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ANXA2 GENE POLYMORPHISM (RS7170178) IS ASSOCIATED WITH OSTEONCROSIS DEVELOPMENT IN SICKLE CELL ANEMIA
Author(s): ,
Diego Antonio Pereira-Martins
Affiliations:
Departament of genetics,Federal University of Pernambuco,Recife,Brazil
,
Juan Luiz Coelho-Silva
Affiliations:
Departament of genetics,Federal University of Pernambuco,Recife,Brazil
,
Anderson Ferreira da Cunha
Affiliations:
Department of Genetics and Evolution,Federal University of São Carlos,São Carlos,Brazil
,
jaqueline Cabral-Peres
Affiliations:
Hematology Hospital,Hematology and Hemotherapy Foundation of Pernambuco,Recife,Brazil
,
Fernando Ferreira Costa
Affiliations:
Haematology and Hemotherapy Centre,University of Campinas,Campinas,Brazil
,
Aderson da Silva Araújo
Affiliations:
Hematology Hospital,Hematology and Hemotherapy Foundation of Pernambuco,Recife,Brazil
,
Antonio Roberto Lucena-Araujo
Affiliations:
Departament of genetics,Federal University of Pernambuco,Recife,Brazil
Marcos André Bezerra
Affiliations:
Departament of genetics,Federal University of Pernambuco,Recife,Brazil
(Abstract release date: 05/19/16) EHA Library. Pereira-Martins D. 06/09/16; 133011; E1462
Mr. Diego Antonio Pereira-Martins
Mr. Diego Antonio Pereira-Martins
Contributions
Abstract
Abstract: E1462

Type: Eposter Presentation

Background
The occurrence of vaso-occlusive crisis (VOC) and chronic hemolysis are clinical complications frequently observed in patients with sickle cell anemia (SCA). Nevertheless, these complications may vary in intensity and frequency within of the disease and several studies support the idea of a genetic component involved in the clinical modulation of these complications. With this in mind, two previously published genetic variants in ANXA2 gene (ANXA2*5681 G>A and IVS-14-1046 C>T) were associated with the development of specific clinical complications in SCA. Initially described as an important modulator of the bone mineralization and co-activator of the fibrinolysis process, the imbalance of the ANXA2 expression may constitute a promising molecular marker for clinical heterogeneity in SCA.

Aims
Here, we evaluated the clinical impact of ANXA2*5681 G>A and IVS-14-1046 C>T polymorphisms in patients with SCA, diagnosed and followed by a single reference center from northeast Brazil.

Methods
Seven hundred fourteen SS-genotyped patients were enrolled. The median age was 25 years (range: 3-61 years), with 347 males (49%). One hundred ninety four (27%) were younger than 18 years. The main clinical complications described in patients with SCA (osteonecrosis, stroke, acute chest syndrome, priapism, leg ulcer) were obtained from medical records. The last update occurred in January 2016. The ANXA2*5681 G>A (rs7170178) and IVS-14-1046 C>T (rs7163836) polymorphisms were detected by real-time PCR. For test if both selected polymorphisms could influence the ANXA2 gene expression, 70 patients with SCA were selected at random and the total RNA was isolated from peripheral blood. The ANXA2 transcript levels (Hs_00743063_s1) were analyzed by real-time quantitative PCR quantified using the GAPDH as endogenous control.

Results
Overall, 144 patients (20%) developed leg ulcer, followed by priapism (97 patients, 14%), osteonecrosis (84 patients, 12%), acute chest syndrome (82 patients, 11%), and stroke (70 patients, 10%). One hundred and thirty-four patients (19%) had none of the main clinical complications aforementioned. According to ANXA2*5681 genotype, 105/714 patients (15%) carried the GG genotype, while 285/714 (40%), and 314/714 (45%) presented the GA and AA genotypes, respectively. ANXA2*5681 polymorphism was associated a higher frequency of osteonecrosis (P<0.0001). In fact, univariate analysis demonstrated that AA-genotyped patients had a 3-fold higher risk to develop osteonecrosis (OR: 3.3, 95%CI: 1.9-5.9; P<0.0001). These data were consistent with multivariate analysis (OR: 3.08, 95%CI: 1.6-5.8; P=0.001), considering fetal hemoglobin levels, number of VOC/year, sex, and age as confounders. In addition, the cumulative probability of osteonecrosis was significantly higher in AA-genotyped patients (88%) compared to non AA-genotyped patients (GG+GA patients, 43%; P=0.001). The AA genotype retained its prognostic value in multivariate proportional hazards regression analysis (HR: 2.4, 95%CI: 1.4-3.8; P<0.001). Finally, AA-genotyped patients with osteonecrosis had a lower ANXA2 transcript levels compared to GG- and GA-genotyped patients (P<0.05). We could find no impact for the IVS-14-1046 polymorphism with none of the variable analyzed.

