
references.pmid: 15710570
references.citation: Am J Hum Genet. 1998 Jun;62(6):1468-74
references.pmid: 9585587
references.citation: Am J Hematol. 2007 Mar;82(3):179-84
references.pmid: 17034027
references.citation: Am J Hematol. 1994 Apr;45(4):279-82
references.pmid: 8178798
references.citation: J Pediatr Gastroenterol Nutr. 2006 Nov;43(5):680-7
references.pmid: 17130748
references.citation: Blood. 1999 Sep 1;94(5):1550-4
references.pmid: 10477679
references.citation: PLoS Genet. 2007 Mar 23;3(3):e48
references.pmid: 17381244
references.citation: South Med J. 1996 Nov;89(11):1097-8
references.pmid: 8903296
references.citation: Am J Med. 1978 Sep;65(3):461-71
references.pmid: 717414
references.citation: Int J Immunogenet. 2008 Apr;35(2):107-9
references.pmid: 18321306
references.citation: Trop Geogr Med. 1979 Mar;31(1):87-91
references.pmid: 483376
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4516-9
references.pmid: 9114021
references.citation: Haematologica. 2006 Sep;91(9):1277-8
references.pmid: 16956834
references.citation: Blood. 1989 Sep;74(4):1403-8
references.pmid: 2475188
references.citation: J Lab Clin Med. 1997 Mar;129(3):288-93
references.pmid: 9042813
references.citation: Curr Opin Hematol. 2006 May;13(3):131-6
references.pmid: 16567954
references.citation: Nat Genet. 2005 Nov;37(11):1253-7
references.pmid: 16227994
references.citation: Blood. 1995 Feb 15;85(4):1111-7
references.pmid: 7531513
references.citation: J Asthma. 2004 Apr;41(2):159-66
references.pmid: 15115168
references.citation: Respir Med. 2003 Dec;97(12):1282-8
references.pmid: 14682408
references.citation: Stroke. 2007 Aug;38(8):2241-6
references.pmid: 17600229
references.citation: Br J Haematol. 1998 Dec;103(4):950-6
references.pmid: 9886305
references.citation: Braz J Med Biol Res. 2006 Oct;39(10):1291-5
references.pmid: 16906320
references.citation: Tissue Antigens. 2004 Nov;64(5):616-8
references.pmid: 15496207
references.citation: Pharmacogenomics J. 2007 Dec;7(6):386-94
references.pmid: 17299377
references.citation: Br J Haematol. 2006 Jun;133(5):570-8
references.pmid: 16681647
references.citation: Am J Hum Genet. 1994 Feb;54(2):214-28
references.pmid: 7508182
references.citation: J Nutr. 2008 Jun;138(6):1148-52
references.pmid: 18492848
references.citation: Blood. 2007 Oct 1;110(7):2727-35
references.pmid: 17600133
references.citation: BMC Genomics. 2007 Jun 11;8:159
references.pmid: 17562002
references.citation: Haematologica. 2005 Jul;90(7):977-9
references.pmid: 15996936
references.citation: Blood. 2003 Mar 15;101(6):2401-4
references.pmid: 12609963
references.citation: Blood. 2000 Jun 1;95(11):3562-7
references.pmid: 10828044
references.citation: Hum Mol Genet. 2008 Jul 15;17(14):2190-5
references.pmid: 18413324
references.citation: Clin Infect Dis. 2006 Sep 1;43(5):593-8
references.pmid: 16886151
references.citation: Prog Clin Biol Res. 1984;165:93-102
references.pmid: 6209732
references.citation: Blood. 1996 Mar 15;87(6):2573-8
references.pmid: 8630425
references.citation: Am J Hematol. 2001 Nov;68(3):164-9
references.pmid: 11754397
references.citation: Hemoglobin. 2007;31(2):209-24
references.pmid: 17486504
references.citation: Am J Hum Genet. 2002 Mar;70(3):793-9
references.pmid: 11822023
references.citation: Proc Natl Acad Sci U S A. 1984 Mar;81(6):1771-3
references.pmid: 6584911
references.citation: Am J Hematol. 1998 Sep;59(1):46-50
references.pmid: 9723576
references.citation: Hum Mol Genet. 2004 Feb 15;13(4):389-96
references.pmid: 14681304
references.citation: Am J Hematol. 1995 Mar;48(3):175-81
references.pmid: 7532353
references.citation: Am J Hematol. 2003 Feb;72(2):121-6
references.pmid: 12555216
references.citation: Am J Hematol. 2004 Jul;76(3):310-1
references.pmid: 15224377
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11346-51
references.pmid: 17592125
references.citation: Science. 2002 Dec 20;298(5602):2381-5
references.pmid: 12493913
references.citation: N Engl J Med. 1991 Jul 4;325(1):11-6
references.pmid: 1710777
references.citation: Am J Respir Crit Care Med. 2001 Dec 15;164(12):2186-90
references.pmid: 11751185
references.citation: Am J Hematol. 1992 Jun;40(2):110-6
references.pmid: 1585908
references.citation: Br J Haematol. 2005 May;129(4):465-81
references.pmid: 15877729
references.citation: Blood. 2003 Apr 1;101(7):2865-9
references.pmid: 12517810
references.citation: Blood. 2004 Mar 15;103(6):2391-6
references.pmid: 14615367
references.citation: Curr Drug Targets Immune Endocr Metabol Disord. 2005 Jun;5(2):163-70
references.pmid: 16089348
references.citation: Hum Immunol. 2007 Oct;68(10):849-53
references.pmid: 17961774
references.citation: Nature. 1959 Jun 27;183:1795-8
references.pmid: 13852873
references.citation: N Engl J Med. 1985 Apr 4;312(14):880-4
references.pmid: 2579336
references.citation: Br J Haematol. 2002 Nov;119(2):567-71
references.pmid: 12406102
references.citation: Nat Genet. 2005 Apr;37(4):435-40
references.pmid: 15778708
references.citation: N Engl J Med. 1995 May 18;332(20):1317-22
references.pmid: 7715639
references.citation: Prog Clin Biol Res. 1989;316B:371-93
references.pmid: 2575756
references.citation: Ann N Y Acad Sci. 1998 Jun 30;850:251-69
references.pmid: 9668547
references.citation: Blood. 2008 Jun 15;111(12):5721-6
references.pmid: 18187665
references.citation: Clin Genet. 2003 Aug;64(2):160-2
references.pmid: 12859413
references.citation: Blood Cells Mol Dis. 2003 Jul-Aug;31(1):38-42
references.pmid: 12850481
references.citation: Blood. 2004 Oct 1;104(7):2184-6
references.pmid: 15205260
references.citation: Am J Hematol. 2001 Apr;66(4):263-6
references.pmid: 11279637
references.citation: Cell Mol Biol (Noisy-le-grand). 2004 Feb;50(1):35-42
references.pmid: 15040425
references.citation: Blood. 1998 Jan 1;91(1):288-94
references.pmid: 9414296
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):11869-74
references.pmid: 18667698
references.citation: N Engl J Med. 1998 Jul 2;339(1):5-11
references.pmid: 9647873
references.citation: N Engl J Med. 1991 Nov 21;325(21):1476-81
references.pmid: 1944426
references.citation: Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8170-4
references.pmid: 9653159
references.citation: Am J Hematol. 1996 Jul;52(3):189-91
references.pmid: 8756085