雌激素对女性神经性厌食5-HT通路相关基因的DNA甲基化调控研究

Anorexia Nervosa (AN) is a chronic refractory mental disorder commonly occurring among young females with high mortality. Its morbidity in China has been increasing rapidly in recent years. It's commonly held that low level of 5-HT is one of the pathogenic factors of AN. However, single usage of 5-HT increasing drugs showed limited effect. Our rudimentary research found that low level of 5-HT was universally accompanied with low level of estrogen among female AN patients, and both 5-HT and estrogen level increased among recovering AN patients. Biological studies found that estrogen, which is a neurosteroid hormone in the brain, showed regulating effect on 5-HT level in the brain. In the current study, we recruit first onset drug na?ve female patients with AN and healthy subjects, adopting a prospective randomized control method to observe the clinical symptoms change before and after treatment among estrogen intervention group and intervention free group. We also investigate the DNA methylation, mRNA expression of the genes related to 5-HT circuit, 5-HT level change and their interrelations. We hypothesize that low level of estrogen is one of the underlying pathophysiological mechanisms resulting the chronic process of AN. We postulate estrogen can increase central 5-HT level through its effect on DNA methylation of 5-HT related genes, and eventually improve core symptoms. The current study will try to explain the neuropathological mechanism of AN, and further offer theoretical evidence for a potential estrogen therapy aiming low body weight AN patients.

神经性厌食（AN）是我国近年来快速增长、年轻女性多发的慢性难治性精神障碍。目前普遍认为5-HT能低下是AN的病因之一，但单用提高5-HT的药物疗效不佳。申请人前期初步证明女性AN患者5-HT水平低下的同时雌激素水平普遍低下，而恢复中的AN患者5-HT水平和雌激素水平均有升高。生物学研究发现脑神经甾体激素- - 雌激素对脑内5-HT具调节作用。本研究拟以首发未治疗的女性AN患者为研究对象，采用同期健康对照，及以雌激素为干预的前瞻性随机对照研究，观察雌激素治疗组和非雌激素治疗组治疗前后临床症状变化，以及5-HT通路相关基因DNA甲基化、mRNA表达及5-HT水平三个层面变化特点和其间的关联，以验证研究假设- - 雌激素可通过影响AN患者5-HT通路相关基因的DNA甲基化水平、最终提高中枢5-HT能而改善AN核心症状；在进一步阐明AN的神经病理机制同时，为AN的潜在治疗方法- - 雌激素治疗法提供理论依据。

神经性厌食（AN）是年轻女性多发的慢性难治性精神障碍。虽认为5-HT能低下是AN的病因之一，但单用提高5-HT的药物疗效不佳。生物学研究发现脑神经甾体激素——雌激素对脑内5-HT具调节作用。本研究以首发未治疗的女性AN患者为研究对象，采用同期健康对照，及以雌激素为干预的前瞻性随机对照研究，观察女性AN患者与健康对照的5-HT通路相关基因的DNA甲基化差异，并观察雌激素治疗组（A组）和常规治疗组（B组）治疗前后5-HT通路相关基因DNA甲基化、血小板5-HT水平及临床症状的三个层面变化特点和其间的关联。结果显示：（1）（1）A组及B组AN患者在治疗前血清雌激素水平均显著低于健康对照（HC）（41.90±48.75 vs. 67.17±46.98，p=0.001；33.86±39.11 vs. 67.17±46.98，p=0.037），两组AN患者的血小板5-HT水平在治疗前与HC相比均无显著性差异；治疗3个月后，两组雌激素水平均显著提高，A组和B组AN患者的5-HT水平均显著低于HC组；女性AN患者的雌激素水平与5-HT水平无相关性。（2）AN患者治疗前5-HTT基因CPG3位点DNA甲基化水平较正常对照低（0.042±0.012 vs. 0.060±0.010，p=0.005），5-HT通路基因其他位点DNA甲基化水平与HC组无显著性差异；AN患者的5-HT通路基因DNA甲基化水平与临床症状的严重程度无相关性。（3）A组及B组在治疗后1个月、3个月后 A组及B组在治疗1个月、3个月后临床症状均有显著改善，A组5-HTT基因CPG3位点（0.046±0.005 vs. 0.0340±0.055，p=0.033）、B组CPG24、25位点的DNA甲基化水平（0.080±0.010 vs. 0.064±0.009， p=0.016）治疗前后有显著变化；A组及B组患者治疗后雌激素水平、5-HTT基因、5-HTR2A基因DNA甲基化水平、血小板5-HT水平、及其临床症状和心理特征无显著差异。. 本研究发现女性AN患者5-HTT基因DNA甲基化水平低于正常对照组，5-HTT基因多个位点的DNA甲基化水平治疗前后随临床症状的改善而有显著变化，从表观遗传学的角度发现了AN的发病与5-HTT基因有关，进一步阐明了AN发病的分子遗传机制。