社會經濟地位與發炎指標及心臟血管疾病與全死因死亡風險－臺灣代表性世代追蹤研究資料分析

Association of Socioeconomic Position with Inflammation Biomarkers and the Risk of Cardiovascular and All-cause Death among a Representative Cohort in Taiwan

林宇旋(Yu-Hsuan Lin)

指導教授 ： 簡國龍

國立臺灣大學/公共衛生學院/流行病學與預防醫學研究所/博士(2017年)

https://doi.org/10.6342/NTU201703662

摘要

背景：過去研究發現發炎與老年期健康變化有關，相關證據顯示發炎為動脈硬化之重要致病機轉，並與心血管疾病或全死因死亡風險相關，而C-反應蛋白(CRP)和細胞介白素第六因子（IL-6）為其中較常被探討的兩項發炎指標。相關流行病學研究發現，社會經濟地位高低與發炎指標數值高低呈反向相關，但其與生命歷程社會經濟地位變化之關聯並不明確，又過去此類研究之對象常侷限於西方族群。因此，本研究旨在運用具全台灣代表性之世代追蹤資料，探討：(1)CRP和IL-6兩項發炎指標是否有助改善心血管疾病和全死因死亡風險模型之預測力；(2)幼年至成年及中老年期社會經濟地位變化軌跡，和心血管疾病風險之相關，而其心血管疾病或全死因死亡風險，係以CRP和IL-6兩項發炎因子為測量指標。
材料和方法：分析資料源自具全台代表性之「台灣中老人社會因素與生物指標研究」長期追蹤研究世代，運用Cox迴歸模型估算控制相關危險因子後，相較於最低四分位，CRP或IL-6在其他三個四分位數之心血管疾病或全死因之死亡風險，再以area under the curve of receiver operator characteristics (ROC curve), integrated discrimination improvement (IDI)和net reclassification improvement(NRI)等三項指標，探討將CRP或IL-6加入死亡機率預測模型後，對心血管疾病和全死因死亡預測力之改善情形。另一方面，則以Group-based Trajectory Modeling方法，進行社會經濟地位發展軌跡之分群，再以線性迴歸模型比較不同軌跡群組之發炎因子高低。
結果：本研究針對1,023名於2000年完成收案之54歲以上世代成員追蹤結果，在中位數為11.2年之追蹤期間內，各項死因之死亡人數為351人，其中82人死於心血管疾病。相較於最低四分位，CRP或IL-6之數值較高者，其在追蹤期間之全死因死亡風險較高，相較於CRP值在最低四分位者，CRP值在最高四分位者之相對風險比值為3.64 (95% 信賴區間：2.44-5.44)； IL-6 值在最高四分位者相對在最低四分位者之風險比值為2.31 (95%信賴區間：1.62-3.29) 。 IL-6值較高亦與心血管疾病死亡風險顯著相關。兩項發炎指標對全死因和心血管疾病死亡風險預測之改善效果，以IL-6較佳。依發展軌跡分群結果，生命週期社會經濟地位變化分為三群：持續偏低組 (36.5%)、由低轉高組 (26.8%)以及持續居高組 (36.7%)。持續居高組之CRP或IL-6兩項發炎指標數值最低，在調整其他變因後，相較於持續偏低組，由低轉高組之CRP值並無顯著差距 (−0.032 ln mg/L; 95% 信賴區間：−0.193, 0.128)，IL-6 值亦無顯著差距(0.017 ln pg/mL; 95%信賴區間：−0.093, 0.128)，但持續居高組之CRP數值則顯著較低(−0.279 ln mg/L; 95%信賴區間： −0.434, −0.125) ，IL-6 值亦顯著較低 (−0.129 ln pg/mL; 95%信賴區間：−0.236, −0.023)。
結論：IL-6和CRP皆與全死因死亡風險相關，但IL-6對死亡風險預測之改善效果較佳，兩項指標僅IL-6與心血管病死亡風險具顯著相關。幼年時期居於低社經地位者，在中老年時期之CRP或IL-6數值均較高，而幼年時期居於低社經地位者，即使成年後之社會經濟地位提升，其CRP或IL-6兩項發炎指標數值，仍與持續處於低社會經濟地位者較為接近。

