Plasma Pro-Enkephalin A and Ischemic Stroke Risk: The Reasons for Geographic and Racial Differences in Stroke Cohort

J Stroke Cerebrovasc Dis. 2022 Feb;31(2):106237. doi: 10.1016/j.jstrokecerebrovasdis.2021.106237. Epub 2021 Dec 9.


Objectives: The opioid neuropeptide pro-enkephalin A (PENK-A) may be a circulating marker of cardiovascular risk, with prior findings relevant to heart failure, kidney disease, and vascular dementia. Despite these findings, the association of PENK-A with ischemic stroke is unknown, so we examined this association in a prospective cohort study and analyzed differences by race and sex.

Materials and methods: The REasons for Geographic and Racial Differences in Stroke study (REGARDS) is a prospective cohort study of 30,239 Black and White adults. Plasma PENK-A was measured in 473 participants that developed first-time ischemic stroke over 5.9 years and 899 randomly selected participants. Cox models adjusted for demographics and stroke risk factors were used to calculate hazard ratios (HRs) of stroke by baseline PENK-A.

Results: PENK-A was higher with increasing age, female sex, White race, lower body mass index, and antihypertensive medication use. Each SD higher increment of PENK-A was associated with an adjusted HR of 1.20 (95% CI 1.01-1.42) for stroke, with minimal confounding by stroke risk factors. Spline plots suggested a U-shaped relationship, particularly in White men, with an adjusted HR 3.88 (95% CI 1.94-7.77) for the 95th versus 50th percentile of PENK-A in White men.

Conclusions: Higher baseline plasma PENK-A was independently associated with future stroke risk in REGARDS. This association was most apparent among White men. There was little confounding by established stroke risk factors, suggesting a possible causal role in stroke etiology. Further research is needed to understand the role of endogenous opioids in stroke pathogenesis.

Keywords: Cohort; Epidemiology; Pro-enkephalin; REGARDS; Risk factors; Stroke risk.

MeSH terms

  • Adult
  • Biomarkers / blood
  • Black People / statistics & numerical data
  • Enkephalins* / blood
  • Female
  • Geography
  • Health Status Disparities*
  • Humans
  • Ischemic Stroke* / blood
  • Ischemic Stroke* / ethnology
  • Male
  • Prospective Studies
  • Protein Precursors* / blood
  • Race Factors
  • Risk Factors
  • White People / statistics & numerical data


  • Biomarkers
  • Enkephalins
  • Protein Precursors
  • proenkephalin