Bae Ji-Hyun, Park Dongjin
Department of Food Science and Nutrition, Keimyung University, Daegu, South Korea.
Department of Food Science and Technology, University of Nebraska-Lincoln, Lincoln, NE, USA.
Clin Nutr. 2022 Mar;41(3):680-686. doi: 10.1016/j.clnu.2022.01.020. Epub 2022 Jan 29.
BACKGROUND & AIMS: Osteoporosis is the most common bone disease and is characterized by low bone mineral density (BMD) and a high risk of fracture. Despite advances in our understanding of the pathogenesis of osteoporosis, complex gene-environment interactions that influence osteoporosis development remain largely unexplored. In this study, we aimed to identify genetic loci associated with low BMD and to evaluate these genetic variants under individual and environmental factors.
A genome-wide association analysis was conducted using 500,568 single-nucleotide polymorphisms (SNPs) in 8842 individuals aged 40-69 years using clinical, demographic, and dietary data (>260 traits) established by the Korean Genome and Epidemiology Study. The gPLINK program was used to detect SNPs associated with osteoporosis at a genome-wide significance level (P < 1.0 × 10) and conduct a haplotype analysis. Statistical differences between the osteoporosis and control groups in categorical variables (sex and dietary profiles) were assessed based on frequency distributions using the chi-squared test.
Of the seven SNPs that were associated with osteoporosis, both rs10977574 and rs4390000 lay in the PTPRD locus encoding a protein tyrosine phosphatase-receptor type D, which has been implicated in bone metabolism. Haplotype analysis identified two minor alleles, C and G, at the rs10977574 and rs4390000 loci, respectively, forming a linkage disequilibrium block. The subsequent gender-stratified analysis using dietary calcium intake revealed an increased correlation between the CG haplotype and osteoporosis (OR = 2.069) in the low-calcium-intake-female group but not in the high-calcium-intake-female or any male group.
This study revealed novel evidence of the sex-specific association of the CG haplotype in the PTPRD locus with osteoporosis and indicated that the association can be influenced by dietary calcium intake.
骨质疏松症是最常见的骨病，其特征是骨矿物质密度（BMD）低和骨折风险高。尽管我们对骨质疏松症发病机制的理解有所进展，但影响骨质疏松症发展的复杂基因-环境相互作用在很大程度上仍未得到探索。在本研究中，我们旨在确定与低骨矿物质密度相关的基因位点，并在个体和环境因素下评估这些基因变异。
使用韩国基因组与流行病学研究建立的临床、人口统计学和饮食数据（>260个特征），对8842名40-69岁个体中的500,568个单核苷酸多态性（SNP）进行全基因组关联分析。使用gPLINK程序在全基因组显著水平（P < 1.0×10）检测与骨质疏松症相关的SNP，并进行单倍型分析。基于频率分布，使用卡方检验评估骨质疏松症组和对照组在分类变量（性别和饮食特征）上的统计差异。
在与骨质疏松症相关的7个SNP中，rs10977574和rs4390000均位于编码蛋白酪氨酸磷酸酶受体D型的PTPRD基因座中，该基因座与骨代谢有关。单倍型分析分别在rs10977574和rs4390000基因座鉴定出两个次要等位基因C和G，形成一个连锁不平衡块。随后使用膳食钙摄入量进行的性别分层分析显示，低钙摄入女性组中CG单倍型与骨质疏松症之间的相关性增加（OR = 2.069），而高钙摄入女性组或任何男性组中未观察到这种相关性。
本研究揭示了PTPRD基因座中CG单倍型与骨质疏松症存在性别特异性关联的新证据，并表明这种关联可能受膳食钙摄入量的影响。