關鍵字

社會經濟地位 ； C-反應蛋白 ； 細胞介白素第六因子 ； 心血管疾病 ； 死亡率 ； 生命週期

並列摘要

Background- Evidence showed that inflammatory response is a key pathway in atherosclerosis and leads to an increased risk of cardiovascular disease (CVD) and all-cause death. Evidence from observational studies suggested that high socioeconomic position (SEP) was inversely associated with the levels of C-reactive protein (CRP) or interleukin-6 (IL-6). However, it is unclear whether the life course SEP affected an association with these biomarker levels. In addition, the data from Asian populations are limited. Therefore, the aims of this study are: (1) to investigate the added values of CRP and IL-6 in predicting cardiovascular mortality and all-cause mortality among a representative adult cohort in Taiwan; and (2) to examine how life course trajectory of SEP predicted the risk of cardiovascular disease and all-cause mortality measured with CRP and IL-6.
Material and Methods- We applied data from the Social Environment and Biomarkers of Aging Study (SEBAS), which was a prospective, population-based study of a national representative cohort in Taiwan. First, we used a Cox regression to estimate adjusted relative risks for of the roles of CRP and IL-6. Second, three indicators were applied to investigate the additive value of IL-6 and CRP to the Framingham risk score and lifestyle factors in predicting all-cause and cardiovascular mortality, including area under the curve of receiver operator characteristics curve, integrated discrimination improvement (IDI), and net reclassification improvement (NRI). Finally, we applied group-based trajectory modeling to determine life course trajectory groups or SEP; then use multivariable linear regressions to compare level of CRP and IL-6 among individuals in different trajectory groups.
Results- Among the population-representative sample of 1,023 adults aged 54 and above in Taiwan, a total of 351 deaths and 82 cardiovascular deaths were identified after a median follow-up of 11.2 years. After adjustment for established risk factors, elevated IL-6 and CRP were associated with a higher risk of all-cause death: the hazard ratio for the highest risk quartile compared with the lowest quartile was 3.64 [95% confidence interval (CI), 2.44-5.44] for IL-6 and 2.31 (95% CI, 1.62-3.29) for CRP. IL-6 was also significantly associated with cardiovascular mortality. For both all-cause and cardiovascular mortality, IL-6 yielded a substantial increase in the area under the receiver operator characteristic curve (ΔAUC=0.036 and 0.024, respectively), but CRP did not (ΔAUC=0.004 and 0.009, respectively). Three trajectories of life-course SEP were identified within the total sample: Low-Low (36.5%), Low-High (26.8%), and High-High (36.7%). Participants in the High-High group had the lowest levels of CRP and IL-6. Compared with those in the Low-Low group, the participants in the Low-High group had a similar adjusted CRP (−0.032 ln mg/L; 95% CI, −0.193, 0.128) and IL-6 (0.017 ln pg/mL; 95% CI, −0.093, 0.128); the participants in the High-High group had a significantly lower level of adjusted CRP concentration (−0.279 ln mg/L; 95% CI, −0.434, −0.125) and similarly lower IL-6 concentration (−0.129 ln pg/mL; 95% CI, −0.236, −0.023) .
Conclusion- IL-6 and CRP were both significantly associated with all-cause mortality; however, only IL-6 provided a substantial improvement in discrimination. IL-6 demonstrated notable prognostic value for predicting cardiovascular mortality, but not CRP. Low SEP in childhood is related to elevated inflammatory markers in older age. Even after the transition from low SEP in childhood to high SEP in older age, the risk remains.

並列關鍵字

socioeconomic position ； cardiovascular disease ； C-reactive protein ； interleukin-6 ； inflammation ； mortality ； life course

參考文獻

1. Pearson TA, Mensah GA, Hong Y, Smith SC, Jr. CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: overview. Circulation. 2004;110(25):e543-4.

2. Singh T, Newman AB. Inflammatory markers in population studies of aging. Ageing research reviews. 2011;10(3):319-29.

3. Ramos AM, Pellanda LC, Gus I, Portal VL. Inflammatory markers of cardiovascular disease in the elderly. Arq Bras Cardiol. 2009;92(3):221-8, 7-34.

4. Johnson TE. Recent results: biomarkers of aging. Exp Gerontol. 2006;41(12):1243-6.

5. Rafnsson SB, Deary IJ, Smith FB, Whiteman MC, Rumley A, Lowe GD, et al. Cognitive decline and markers of inflammation and hemostasis: the Edinburgh Artery Study. J Am Geriatr Soc. 2007;55(5):700-7.