Table 4.

Genetic associations with subphenotypes of sickle cell anemia

Subphenotype	Genes	References
Survival	Multiple including TGFBR3	22,23–26
Stroke, silent infarction, TCD velocity	Multiple gene identified, VCAM1, ILR4, ADBR2, HLA, LDLR, but few have been validated (see text)	27,28–30
Painful episodes	GCH1-results reported in abstract only. Biologically plausible. MBL2 in children, low expression associated with increased pain PLA2G4A.	31–34 35
Acute chest syndrome	Many genes have been “identified” but no study has been validated. HMOX1 (GT)n S/S – Reduce incidence Intergenic region between DNMT3B –COMMD7 significant in children <age 5 years.	36–39 40 35
Bacteremia/Infection	MBL2-contradictory evidence in different populations that that low level protective. Other genes include CCL5, various HLA alleles, IGF1R, TGF-β/SMAD/BMP pathway HLA-E*0101 HLA class 1 Susceptibility for infection in homozygotes HLA-E*0103 HLA class 1 Protection against infection in heterozygotes HLA-DRB1*15 HLA class 2 Protection HLA-DQB1*03 HLA class 2 Increased risk IGF1, TGFβ/BMP	41–43 44,41,45
Osteonecrosis	Little evidence for MTHFR;BMP6-results validated in 2 different populations	38,46–48
Priapism	KL, TEK, TGFBR3, AQP1	49–51
Leg ulcers	TGF-β/SMAD/BMP pathway, KL, possibly HLA alleles	51–53
Sickle vasculopathy/TRV velocity	BMP6, TGFBR3, ACVR1, BMP2	54
Cholelithiasis	Promoter repeats in UGT1A1 associated with serum bilirubin	55–57
Renal function/albuminuria/Glomerular hyperfiltration	DARC FY- associated with proteinuria, TGF-β/Smad/BMP pathway, MYH9, APOL1	58–61
Multiple subphenotypes	Duffy antigen receptor (DARC) No relationship to leg ulcers,? nephropathy, priapism, osteonecrosis, response to opioids	62–64
Hemolysis	NPRL3 VCAM1, CD36 NOS3	65,66

S/S: homozygous for the short GT_n repeat allele for HMOX1