Novel Plasma Proteins in Nepalese School‐aged Children Are Associated with a Small Head at Birth
Authors: Lee Sun Eun , West Keith P. , Cole Robert N. , Schulze Kerry , Yager James D. , Groopman John , Christian Parul 
Published: November 2023

Background

Fetal growth restriction may have long‐term effects on health and function mediated by permanent changes in cell size or number and modification of gene expression and organ structure. Yet, little is known about protein biomarkers of fetal metabolic programming that persist into childhood.

Objective

We explored the plasma proteome of school‐aged children to identify proteins that may be differentially abundant by size at birth and reflect a sustained proteomic phenotype of intrauterine growth restriction.

Methods

Plasma proteins were profiled using tandem mass spectrometry in a cohort of 500 6–8 year old children living in the southern plains of Nepal on whom weight, length, and head circumference had been measured at birth. Small birth size was defined by weight, length, weight‐for‐length or head circumference (HC) being < ‐2 Z‐scores of the WHO growth standards. We estimated differences in relative abundance of proteins between children born small vs normal (≥ ‐2 Z‐scores) in size. Pathway analysis using the Gene Ontology database was performed to identify functional protein clusters associated with birth size. Significance was defined by a false discovery rate (q) < 0.10.

Results

Among 982 plasma proteins detected in >10% of children, 21 proteins were differentially abundant in children with a small vs normal HC at birth. No proteins differed by other indicators of birth size (q ≥0.10). After adjusting for gestational age at birth, child sex, current anthropometry and maternal and household characteristics, 19 proteins differed by HC at birth (q <0.10), with 18 being 8–22% less abundant in plasma of children with a small HC at birth: i.e., HC < ‐2 Z‐scores (□ 32 cm) at birth. Affected proteins were mostly actin (α‐actin), actin filament organizing molecules (α‐actinin, talin, filamin, transgelin‐2, tropomyosin 3 and 4, etc.), actin‐binding motor protein (myosin 6), and cytoskeleton‐binding glycolytic enzymes (glyceraldehyde‐3‐phosphate dehydrogenase). A correlation matrix revealed high, positive correlations among these cytoskeletal proteins (average r=0.68). One protein, angiopoietin‐like 6, recently reported to be elevated in malnutrition and metabolic disorders, was elevated by 22% in children with a small vs normal head size at birth. Pathway analysis confirmed cytoskeleton protein sets such as cellular morphogenesis and muscle contraction were over‐represented in the proteins associated with a small HC (Bonferroni corrected p<0.05).

Conclusions

A novel cluster of plasma proteins of actin cytoskeletal origin assessed in childhood that regulate fundamental developmental processes was negatively associated with small head size at birth. The childhood plasma proteome stably reflects specific aspects of poor growth early in life which may have prognostic value for later life disease risk.

Support or Funding Information

Grant funding: Bill and Melinda Gates Foundation (OPP5241 and GH614).