Peter Rock

Publication Detail

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A functional haplotype in EIF2AK3, an ER stress sensor, is associated with lower bone mineral density.

Jie Liu; Nicole Hoppman; Jeffrey R O'Connell; Hong Wang; Elizabeth A Streeten; John C McLenithan; Braxton D Mitchell; Alan R Shuldiner (Profiled Authors: John McLenithan; Braxton D Mitchell Jr.; Jeffrey R O'Connell; Alan R Shuldiner; Elizabeth Streeten)

Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2012;27(2):331-41.

EIF2AK3 is a type I transmembrane protein that functions as an endoplasmic reticulum (ER) stress sensor to regulate global protein synthesis. Rare mutations in EIF2AK3 cause Wolcott-Rallison syndrome (OMIM 226980), an autosomal recessive disorder characterized by diabetes, epiphyseal dysplasia, osteoporosis, and growth retardation. To investigate the role of common genetic variation in EIF2AK3 as a determinant of bone mineral density (BMD) and osteoporosis, we sequenced all exons and flanking regions, then genotyped six potentially functional single nucleotide polymorphisms (SNPs) in this gene in 997 Amish subjects for association analysis, and attempted replication in 887 Mexican Americans. We found that the minor allele of a nonsynonymous SNP rs13045 had borderline associations with decreased forearm BMD in both discovery and replication cohorts (unadjusted p = 0.036 and β = -0.007 for the Amish; unadjusted p = 0.031 and β = -0.008 for Mexican Americans). A meta-analysis indicated this association achieved statistical significance in the combined sample (unadjusted p = 0.003; Bonferroni corrected p = 0.009). Rs13045 and three other potentially functional SNPs, a promoter SNP (rs6547787) and two nonsynonymous SNPs (rs867529 and rs1805165), formed two haplotypes: a low-BMD associated haplotype, denoted haplotype B [minor allele frequency (MAF) = 0.311] and a common haplotype A (MAF = 0.676). There were no differences in mRNA expression in lymphoblastoid cell lines between the two haplotypes. However, after treating lymphoblastoid cell lines with thapsigargin to induce ER stress, cell lines with haplotype B showed increased sensitivity to ER stress (p = 0.014) compared with cell lines with haplotype A. Taken together, our results suggest that common nonsynonymous sequence variants in EIF2AK3 have a modest effect on ER stress response and may contribute to the risk for low BMD through this mechanism.

4 Originating Grant

• 1.

  SHULDINER, ALAN R.

  Mid-Atlantic Nutrition Obesity Research Center

  15 September 2005 - 31 August 2015

  NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES

• 2.

  Shuldiner, Alan R

  Longevity Genes in Founder Populations

  15 July 2001 - 30 June 2006

  NATIONAL INSTITUTE ON AGING

• 3.

  Shuldiner, Alan R

  GENETICS OF OSTEOPOROSIS IN THE AMISH

  1 September 2000 - 30 June 2007

  NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES

• 4.

  Mitchell, Braxton D

  Genetics of Bone Density in Mexican Americans

  6 June 1997 - 31 January 2009

  NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES

Scientific Context

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