維生素D 缺乏症和SPP1（骨橋蛋白）遺傳多態性與 中年女性骨密度的相互關係。橫斷面研究

Abstract

目標： 本研究目的在檢驗以下兩點：1）25-羥基膽鈣化醇濃度與骨密度之間的線性和非線性關聯性；以及2）SPP1（secreted phosphoprotein 1）基因多態性與維生素D缺乏對骨密度的聯合影響。 方法： 此橫斷面研究共招募了657名中年女性，其中包括524名停經前及133位停經後。利用雙能量X光吸光式測定儀測量了腰椎的面積性骨密度（g/cm2）。我們從SPP1基因中選擇了三個標記SNP作分析（rs11730582來自啟動子，rs6839524來自外顯子，rs4754來自內含子）。我們用不同方法評估了25-羥基膽鈣化醇對骨密度的影響，作為連續變項、序列變項（三分等級）或二元變項（維生素D缺乏，臨界值25-羥基膽鈣化醇 <20 ng/mL）指標。根據女性的更年期狀態，低骨密度的定義有所不同。在停經前女性中，以Z分數(Z-score)落在最低四分位數內定義為低骨密度。相反，在停經後女性中，低骨密度定義包括帶有骨質稀少(osteopenia)或骨質疏鬆症(osteoporosis)。 結果： 中年女性併維生素D缺乏會增加低骨密度風險（調整過的勝算比在停經前女性為1.65，95%信賴區間為1.06-2.61；停經後女性其調整過的勝算比3.04，95%信賴區間為1.08-9.36），在調整了年齡、BMI (body mass index)、體脂肪、測量維生素D的季節、體力活動、鈣質補充和久坐工作後。多項式回歸分析顯示25-羥基膽鈣化醇的二次項為顯著，在停經前和停經後婦女中，25-羥基膽鈣化醇濃度與低骨密度風險之間呈倒J型關係。停經後且維生素D充足的女性，若攜帶rs11730582 變異體或者包含等位基因的 CCT 單倍體，則會有減少的低骨密度風險；然而，停經後女性併維生素D缺乏且攜帶 rs6839524 變異體，或者攜帶 rs4754 野生型基因，則有上升的低骨密度風險。 結論： 我們的結果表示，充足的維生素D濃度在中年女性的骨質健康扮演角色。且維他命D濃度與低骨密度風險間有非線性關係。停經後女性較易受到SPP1基因多態性和維生素D缺乏的聯合影響。

Objectives: The study aimed to investigate the followings: 1) the association of 25-hydroxycholecalciferol levels with bone mineral density (BMD) using linear and nonlinear analyses, and 2) the joint effect of secreted phosphoprotein 1 (SPP1) genetic polymorphisms and vitamin D deficiency on BMD. Materials and methods: A total of 657 women, including 524 premenopausal and 133 postmenopausal individuals, were enrolled. Areal BMD (g/cm2) of the lumbar spine was measured by dual-energy X-ray absorptiometry. Three tagging single nucleotides polymorphisms (SNPs) from promotor (rs11730582), exon (rs6839524), and intron (rs4754) were selected from the SPP1 gene. The effect of 25-hydroxycholecalciferol on BMD was assessed as a continuous, ordinal (tertile), or dichotomous (vitamin D deficiency with a cut-off value of 25-hydroxycholecalciferol < 20 ng/mL) indicator. Low BMD was characterized differently depending on the menopausal status of the women. In premenopausal women, it was determined by a Z-score that fell within the lowest quartile. Conversely, in postmenopausal women, the definition included the presence of osteopenia or osteoporosis. Results: A significant association of vitamin D deficiency with the risk of low BMD was observed in premenopausal (adjusted odds ratio [aOR]: 1.65, 95% confidence interval [CI]: 1.06-2.61) and postmenopausal women (aOR: 3.04, 95% CI 1.08-9.36), after adjustments for age, body mass index, body fat percentages, seasons of blood collection, physical activity, calcium supplementations, and sedentary work. Nonlinear, polynomial regression analyses indicated that the quadratic term of 25-hydroxycholecalciferol levels was significant and a reverse J-shaped relationship between 25-hydroxycholecalciferol levels and the risk of low BMD in midlife women was found. Postmenopausal, vitamin D-repleted women who carry rs11730582 variant or the haplotype CCT have a reduced risk of low BMD, while vitamin D-deficient, postmenopausal women carrying rs6839524 variant or rs4754 wild type have an elevated risk of low BMD. Conclusion: Adequate vitamin D levels play a role in bone health in midlife women. A nonlinear association of 25-hydroxycholecalciferol levels with the risk of low BMD was observed. Postmenopausal women may be susceptible to the joint effect of vitamin D deficiency and SPP1 genetic polymorphisms.