Abstract
The skeletal manifestations of sickle cell disease are the result of changes in bone and bone marrow caused by chronic tissue hypoxia that is exacerbated by episodic occlusion of the microcirculation by the abnormal sickle cells. Furthermore, the occurrence of osteonecrosis is under the control of some modifier gene. BMP6 (Bone morphogenetic protein) has been reported as associated with osteonecrosis in sickle cell anemia (SCA). Herein, we intend to study the impact of rs267196, rs267201, rs408505 and rs449853 of BMP6 gene in the occurrence of osteonecrosis among sickle cell patients in Tunisia. Our study involved 100 SCA patients among whom 19 have osteonecrosis of the head of the femur. The latter polymorphisms of BMP6 gene were analyzed for all subjects by PCR/sequencing. To test for trait association with the candidate SNPs, genotype and allele frequencies between cases (osteonecrosis group) and controls (non-osteonecrosis group) were compared using Pearson's chi_square test with a significance threshold of P<0.05 (compare 2, version 1.02). Our findings showed that the patients carried genotype TA of rs 267196 and genotype AG of rs267201 present a high risk factor for developing osteonecrosis RR=1.317 and RR=1.3 respectively. The results showed a significant association between the alleles A of rs 267196 and G of rs267201 and osteonecrosis P=0.0023; RR=2.42 and P=0.041; RR=2.24 respectively. Interestingly, SCA patients with the combined genotype TA/AG were found to be at higher risk of developing osteonecrosis (P=0.009). As for rs408505 and rs449853 of BMP6 gene no significant association was found among SCA patients.
Highlights
sickle cell anemia (SCA) is a single-gene mutation genetic disease caused by change of Glu6Val at the hemoglobin beta chain gene and characterized by high variable clinical complications[1]
The skeletal manifestations of sickle cell disease are the result of changes in bone and bone marrow caused by the chronic tissue hypoxia that is exacerbated by episodic occlusion of the microcirculation by the abnormal sickle cells
As for bone morphogenetic protein6 (BMP6) polymorphisms, the distribution of genotypes and alleles was analyzed for all patients (Table 3)
Summary
SCA is a single-gene mutation genetic disease caused by change of Glu6Val at the hemoglobin beta chain gene and characterized by high variable clinical complications[1]. BMP6 (Bone morphogenetic protein) has been reported as associated with osteonecrosis in sickle cell anemia (SCA) (ref.[2]). Bone morphogenetic proteins (BMPs) are members of the TGF-beta superfamily of molecules. They are multifunctional cytokines involved in many aspects of tissue development and morphogenesis. BMP6 promotes osteoblast differentiation from mesenchymal stem cells[4,5] studied the role of BMP6 in cartilage homeostasis; they discovered an essential involvement of this gene in the repair/maintenance of human articular cartilage. Baldwin et al.[6] have reported the role of rs267196, rs267201 and rs449853 in the occurrence of osteonecrosis in sickle cell disease
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