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Genetic analysis of the M2/ANXA5 haplotype as recurrent pregnancy loss predisposition in the Malay population

  • Genetics
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Abstract

Purpose

The aim of this study was to evaluate a new predisposition factor, M2/ANXA5 (RPRGL3), in recurrent pregnancy loss (RPL) patients of Malay origin, since it was previously known that the prevalence of this condition is relatively high among the Malay population of Malaysia, where conventional hereditary thrombophilia factors have been generally ruled out.

Methods

A total of 232 women who had experienced ≥2 unexplained RPL and 141 available male partners were recruited, with 360 healthy Malay and 166 parous female controls. Prevalence of M2 carriage and RPL odds ratios were calculated in (a) control and patient groups; (b) clinically defined subgroups in categories of pregnancy loss, primary, secondary, and tertiary; and (c) timing of pregnancy loss in early, ≤15th gestation week and “late” fetal losses, and >15th gestation week subgroups.

Results

Both male and female subjects had similar M2/ANXA5 allele frequencies. The carrier rate of M2/ANXA5 for the general Malay population was 42.2 and 34.9% for parous controls. These carrier rates compared to Malay RPL subjects (52% M2 carriers) resulted in elevated odds ratios (95% confidence interval) of 1.53 (1.1 to 2.1) and 1.97 (1.3 to 3.1) accordingly for early fetal losses. Moreover, exceeding copy numbers of M2/ANXA5 alleles seemed to afflict a greater chance of RPL in couples, especially when both partners were M2 carriers.

Conclusion

This study confirmed the proposed role of M2/ANXA5 as embryonic, genetically associated thrombophilia predisposition factor for early RPL among ethnic Malay of Malaysia.

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Acknowledgements

The authors thank the women and their partners who participated in this study.

Author information

Authors and Affiliations

  1. Advanced Medical and Dental Institute, University Sains Malaysia, Bertam, Penang, Malaysia

    Kai-Cheen Ang, Ewe Seng Ch’ng, Narazah Mohd Yusoff & Thean-Hock Tang

  2. Department of Obstetrics and Gynaecology, Hospital Sultan Abdul Halim, Sungai Petani, Malaysia

    Sushilnathan Kathirgamanathan & Ridzuan Abdullah

  3. Department of Obstetrics and Gynaecology, Hospital Tuanku Jaafar, Seremban, Malaysia

    Yan-Yeow Lee & Krishna Kumar

  4. Department of Obstetrics and Gynaecology, Hospital Tengku Ampuan Afzan, Kuantan, Malaysia

    Anna-Liza Roslani

  5. Department of Obstetrics and Gynaecology, Hospital Sultanah Bahiyah, Alor Setar, Malaysia

    Bavanandan Naidu

  6. Department of Pathology, Hospital Sultan Abdul Halim, Sungai Petani, Malaysia

    Siti-Nadiah Abdul Kadir

  7. Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia

    Wan Zaidah Abdullah

  8. Institute of Human Genetics, University of Muenster, Muenster, Germany

    Nadja Bogdanova, Peter Wieacker & Arseni Markoff

  9. Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, 13200 Bertam, Kepala Batas, Penang, Malaysia

    Thean-Hock Tang

Authors
  1. Kai-Cheen Ang
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  2. Sushilnathan Kathirgamanathan
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  3. Ewe Seng Ch’ng
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  4. Yan-Yeow Lee
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  5. Anna-Liza Roslani
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  6. Bavanandan Naidu
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  7. Krishna Kumar
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  8. Ridzuan Abdullah
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  9. Siti-Nadiah Abdul Kadir
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  10. Narazah Mohd Yusoff
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  11. Wan Zaidah Abdullah
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  12. Nadja Bogdanova
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  13. Peter Wieacker
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  14. Arseni Markoff
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  15. Thean-Hock Tang
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Corresponding authors

Correspondence to Arseni Markoff or Thean-Hock Tang.

Ethics declarations

The present genetic association study was approved by the Human Ethics Research Committee of the Universiti Sains Malaysia (USMKK/PPP/JEPeM [245.3.(2)]) and from the National Institutes of Health, Ministry of Health, Malaysia (NMRR-11-1044-9519). The study was carried out in accordance with The Code of Ethics of the World Health Organization (Declaration of Helsinki), and the criteria of strengthening the reporting of genetic association studies were observed as far as applicable. The volunteer subjects who agreed to participate have signed an informed consent before collection of peripheral blood samples. Random Malay population subjects were recruited at the Universiti Sains Malaysia, Penang campus from January 2011 to May 2013 with appropriate informed consent.

Funding

This work was supported by Universiti Sains Malaysia Research Universiti Grant (USM RU grant no: 1001/CIPPT/812100) awarded to TTH. AM was funded by a PI grant of the German Research Community, DFG, MA-6288/1-1. AKC was supported by MyBrain15 Program (KPM (b) 850304015158) under the Malaysian Ministry of Education.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Supplementary Table S1

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Supplementary Table S2

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Supplementary Fig. S1

AS-PCR- lane 1: negative control (1st PCR); lanes 2 and 3: negative control (2nd PCR) for ‘normal’ and M2/ANXA5 specific primers; lanes 4: M2 heterozygous DNA template; lanes 5: DNA sample of a ‘normal’ genotype; lanes 6: M2 homozygous DNA template. Double lanes 4, 5 and 6: 1st track is specific for the ‘normal’ allele, 2nd track discriminates the M2 haplotype. (GIF 91 kb)

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Ang, KC., Kathirgamanathan, S., Ch’ng, E.S. et al. Genetic analysis of the M2/ANXA5 haplotype as recurrent pregnancy loss predisposition in the Malay population. J Assist Reprod Genet 34, 517–524 (2017). https://doi.org/10.1007/s10815-017-0871-0

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  • DOI: https://doi.org/10.1007/s10815-017-0871-0

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