alexa Influence of Imprinting of an X Chromosome and of the Methylene Tetrahydrofolate Reductase (MTHFR) 677Candgt;T Polymorphism on FVIII Activity | OMICS International | Abstract
ISSN: 2329-8790

Journal of Hematology & Thromboembolic Diseases
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Research Article

Influence of Imprinting of an X Chromosome and of the Methylene Tetrahydrofolate Reductase (MTHFR) 677C>T Polymorphism on FVIII Activity

Birgit Horvath1, Raute Sunder-Plassmann1, Cihan Ay2, Sylvia Reitter-Pfoertner2, Sylvia Kepa2, Christoph Male3, Ingrid Pabinger2 and Christine Mannhalter1*
1Department of Laboratory Medicine, Medical University of Vienna, Austria
2Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Austria
3Department of Pediatrics, Medical University of Vienna, Austria
Corresponding Author : Christine Mannhalter
Department of Laboratory Medicine
Medical University of Vienna
Waehringer Guertel 18-20
A-1090 Vienna, Austria
Tel: +43 1 40400 73759
Fax: +43 1 40400 73591
E-mail: [email protected]
Received: July 23, 2015 Accepted: September 08, 2015 Published: September 15, 2015
Citation: Horvath B, Plassmann RS, Ay C, Pfoertner SR, Kepa S, et al. (2015) Influence of Imprinting of an X Chromosome and the Methylene Tetrahydrofolate Reductase (MTHFR) 677C>T Polymorphism on FVIII Activity. J Hematol Thrombo Dis 3:218. doi:10.4172/2329-8790.1000218
Copyright: © 2015 Horvath B, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Abstract

Background: In females, one X-chromosome is transcriptionally silenced by methylation of CpG sites in every cell during early embryogenesis. The methyl groups needed for DNA methylation are provided by the methylenetetrahydrofolate reductase (MTHFR). A polymorphism in the enzyme (677C>T, rs1801133) affects MTHFR concentrations and possibly also methylation of X-chromosomal genes. Whether X-chromosome inactivation (XCI) by methylation is associated with the MTHFR 677C>T genotype is currently unknown. It is also unclear whether the imprinting subsequently influences factor VIII activity in carrier females.

Methods: We determined XCI in 61 hemophilia A carrier females and 174 control females by analysis of the human androgen receptor locus. Genotyping of MTHFR 677C>T was performed by mutagenically separated PCR, FVIII:C was tested by one-stage coagulation assays.

Results: Slight skewing of XCI (X1:X2<1:3) was not associated with FVIII:C activity in hemophilia A carriers and controls. In contrast, strongly skewed XCI, which was observed in 10 carrier females, was associated with FVIII:C activity levels. If the X-chromosome carrying the mutated F8 gene was methylated, FVIII:C levels were higher. In contrast, FVIII:C levels were lower if the X-chromosome with the intact F8 gene was imprinted. We found a significant association of the 677TT MTHFR genotype with low FVIII in carrier females. The MTHFR genotype was not associated with FVIII:C in control females.

Conclusion: Highly skewed imprinting of the X-chromosome influenced FVIII:C levels in carriers of hemophilia A. We found a significant association of MTHFR 677TT with low FVIII: C in hemophilia A carriers. Surprisingly, the MTHFR 677TT genotype was not significantly associated with X-chromosome inactivation. To elucidate the underlying mechanisms further studies will be necessary.

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