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Maternal inheritance of a promoter variant in the imprinted PHLDA2 gene significantly increases birth weight

Miho Ishida1, David Monk, Andrew J Duncan

  • 1Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, London, UK.

American Journal of Human Genetics
|March 27, 2012
PubMed

Insights

A specific gene variant (RS1) in the PHLDA2 promoter, when inherited from the mother, significantly increases birth weight. Maternal inheritance of this variant can lead to a substantial gain in infant weight.

Area of Science:

  • Genetics
  • Developmental Biology
  • Reproductive Medicine

Background:

  • Birth weight is a critical predictor of perinatal and adult health.
  • Intrauterine growth restriction is linked to perinatal complications and adult diseases.
  • The genetic regulation of birth weight and its variability remains incompletely understood.

Purpose of the Study:

  • To investigate the genetic factors influencing birth weight.
  • To identify polymorphic variants in the PHLDA2 promoter region.
  • To elucidate the mechanism of PHLDA2 transcriptional regulation on in utero growth.

Main Methods:

  • Sequencing of the PHLDA2 promoter region in fetal DNA samples.
  • Luciferase reporter assay to assess promoter efficiency of identified variants.
  • Genotyping of the RS1 variant in three independent European birth cohorts.
  • Meta-analysis of genetic data from a total of 9,433 individuals.

Main Results:

  • A 15 bp repeat sequence (RS1) variant was identified in the PHLDA2 promoter, reducing its efficiency.
  • Maternal inheritance of the RS1 variant was associated with a significant increase in birth weight (93g).
  • Homozygosity for the maternal RS1 variant showed a larger effect on birth weight (155g), comparable to maternal smoking's impact.

Conclusions:

  • The RS1 variant in the PHLDA2 promoter is a novel genetic determinant of birth weight.
  • Maternal inheritance of RS1 positively influences fetal growth.
  • Understanding genetic contributions to birth weight can inform strategies for preventing growth-related complications.

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