Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
J Bone Miner Res. 2012 Feb;27(2):331-41. doi: 10.1002/jbmr.549.
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.
EIF2AK3 是一种 I 型跨膜蛋白，作为内质网（ER）应激传感器发挥作用，调节全身蛋白质合成。EIF2AK3 的罕见突变导致沃尔科特-拉利森综合征（OMIM 226980），这是一种常染色体隐性疾病，其特征是糖尿病、骨骺发育不良、骨质疏松和生长迟缓。为了研究 EIF2AK3 中的常见遗传变异作为骨密度（BMD）和骨质疏松症决定因素的作用，我们对该基因的所有外显子和侧翼区域进行了测序，然后对 997 名阿米什人群中的 6 个潜在功能单核苷酸多态性（SNP）进行了基因分型，以进行关联分析，并尝试在 887 名墨西哥裔美国人中进行复制。我们发现，非同义 SNP rs13045 的次要等位基因与发现和复制队列中前臂 BMD 降低呈边缘关联（未调整的阿米什人群的 p = 0.036 和 β = -0.007；未调整的墨西哥裔美国人的 p = 0.031 和 β = -0.008）。一项荟萃分析表明，在合并样本中，这种关联具有统计学意义（未调整的 p = 0.003；Bonferroni 校正的 p = 0.009）。rs13045 和另外三个潜在的功能 SNP，一个启动子 SNP（rs6547787）和两个非同义 SNP（rs867529 和 rs1805165），形成了两种单倍型：低 BMD 相关的单倍型 B[次要等位基因频率（MAF）= 0.311]和常见的单倍型 A（MAF = 0.676）。在两种单倍型之间，淋巴母细胞系中的 mRNA 表达没有差异。然而，在用 thapsigargin 诱导 ER 应激处理淋巴母细胞系后，与单倍型 A 的细胞系相比，具有单倍型 B 的细胞系对 ER 应激的敏感性增加（p = 0.014）。综上所述，我们的研究结果表明，EIF2AK3 中的常见非同义序列变异对 ER 应激反应有适度影响，并且可能通过这种机制导致低 BMD 风险增加。
