Aplastic anemia (AA) is a heterogeneous disease characterized by bone marrow aplasia and peripheral blood pancytopenia, a profound deficit of hematopoietic stem and progenitor cells. Although the causes for aplastic anemia are multiple, the pathogenic mechanism leading to the disease might be limited to two main pathways: environmental factors and genetic susceptibility. The mammalian Notch family has four homologs, Notch1 to 4. Notch4 signaling plays a role in lineage commitment in hematopoiesis. The human Notch4 gene is located at the MHC on chromosome 6p21.3. Many single nucleotide polymorphisms (SNP) have been mapped to the Notch4 locus. Therefore, we hypothesized that some of these variants could potentially influence the expression level of Notch4 protein. To investigate the role of the two Notch4 rs2071282 (+2763 C>T, Pro204Leu) and 422951(+3323 A>G, Thr320Ala) polymorphisms in susceptibility to AA, a case-control study was conducted in Chonnam National University Hwasun Hospital between March 2002 and June 2006. We genotyped in 151 AA patients and 552 healthy control subjects using PCR-RFLP. Here, we report that rs2071282 CT genotype is significantly associated with increased risk for AA. Using subjects with the rs2071282 CC as a reference group, the odds ratio (OR) of CT is 1.77 (95% CI 1.05–2.98, p=0.032). The haplotype CG is significantly associated with the risk of AA. Using subjects with the haplotype CA, the OR of haplotype CG is 0.70 (95% CI 0.50–0.98, p= 0.037).

In conclusion, we were able to identify two polymorphisms of Notch4, therefore, theses results suggest that Notch polymorphism may play an important role in the susceptibility to AA.

Distribution of Notch polymophisms in aplastic anemia patients and controls

Control (%)AA(%)OR (95% CI)p
Rs 422951 AA 302(54.8) 94(62.3) 1  
 AG 216(39.2) 49(32.5) 0.72(0.478–1.098) 0.128 
 GG 33(6.0) 8(5.3) 0.54(0.23–1.279) 0.163 
 Total 551 151   
Rs 2071282 CC 481(87.1) 120(81.1) 1  
 CT 68(12.3) 28(18.9) 1.769(1.049–2.982) 0.032 
 TT 3(0.5) 0 - - 
 Total     
Control (%)AA(%)OR (95% CI)p
Rs 422951 AA 302(54.8) 94(62.3) 1  
 AG 216(39.2) 49(32.5) 0.72(0.478–1.098) 0.128 
 GG 33(6.0) 8(5.3) 0.54(0.23–1.279) 0.163 
 Total 551 151   
Rs 2071282 CC 481(87.1) 120(81.1) 1  
 CT 68(12.3) 28(18.9) 1.769(1.049–2.982) 0.032 
 TT 3(0.5) 0 - - 
 Total     
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Haplotype frequency for AA and controls

HaplotypeControl (%)AA(%)P (Chi-square)OR (95% CI)p
*Haplotype frequencies were estimated from genotype data using Gibbs- algorithm.*OR and 95%Cis were estimated using based logistc regression and adjusted for sex and age 
C-A 743(67.7) 206(70.0) 0.062 1  
C-G 281(25.6) 60(20.4)  0.70(0.50–0.98) 0.037 
T-A 72(6.5) 28(9.5)  1.49(0.90–2.47) 0.126 
HaplotypeControl (%)AA(%)P (Chi-square)OR (95% CI)p
*Haplotype frequencies were estimated from genotype data using Gibbs- algorithm.*OR and 95%Cis were estimated using based logistc regression and adjusted for sex and age 
C-A 743(67.7) 206(70.0) 0.062 1  
C-G 281(25.6) 60(20.4)  0.70(0.50–0.98) 0.037 
T-A 72(6.5) 28(9.5)  1.49(0.90–2.47) 0.126 
View Large

Topics:
aplastic anemia, genetic predisposition to disease, chief complaint, notch4 receptor, pancytopenia, polymerase chain reaction, environmental factors, bone marrow, heterogeneity, mammals

Disclosure: No relevant conflicts of interest to declare.

Author notes

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Corresponding author

2006, The American Society of Hematology
2006
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