||FGF21 and LEPR polymorphisms predict valproate treatment outcome in patients with bipolar II disorder
||Institute of Clinical Pharmacy and Pharmaceutical sciences
fibroblast growth factor-21 (FGF21)
leptin receptor gene (LEPR)
研究背景: 丙戊酸是一種用於治療雙極性疾患的情緒穩定劑，也是雙極性疾患病人出現代謝異常的風險因子之一。而近期的研究指出代謝恆定與情緒可能由共同的機制所調控。由肝臟分泌的第二十一型纖維母細胞生長因子 (FGF21)，先前的研究指出它對血脂肪與血糖調控發揮有益的作用。最近的動物研究指出使用丙戊酸會使第二十一型纖維母細胞生長因子的表現增加，雖然目前還沒有研究指出FGF21對情緒的調節與雙極性疾患使用丙戊酸治療的治療反應是否有關連，我們研究假設FGF21是代謝系統與情緒疾患的一個共同調節因子。另一方面，已有研究指出瘦素－瘦素受體蛋白系統與情緒和代謝調節有關聯，而且先前研究指出使用丙戊酸治療的確會造成周邊瘦素血中濃度增加。另外，瘦素受體基因(LEPR)的基因多型性已證實與代謝異常有關連，但目前尚未有研究針對瘦素受體基因之單一位點核苷酸變異，是否與服用丙戊酸所引起的代謝異常有關。
研究對象與方法：本研究從成大醫院招募18到65歲，符合精神疾病診斷與統計手冊第四版(DSM-IV)、中文版的終生精神疾病診斷晤談手冊(SADS-L)之第二型雙極性疾患診斷的病人。而本研究也透過社區廣告招收無精神疾患的健康受試者。在簽署受試者同意書後，所有被收錄進來的病人會每天服用丙戊酸500至1000毫克維持12周，併用氟西汀(Fluoxetine)來治療憂鬱症狀或Lorazepam治療夜間鎮靜與失眠是允許的。這些病患在尚未用藥前的漢氏憂鬱量表分數必須要大於15分，在臨床上代表著這些病患是處於憂鬱階段的雙極性疾患。健康人與病人尚未用藥前會評估並嚴重程度，抽取空腹靜脈血測量代謝指標與血中FGF21濃度，並且病人組於用藥後2周、8周、12周再做一次評估與測量。瘦素受體基因單一位點核苷酸變異rs113101, rs1137100, rs1327121, rs8179183, rs12145690, rs4655555, rs6588147, rs10889557, rs9436747的基因分型使用TaqMan SNP 基因分型方法完成。
結果：本研究收錄了137位第二型雙極性疾患患者與78為社區招募來的健康受試者。病人的平均年齡32.1±11.6歲，而健康受試者的平均年齡31.0±10.7歲。病人有51.1%為女性，而健康受試者有56.4% 為女性。在尚未服用藥物前，病人的漢式憂鬱量表分數與楊式躁症量表分數(疾病嚴重程度)比健康人高，但FGF21濃度與其他代謝指標在兩組並無差異。病人服用丙戊酸12周後，病人的疾病嚴重程度明顯改善。FGF21濃度、體重與腰圍皆比用藥前明顯增加。結果一：在健康人組與病人尚未服藥前，FGF21濃度與腰圍和三酸甘油酯濃度在校正年齡後呈顯著正相關(健康人組:相關係數分別為0.310、r=0.461，P值分別為0.009、<0.001。病人組: 相關係數分別為0.231、0.187，P值分別為0.008、0.033)；但與疾病嚴重程度皆無關。在病人使用丙戊酸的治療12周後，FGF21濃度的改變量與漢式憂鬱量表分數改變量呈顯著正相關(相關係數為0.393,P值為0.002)，與總膽固醇、高密度脂蛋白、低密度脂蛋白皆呈顯著負相關(相關係數分別為−0.344、−0.298、−0.347，P值分別為0.008、0.022、0.007)。而FGF21濃度的改變量顯著與憂鬱症狀中的失眠和焦慮的嚴重程度改變量有相關(相關係數分別為0.373、0.270，P值分別為0.004、0.042)。結果二：在瘦素受體基因多型性的分析中，我們發現健康人組別裡與體重和腰圍有關聯的瘦素受體基因多型性有rs1137100, rs1137101, rs1327121, rs6588147, rs10889557, rs4655555。在病人組尚未用藥前，我們發現與總膽固醇有關聯的基因多型性是rs10889557和rs12145690，而在疾病嚴重程度方面，rs1137100 帶有AA或AG基因型的病人有較高的楊氏躁症評估分數(10.4±4.1分比上8.8±3.9分，p值為0.032)，且在丙戊酸治療12周之後，rs1137100帶有AA或AG基因型的病人有較高比例的人是屬於躁症有治療反應者(43.5%比上25%，p值為0.030)。另一方面，針對瘦素受體基因多型性和丙戊酸治療的交互作用對病人的治療反應和代謝指標的影響，這部分的結果顯示rs1137100與rs12145690會影響療程中臀圍、總膽固醇數值；rs9436747、rs6588147、rs8179183會影響胰島素濃度和胰島素抗性之恆定模式的評估方法的數值，然而，在經過Bonferroni事後校正後，上述的瘦素受體基因多型性關聯性皆未達到統計上的顯著。但是rs1137100基因多型性對丙戊酸療程中膽固醇改變量的影響，以及rs8179183對丙戊酸療程中三酸甘油酯、胰島素濃度和胰島素抗性之恆定模式的評估方法數值的影響，經Bonferroni事後校正仍有達到統計上的顯著。我們進一步在我們的族群中進行瘦素受體基因單倍型(haplotype)的分析，發現最常見的單倍型是CGGA (順序：rs12145690 /rs1137100 /rs1137101 /rs4655555), 其分布頻率在病人組是63.3%，在健康人組是62.7%。在病人組中以楊式躁症治療反應區分有無治療反應兩組後，我們發現瘦素受體基因單倍型組合之一的CAGA型在有治療反應的組別中佔有較高的比例(9.2%比上2.2%，p值為0.011)。
