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Circulation(IF=23.054):更年期后的女性冠心病患者代謝組學研究

分類:行業資訊   發布時間 2020-05-18   閱讀: 1185

冠心病(CHD,coronary heart disease)目前仍然是導致全球女性和男性死亡的主要原因。然而冠心病在不同性別中的臨床表現不同,女性表現出更高比例的非阻塞性動脈粥樣硬化和微血管疾病以及死亡率[1]。糖尿病是女性冠心病患者的高風險因子,2型糖尿病女性比男性有大于40%概率的高風險易患冠心病[2,3]。此外,現在已有報道TCA循環代謝物、腸道菌群代謝物TMAO、脂類代謝物與冠心病事件發生密切相關,glutamate和glutamine以及芳香族氨基酸與糖尿病和冠心病密切相關[4-13]。但是,盡管已有證據表明性別會影響人體代謝物輪廓譜[14,15],而國際上使用代謝組學研究代謝物與女性患冠心病風險,尤其是女性絕經與冠心病之間的相關研究更是稀缺[16]。因此,本研究先采用LC-MS代謝組學技術去挖掘WHI (Women’s Health Initiative) [17]和 WHI-OS (Women’s Health Initiative-Observational Study) [18]人群隊列中絕經女性冠心病事件與代謝物間的關系,然后在WHI-HT (Women’s Health Initiative-Hormone Trials)[19]人群隊列中進行驗證,最后在另一個獨立的PREDIMED飲食干預 (Prevención con Dieta Mediterránea) [20,21]人群隊列中評估了這些顯著性關聯物質在男女性別中的普適性。

本研究[22]從WHI-OS人群隊列(含>93676位絕經女性)中挑選出472對絕經女性冠心病患者和健康對照絕經女性,匹配了種族、民族、子宮切除手術、年齡(±5年)、以及納入隊列時間(±2年)等因素;從WHI-HT人群隊列(含>16608位絕經女性,>10739位子宮切除女性)中挑選出312位絕經女性冠心病和315位健康對照女性,匹配了種族、民族、子宮切除手術、年齡(±5年)以及納入隊列時間(±2年)等因素(如 table1 所示),從PREDIMED人群隊列(含1017位男性和女性地中海飲食干預冠心。┻x出980位參與者(230位有心血管疾病事件)的血漿樣本進行代謝組學檢測,在該研究中使用4種互補的LC-MS檢測方法(HILIC-positive(Q Exactive hybrid quadrupole orbitrap mass spectrometer (Thermo Fisher Scientific))、HILIC-negative(5500 QTRAP mass spectrometer [SCIEX]))、C8-positive(Exactive Plus orbitrap mass spectrometer (Thermo Fisher Scientific))、C18-negative(Q Exactive hybrid quadrupole orbitrap mass spec- trometer (Thermo Fisher Scientific))在WHI(-OS/-HT)人群樣本中檢測到了371個代謝物,其中PREDIMED只使用HILIC-positive、C8-positive兩種方法檢測。

代謝組學

在WHI-OS人群隊列中,通過使用邏輯回歸模型發現檢測出的371個代謝物中有60個物質與冠心病事件發生顯著性相關(以樣本篩選匹配的變量為協變量,校正后P<0.05),加上CHD臨床風險因子作為協變量發現36個物質與冠心病事件發生顯著性相關,17個物質不受CHD臨床風險因子影響。在WHI-HT人群隊列中驗證發現,以樣本篩選匹配的變量為協變量有33個物質與冠心病事件發生顯著性相關(校正后P<0.05),加上CHD臨床風險因子為協變量有8個物質與冠心病事件發生顯著性相關,其中7個物質具有增加冠心病發病風險:C34:2 hydroxy-PC, C36:4 hydroxy-PC, 5-hydroxyeicosatetraenoic acid (HETE), 15-HETE, 11-HETE, glutamate, cytidine monophosphate,1個物質具有降低冠心病發病風險:glutamine(如 table2 所示)。