Conclusion
ANXA2*5681 polymorphism in homozygosis may be an independently predictor of osteonecrosis and may impact the ANXA2 transcript levels, with possible decrease of the encoded protein, in SCA.

Session topic: E-poster

Keyword(s): Genetic modifiers, Osteonecrosis, Sickle cell anemia
Abstract: E1462

Type: Eposter Presentation

Background
The occurrence of vaso-occlusive crisis (VOC) and chronic hemolysis are clinical complications frequently observed in patients with sickle cell anemia (SCA). Nevertheless, these complications may vary in intensity and frequency within of the disease and several studies support the idea of a genetic component involved in the clinical modulation of these complications. With this in mind, two previously published genetic variants in ANXA2 gene (ANXA2*5681 G>A and IVS-14-1046 C>T) were associated with the development of specific clinical complications in SCA. Initially described as an important modulator of the bone mineralization and co-activator of the fibrinolysis process, the imbalance of the ANXA2 expression may constitute a promising molecular marker for clinical heterogeneity in SCA.

Aims
Here, we evaluated the clinical impact of ANXA2*5681 G>A and IVS-14-1046 C>T polymorphisms in patients with SCA, diagnosed and followed by a single reference center from northeast Brazil.

Methods
Seven hundred fourteen SS-genotyped patients were enrolled. The median age was 25 years (range: 3-61 years), with 347 males (49%). One hundred ninety four (27%) were younger than 18 years. The main clinical complications described in patients with SCA (osteonecrosis, stroke, acute chest syndrome, priapism, leg ulcer) were obtained from medical records. The last update occurred in January 2016. The ANXA2*5681 G>A (rs7170178) and IVS-14-1046 C>T (rs7163836) polymorphisms were detected by real-time PCR. For test if both selected polymorphisms could influence the ANXA2 gene expression, 70 patients with SCA were selected at random and the total RNA was isolated from peripheral blood. The ANXA2 transcript levels (Hs_00743063_s1) were analyzed by real-time quantitative PCR quantified using the GAPDH as endogenous control.

Results
Overall, 144 patients (20%) developed leg ulcer, followed by priapism (97 patients, 14%), osteonecrosis (84 patients, 12%), acute chest syndrome (82 patients, 11%), and stroke (70 patients, 10%). One hundred and thirty-four patients (19%) had none of the main clinical complications aforementioned. According to ANXA2*5681 genotype, 105/714 patients (15%) carried the GG genotype, while 285/714 (40%), and 314/714 (45%) presented the GA and AA genotypes, respectively. ANXA2*5681 polymorphism was associated a higher frequency of osteonecrosis (P<0.0001). In fact, univariate analysis demonstrated that AA-genotyped patients had a 3-fold higher risk to develop osteonecrosis (OR: 3.3, 95%CI: 1.9-5.9; P<0.0001). These data were consistent with multivariate analysis (OR: 3.08, 95%CI: 1.6-5.8; P=0.001), considering fetal hemoglobin levels, number of VOC/year, sex, and age as confounders. In addition, the cumulative probability of osteonecrosis was significantly higher in AA-genotyped patients (88%) compared to non AA-genotyped patients (GG+GA patients, 43%; P=0.001). The AA genotype retained its prognostic value in multivariate proportional hazards regression analysis (HR: 2.4, 95%CI: 1.4-3.8; P<0.001). Finally, AA-genotyped patients with osteonecrosis had a lower ANXA2 transcript levels compared to GG- and GA-genotyped patients (P<0.05). We could find no impact for the IVS-14-1046 polymorphism with none of the variable analyzed.

Conclusion
ANXA2*5681 polymorphism in homozygosis may be an independently predictor of osteonecrosis and may impact the ANXA2 transcript levels, with possible decrease of the encoded protein, in SCA.

Session topic: E-poster

Keyword(s): Genetic modifiers, Osteonecrosis, Sickle cell anemia

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