Background: Valproate (VPA) is a mood stabilizer for treating patients with bipolar disorder (BD), and it is known to be one of risk factors associated with metabolic disturbances in BD patients. Recent studies had pointed out the metabolic regulation and mood symptoms might be mediated by the common underlying mechanisms. However, previous studies have found that hepatokine FGF21 exerts beneficial effects on lipid and glucose regulation. Nevertheless, current studies indicated that VPA upregulated fibroblast growth factor-21 (FGF21) expression, although the role of FGF21 between mood regulation and valproate treatment outcome in bipolar patients is still unknown. Therefore, we hypothesized that FGF21 is a common mediator in metabolic system and mood disorder. In addition, the role of leptin-leptin receptor system in mood symptom and metabolic regulation is well studied, and our previous studies found that bipolar patient received valproate would increase the peripheral leptin level. Besides, the leptin receptor gene (LEPR) has been associated with metabolic disturbances, yet the association between LEPR polymorphism and valproate-induced metabolic disturbance is still unknown.
Materials and Methods: we enrolled patients (aged 18–65 years) who met the Diagnostic and Statistical Manual of Mental Disorders, 4th version (DSM-IV) and the Chinese Version of the Modified Schedule of Affective Disorder and Schizophrenia-Life Time (SADS-L) diagnostic criteria for BD II consecutively. We recruited healthy controls without mental illness from the community. All subjects signed the informed consent and the BD II patients started to receive VPA 500-100mg for 12 weeks. Concomitant fluoxetine for depressive symptoms or lorazepam for nighttime sedation and insomnia were permitted during the study. All BD patients were in major depressive status at the time of study entry, with a 17-item Hamilton Depression Rating Scale (HAMD) score >15. The disease severity and metabolic indexes including plasma FGF21 level were measured. The same measurements conducted at 2 weeks, 8 weeks and 12 weeks in BD II patients after the initiation of valproate treatment. The LEPR rs113101, rs1137100, rs1327121, rs8179183, rs12145690, rs4655555, rs6588147, rs10889557, rs9436747 polymorphisms were detected by TaqMan SNP Genotyping Assays.
