New associations: INFG and TGFB1 genes and the inhibitor development in severe haemophilia A.
BACKGROUND
The development of factor VIII (FVIII) inhibitor is the main complication of replacement therapy in patients with haemophilia A (HA). A ratio of 5-7% of individuals HA develops antibodies (inhibitors) against the FVIII infused during the treatment, thereby reducing their pro-coagulant activity. The immunomodulatory cytokine genes have been related to the risk of development of alloantibodies in several studies, mainly in HA with severe form.


OBJECTIVE
We investigated the polymorphisms in regulatory regions of cytokine genes (IL1A, IL1B, IL1R, IL1RA, IL4RA, IL12, INFG, TGFB1, TNF, IL2, IL4, IL6, IL10) that could influence the risk of developing inhibitors in patients with severe HA.


METHODS
The genotyping of cytokine genes of 117 patients with HA was performed by polymerase chain reaction with sequence-specific primers (PCR-SSP) using the protocol recommended by the manufacturer (Invitrogen kit Cytokines(®) , Canoga Park, USA) RESULTS: From the cohort of 117 patients with severe HA, 35 developed inhibitors. There was a higher frequency of +874 T allele in INFG and of +869 TT and TG/TG in TGFB1 genes on patients with inhibitors.


CONCLUSIONS
This suggests that polymorphisms in INFG and in TGFB1 genes are related to risk of developing inhibitor, and could contribute to a genetic profile of the individual HA for the risk of inhibitors development to FVIII.
Departamento de Análises Clínicas e Biomedicina, Universidade Estadual de Maringá, Maringá, PR.
J B
JB
de Alencar
Departamento de Análises Clínicas e Biomedicina, Universidade Estadual de Maringá, Maringá, PR.
L C
LC
Macedo
Centro de Ciências Médicas e Farmacêuticas, Universidade Estadual do Oeste do Paraná, Cascavel, PR.
M F
MF
de Barros
Departamento de Análises Clínicas e Biomedicina, Universidade Estadual de Maringá, Maringá, PR.
C
C
Rodrigues
Departamento de Medicina, Universidade Estadual de Maringá, Maringá, PR.
A H
AH
Shinzato
Laboratório de Hematologia, Centro de Hematologia e Hemoterapia do Paraná (HEMEPAR), Curitiba, PR.
C B
CB
Pelissari
Laboratório de Hematologia, Centro de Hematologia e Hemoterapia do Paraná (HEMEPAR), Curitiba, PR.
J
J
Machado
Departamento de Ciências Básicas da Saúde, Universidade Estadual de Maringá, Maringá, PR, Brazil, PR, Brazil.
A M
AM
Sell
Departamento de Ciências Básicas da Saúde, Universidade Estadual de Maringá, Maringá, PR, Brazil, PR, Brazil.
J E L
JE
Visentainer
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D019774:Blood Coagulation Factor Inhibitors / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D005169:Factor VIII / Q000276:immunology / Q000627:therapeutic use; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006467:Hemophilia A / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007223:Infant; D007371:Interferon-gamma / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index; D053773:Transforming Growth Factor beta1 / Q000235:genetics*; D055815:Young Adult
D019774:Blood Coagulation Factor Inhibitors; C573415:IFNG protein, human; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D007371:Interferon-gamma; D005169:Factor VIII
cytokine; factor VIII; haemophilia A; immune response genes; inhibitor; polymorphisms