HIF3A cord blood methylation and systolic blood pressure at 4 years – a population-based cohort study

ABSTRACT

Methylation levels at the hypoxia-inducible factor 3α gene (HIF3A) in blood have been linked to body mass index (BMI) in adults. Despite evidence implicating HIF3A in angiogenesis and metabolism, no studies have examined links between HIF3A methylation in early life and cardiovascular health. Here, we investigated the relationship between HIF3A methylation in blood at birth and 12 months of age with cardiovascular measures at 4 years. We also examined influences of prenatal exposures, birth outcomes, and genetic variation. Methylation of two HIF3A promoter regions in cord blood was measured using Sequenom EpiTYPER mass-spectrometry. The first promoter region was also measured in 12-month blood. Four-year cardiovascular measures included blood pressure, pulse wave velocity, and aortic and carotid intima-media thickness. Associations were tested using partial correlation tests and linear regression modelling. Methylation of the first HIF3A promoter in cord and 12-month blood was not associated with four-year measures. There was modest evidence of an association between DNA methylation at the second HIF3A promoter in cord blood and four-year systolic blood pressure (n = 353, r = 0.12, p = 0.03). In sex-stratified analysis, methylation of the second promoter was modestly associated with systolic and diastolic blood pressure (r = 0.16, p = 0.03 for both) in males only. In conclusion, HIF3A methylation at birth shows some evidence of an association with later blood pressure in childhood. Further work should determine whether this relationship persists into later childhood, and should assess potential functional links between HIF3A methylation and cardiovascular health more generally.

KEYWORDS:

• DNA methylation
• HIF3A
• cardiovascular
• paediatrics
• cord blood

Acknowledgments

We thank QIMR Berghofer Medical Research Institute for their role in coordinating the genotyping of BIS samples.

Disclosure statement

No potential conflict of interest was reported by the authors.

Barwon Infant Study Investigator Team

The members of the Barwon Infant Study Investigator Team are the following: Peter Vuillermin and Fiona Collier, Barwon Health, Deakin University, the Murdoch Children’s Research Institute; Anne-Louise Ponsonby, John Carlin, Katie Allen, Mimi Tang, Richard Saffery, Sarath Ranganathan, and David Burgner, the Murdoch Children’s Research Institute, University of Melbourne; Terry Dwyer, the Murdoch Children’s Research Institute and the George Institute for Global Health; and Peter Sly, University of Queensland, Queensland Children’s Medical Research Institute.

Supplemental material

Supplemental data for this article can be accessed here.

Additional information

Funding

The establishment work and infrastructure for the BIS were provided by the Murdoch Children’s Research Institute, Deakin University, and Barwon Health. Subsequent funding was secured from the National Health and Medical Research Council of Australia, The Jack Brockhoff Foundation, the Scobie Trust, the Shane O’Brien Memorial Asthma Foundation, the Our Women’s Our Children’s Fund Raising Committee Barwon Health, The Shepherd Foundation, the Rotary Club of Geelong, the Ilhan Food Allergy Foundation, GMHBA Limited, and the Percy Baxter Charitable Trust, Perpetual Trustees. In-kind support was provided by the Cotton On Foundation and CreativeForce. The study sponsors were not involved in the collection, analysis, and interpretation of data; writing the report; or the decision to submit the report for publication. Research at Murdoch Children’s Research Institute is supported by the Victorian Government’s Operational Infrastructure Support Program. This work was also supported by a Research Training Program Stipend through the University of Melbourne [to TM], NHMRC Senior Research Fellowships [APP1008396 to ALP; APP1045161 to RS]; and an NHMRC Boosting Dementia Research Leader Fellowship [APP1135727 to JR].