代謝組學

將8個在2個獨立人群隊列中經過驗證的代謝物在邏輯回歸模型中進行相互校正,發現只有C34:2 hydroxy-PC在WHI人群中仍然與冠心病事件發生顯著性相關,該物質含量最高四分位絕經女性人群比最低四分位絕經女性人群有4.69倍 (95% confidence interval, 2.84– 7.90) 的風險患冠心病。如圖1所示根據C34:2 hydroxy-PC含量進行WHI-HT人群隊列亞組分型,該物質與冠心病臨床風險因子關系仍然顯著相關。典型CHD風險因子(ROC曲線下面積AUC=0.76)與C34:2 hydroxy-PC結合(AUC=0.79)進行冠心病預測顯著性提高了AUC(95% confidence interval, 0.01–0.05; P<0.01)。

代謝組學
圖1. WHI-HT隊列中C34:2 hydroxy-PC含量亞組分型分析。BMI indicates body mass index; CI, confidence interval; CRP, C-reactive protein; HDL, high-density lipopro- tein; hydroxy-PC, hydroxy-phospha- tidylcholine; OR, odds ratio; and WHI-HT, Women’s Health Initiative- Hormone Trials.

為了驗證WHI人群隊列發現的代謝物與冠心病事件的關聯是否具有普適性,使用2種LC-MS檢測方法在PREDIMED人群隊列中驗證了4個物質(glutamine, glutamate, C34:2 hydroxy-PC, and C36:4 hydroxy-PC)與冠心病事件發生的相關性。研究發現:1)除了glutamine物質,其他3個物質在男女混合冠心病事件發生中具有顯著性關聯且在女性中關聯更顯著;2)只有glutamate單獨在男性冠心病事件發生中顯著關聯;3)Wald test檢驗發現性別與hydroxy-PCs間的相互作用顯著 (P for interaction <0.001)。

代謝組學

此外,如圖2所示,將這8個代謝物與心血管疾病臨床標記物等臨床指標進行關聯分析意外發現,氧化性脂類(C34:2 hydroxy-PC, C36:4 hydroxy-PC, 5-HETE, 15-HETE, and 11-HETE)與 CRP、LPA、Lipoprotein-associated phospholipase A2 activity MASS 指標無顯著性相關性。

代謝組學
圖2. 代謝物與心血管疾病標記物等臨床指標間的斯皮爾曼相關性分析。Left, Spearman correlations are shown on the bottom and confidence interval on the top. Right, Heat map. Both figures are ordered by using hierarchical clustering. ACT indicates Lp-PLA2 activity; BMI, body mass index; BNP, N-terminal pro- brain natriuretic peptide; CMP, cytidine monophosphate; CRP, log C-reactive protein; HETE, hydroxyeicosatetraenoic acid; HDL, high-density lipoprotein; LPA, lipoprotein(a); MASS, Lipoprotein-associated phospholipase A2 mass; SBP, systolic blood pressure; and TCHL, total cholesterol.

為了研究371個代謝物間的相關性,使用偏相關分析校正“是否患冠心病”這個協變量,以 |偏相關系數| >0.7為條件,發現有6個cluster物質聚類間的關聯與冠心病相關,如圖3所示的一個cluster包含了氧化性脂質,且都是上述研究發現的與冠心病事件發生顯著性關聯的2 個hydroxy-PCs 和4 個HETEs,該cluster與冠心病事件發生顯著性相關(P=3.185E-07) 。在該cluster中,以CHD臨床風險因子為協變量校正發現有3個物質仍然與冠心病事件發生顯著性相關,以樣本篩選匹配的變量為協變量校正發現只有1個物質(12-HETE)與冠心病事件發生顯著性相關(校正后P<0.05)。

代謝組學
圖3. 六個氧化脂類間的偏相關斯皮爾曼相關性分析。Enrichment P value=3.185E-07. All markers are positively associated with increased CHD risk. All correlations (edges) are positive. CHD indicates coronary heart disease; HETE, hydroxyeicosatetraenoic acid; OH-PC, hydroxy-phosphatidyl- choline; and OR, odds ratio. 

綜上所述,通過對WHI-OS和WHI-HT兩個人群隊列中絕經女性的血漿代謝組學進行相互的獨立驗證研究,發現新的與冠心病事件發生顯著性相關的代謝物(如hydroxy-PCs,HETEs,glutamate,glutamine),且在PREDIMED人群隊列中再次驗證表明C34:2 hydroxy-PC物質與性別和冠心病事件發生具有顯著性關聯,這些結果為氧化脂質與冠心病的相互關聯提供了數據支持和潛在靶點。

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代謝組學

玩朋友的丰满人妻,朋友的丰满人妻中文字幕,从后面挺进邻居丰满少妇