RESUMEN
AIMS: 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. METHODS: 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). RESULTS: 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.
Asunto(s)
Anemia de Células Falciformes/genética , Proteína Morfogenética Ósea 6/genética , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Osteonecrosis/genética , Polimorfismo Genético , ARN Neoplásico/genética , Adulto , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/metabolismo , Proteína Morfogenética Ósea 6/metabolismo , Femenino , Frecuencia de los Genes , Humanos , Masculino , Osteonecrosis/etiología , Osteonecrosis/metabolismo , Fenotipo , Reacción en Cadena de la Polimerasa , Factores de RiesgoRESUMEN
Bilirubin is conjugated with glucoronic acid in the liver by UDP-glucuronosyltransferase 1A1 (UGT1A1). Polymorphisms at the promoter region or exon1 of UGT1A1 gene result in unconjugated hyperbilirubinemia and could be at the origin of gallstone formation. The purpose of this study is to determine whether polymorphisms in the promoter area and exon 1 of UGT1A1 can be considered as a risk factor for lithogenesis. Our study involved 76 patients with cholelithiasis as well as 141 unaffected subjects. For each subject an analysis of the bilirubin parameters was performed. We screened genetic variation in the promoter and exon1 UGT1A1 namely the A (TA) nTAA and the six following SNPs: 44T>G, 101C>A, 115C>G, 145C>T, 211G>A and 222 C>A by PCR/sequencing. Our findings show that subjects with (TA)(7) or (TA)(8) variant in their genotypes are associated with high bilirubin level. Furthermore, the comparison between patients and controls according to A(TA)nTAA variation demonstrated that (TA)(6)/(TA)(7) and (TA)(7)/(TA)(7) genotype and (TA)(7) and (TA)(8) alleles were significantly associated with an increased risk of gallstone diseases p=0.0017, p= 6.1 10(-6), p=1.5 10(-6) and p=0.025 respectively. However, polymorphisms in exon1 were normal in all studied subjects except for the 211G>A which appears to be associated with a protective effect p=7.910(-9); OR=0.03, CI95% (0.001-0.158).