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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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.