A Common DIO2 Polymorphism and Alzheimer Disease Dementia in African and European Americans

J Clin Endocrinol Metab. 2018 May 1;103(5):1818-1826. doi: 10.1210/jc.2017-01196.

Abstract

Context: A common single nucleotide polymorphism in DIO2, Thr92AlaD2, has been associated with a transcriptome typically found in neurodegenerative diseases in postmortem human brain tissue.

Objective: To determine whether Thr92AlaD2 is associated with incident Alzheimer disease (AD).

Design: Population-based study; human brain tissue microarray.

Setting: Community-based cohorts from Chicago and northeastern Illinois and religious clergymen from across the United States constituted the primary population. A representative sample of the U.S. population was used for secondary analyses.

Participants: 3054 African Americans (AAs) and 9304 European Americans (EAs).

Main outcome measure: Incident AD.

Results: In the primary population, AAs with Thr92AlaD2 had 1.3 times [95% confidence interval (CI), 1.02 to 1.68; P = 0.048] greater odds of developing AD. AAs from a second population with Thr92AlaD2 showed a trend toward increased odds of dementia (odds ratio, 1.33; 95% CI, 0.99 to 1.78; P = 0.06) and 1.35 times greater odds of developing cognitive impairment not demented (CIND; 95% CI, 1.09 to 1.67; P = 0.006). Meta-analysis showed that AAs with Thr92AlaD2 had 1.3 times increased odds of developing AD/dementia (95% CI, 1.07 to 1.58; P = 0.008). In EAs, no association was found between Thr92AlaD2 and AD, dementia, or CIND. Microarray of AA brain tissue identified transcriptional patterns linked to AD pathogenesis.

Conclusions: Thr92AlaD2 was associated with molecular markers known to underlie AD pathogenesis in AAs, translating to an observed phenotype of increased odds of developing AD/dementia in AAs in these populations. Thr92AlaD2 might represent one factor contributing to racial discrepancies in incident AD.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural

MeSH terms

  • African Americans / genetics
  • Aged
  • Aged, 80 and over
  • Alanine / genetics
  • Alzheimer Disease / epidemiology
  • Alzheimer Disease / ethnology*
  • Alzheimer Disease / genetics*
  • Amino Acid Substitution
  • Case-Control Studies
  • Dementia / epidemiology
  • Dementia / ethnology
  • Dementia / genetics
  • Female
  • Gene Frequency
  • Humans
  • Iodide Peroxidase / genetics*
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Threonine / genetics
  • United States / epidemiology
  • Whites / genetics

Substances

  • Threonine
  • iodothyronine deiodinase type II
  • Iodide Peroxidase
  • Alanine