Results: We recruited 137 BD II patients and 78 community-dwelling controls. The mean age of BD II patients and healthy controls were 32.1±11.6 and 31.0±10.7 years old, respectively. There were 51.1% female in BD II patients and 56.4% female in healthy controls. At baseline, the HAMD and YMRS score were higher in BD II patients whereas FGF21 level and metabolic indices did not differ significantly between the controls and BD II patients. After 12 weeks of VPA treatment, the disease severity significantly improved in BD II patients. The FGF21 level (167.7±122 and 207.1±162.3 pg/ml, p=0.001), body weight and waist circumference had increased significantly (p<0.001 and p=0.028, respectively). Result 1: The baseline FGF21 was significcantly positively correlated with waist circumference and TG level in both populations after adjustment for age (in healthy controls: r=0.310 and p=0.009, r= 0.461 and p<0.001, respectively; in BD II patients: r=0.231 and p=0.008, r=0.187 and p=0.033, respectively). However, there was no correlation between FGF21 and disease severity in both groups at baseline. Moreover, the change in FGF21 level was significantly correlated with the changes in HAMD score (r=0.393, p=0.002), total cholesterol (r=−0.344, p=0.008), HDL (r=−0.298, p=0.022) and LDL (r=−0.347, p=0.007). Furthermore, the change in FGF21 level was specifically correlated with change score in insomnia and anxiety subscale from HAMD scores (p=0.004, p=0.042, respectively). Result 2: Regarding the analysis of the LEPR polymorphism in our population, we found that LEPR SNPs rs1137100, rs1137101, rs1327121, rs6588147, rs10889557, rs4655555 were associated with body weight and waist circumference in healthy controls. In BD patients at baseline, we found that rs10889557 and rs12145690 were associated with total cholesterol level. Moreover, rs1137100 AA or AG carriers had a higher YMRS score than GG carriers (10.4±4.1 vs. 8.8±3.9, p=0.032). After 12-week treatment course, rs1137100 AA or AG carriers had a higher portion of YMRS remitter than GG carriers (43.5% vs.25.0%, p=0.030). On the other hand, regarding the interaction effect of LEPR polymorphism and VPA treatment on the treatment response and metabolic indices, the results showed that rs1137100 and rs12145690 influenced the hip circumference and total cholesterol level during the treatment course. In addition, rs9436747, rs6588147, rs8179183 influenced the insulin level and the value of HOMA-IR during the treatment course. However, the above results of LEPR polymorphism were not statistically significant after Bonferroni correction. But the effect of rs1137100 on the change level of total cholesterol during the treatment course, and the effect of rs8179183 on the value of triglyceride, insulin, and HOMA-IR during the treatment course remained statistically significant after Bonferroni correction. We further analysis the LEPR haplotype frequencies in our population. The commonest LEPR haplotype in BD II patients and healthy controls was haplotype 1 (CGGA: rs12145690 /rs1137100 /rs1137101 /rs4655555), and the frequency was 63.3% and 62.7%, respectively. The haplotype frequencies were not different between the two populations. Regarding the treatment response in BD II patients, the frequency of LEPR haplotype CAGA was significantly different between YMRS responders and non-responders (9.2% and 2.2%, p=0.011).
Conclusion: Our findings suggested that FGF21 could be a common mediator of a shared mechanism of mood response and metabolic effects in VPA-treated BD patients. FGF21-based therapies could potentially represent novel targets to prevent and treat a variety of mood and metabolic disorders. On the other hand, the LEPR polymorphism was associated with mood and metabolic regulation in BD II patients during the VPA course. Moreover, LEPR haplotype 6 conferred susceptibility to mania treatment response in our patients. In the future study, we may use complicated models, such as functional linear model or artificial neural networks to predict VPA treatment outcome.
Table of Content VI
List of Tables VIII
List of Figures XIV
Chapter 1 Introduction 1
1.1 Bipolar disorder 1
1.2 Valproate 3
1.3 Fibroblast growth factor 21 4
1.4 Leptin 7
1.5 Pharmacogenomics 8
Chapter 2 Object of current study 9
Chapter 3 Material and methods 10
3.1 Study design 10
3.2 Subjects and method 10
3.3 Measurement 10
3.4 Statistics 15
Chapter 4 Result 18
4.1 Demographic characteristics of BD II patients and healthy controls 18
4.2 FGF21 level and metabolic indices level 19
4.3 The effect of plasma VPA level on clinical features 20
4.4 Potential confounding factors influence the difference between baseline and after treatment FGF21 level in BD patients 21
4.5 The association between FGF21 level and clinical features in healthy controls and BD II patients 21
4.6 The association between leptin level and clinical features in healthy controls and BD II patients 24
4.7 The association between LEPR polymorphisms and treatment outcomes in BD II patients 26
Chapter 5 Discussion 274
5.1 The role of FGF21 in bipolar disorder and valproate treatment response 274
5.2 The role of LEPR in bipolar disorder and valproate treatment response 277
5.3 Strategies against VPA-induced metabolic disturbances in BD II patients 282
5.4 Limitations 283
Chapter 6 Conclusion 284
Chapter 7 Reference 285
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