Association between a functional interleukin 6 receptor genetic variant and risk of depression and psychosis in a population-based birth cohort.
Association between a functional interleukin 6 receptor genetic variant and risk of depression and psychosis in a population-based birth cohort.
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DOI：
10.1016/j.bbi.2017.11.020
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Jones PB
中科院分区：
文献类型：
--
作者：
Khandaker GM;Zammit S;Burgess S;Lewis G;Jones PB
功能性白细胞介素6受体（IL6R）变异体天冬氨酸358丙氨酸（IL6R rs2228145；A＞C）与严重抑郁症和/或精神病风险降低相关。
该变异体在白细胞介素 - 6下游发挥抗炎作用。
rs2228145与血清白细胞介素 - 6升高但血清C反应蛋白（CRP）水平降低相关。
rs2228145与白细胞介素 - 6、抑郁症和精神病关系的常见混杂因素无关。
白细胞介素6（IL - 6）水平在抑郁症和精神病患者以及有患这些疾病风险的人群中通常升高。白细胞介素6受体基因（IL6R）的一个常见功能性变异体（IL6R天冬氨酸358丙氨酸；rs2228145 A＞C）已知通过损害白细胞介素6受体信号传导来抑制炎症。我们研究了天冬氨酸358丙氨酸与抑郁症和精神病的诊断、血清白细胞介素 - 6、C反应蛋白水平以及一些通常与炎症、抑郁症或精神病相关的风险因素的关联。我们预测，如果白细胞介素 - 6与抑郁症/精神病风险存在因果关系，而非由于混杂因素，那么天冬氨酸358丙氨酸将与这些疾病的风险、血清白细胞介素 - 6、C反应蛋白水平相关，但与任何混杂因素无关。
我们使用了基于人群的埃文亲子纵向研究（ALSPAC）出生队列的数据。在9岁时测量血清白细胞介素 - 6和C反应蛋白水平。在18岁时评估精神病性障碍、国际疾病分类第10版（ICD - 10）中严重抑郁发作的诊断以及总抑郁评分。使用Illumina HumanHap550四芯片全基因组单核苷酸多态性（SNP）基因分型平台对IL6R天冬氨酸358丙氨酸进行基因分型。评估的风险因素包括性别、体重指数、社会阶层、种族、母亲教育程度、出生体重、胎龄、母亲产后抑郁症、儿童心理和行为问题以及总智商分数。
天冬氨酸358丙氨酸与严重抑郁症和/或精神病风险降低相关；与AA基因型相比，CC基因型个体的校正优势比为0.38（95%置信区间，0.15 - 0.94）。该变异体与血清白细胞介素 - 6水平升高（P = 5.5×10⁻²²）但血清C反应蛋白水平降低（P = 3.5×10⁻⁵）相关，这与白细胞介素 - 6下游的抗炎作用一致。天冬氨酸358丙氨酸与总抑郁评分无关。天冬氨酸358丙氨酸与其他任何通常与炎症、抑郁症或精神病相关的风险因素均无关（所有P＞0.20）。
这些研究结果进一步证明白细胞介素 - 6/白细胞介素6受体通路参与严重抑郁症和精神病的发病机制，并且可能是新的治疗靶点。先前报道的白细胞介素 - 6、抑郁症和精神病之间的关联不太可能完全由混杂因素解释。基于少量病例，当前研究的结果需要在其他样本中进行重复验证。
Functional IL6R variant Asp358Ala (IL6R rs2228145; A > C) is associated with decreased risk of severe depression and/or psychosis. The variant exerts anti-inflammatory effect downstream of IL-6. rs2228145 is associated with increased serum IL-6 but decreased serum CRP levels. rs2228145 is not associated with common confounders of IL-6, depression and psychosis relationship. Interleukin 6 (IL-6) levels are commonly elevated in patients with depression and psychosis and in people who are at risk of developing these disorders. A common, functional variant in the IL6R gene (IL6R Asp358Ala; rs2228145 A > C) is known to dampen down inflammation by impairing IL6R signaling. We have examined the association of Asp358Ala with diagnosis of depression and psychosis, serum IL-6, CRP levels, and a number of risk factors commonly linked with inflammation, depression or psychosis. We predicted that if IL-6 were related to depression/psychosis risk causally, rather than due to confounding, Asp358Ala would be associated with risk of these disorders, serum IL-6, CRP levels, but not with any of the confounders. We used data from the population-based ALSPAC birth cohort. Serum IL-6 and CRP levels were measured at age 9 years. Psychotic disorder, ICD-10 diagnosis of severe depressive episode, and total depression score were assessed at age 18 years. IL6R Asp358Ala was genotyped using the Illumina HumanHap550 quad genome-wide SNP genotyping platform. Risk factors assessed include sex, body mass index, social class, ethnicity, maternal education, birth weight, gestational age, maternal post-natal depression, childhood psychological and behavioral problems, and total IQ score. Asp358Ala was associated with decreased risk of severe depression and/or psychosis; adjusted odds ratio for those with CC, compared with AA, genotype was 0.38 (95% CI, 0.15–0.94). The variant was associated with increased serum IL-6 levels (P = 5.5 × 10−22) but decreased serum CRP levels (P = 3.5 × 10−5), consistent with an anti-inflammatory effect downstream of IL-6. Asp358Ala was not associated with total depression score. Asp358Ala was not associated with any of the other risk factors commonly linked with inflammation, depression or psychosis (all P > 0.20). The findings provide further evidence that the IL-6/IL6R pathways are involved in pathogenesis of severe depression and psychosis, and may be novel therapeutic targets. Previously reported associations between IL-6, depression and psychosis are unlikely to be fully explained by confounding. Based on a small number of cases, findings from the current study need replication in other samples.
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影响因子：
15.8
作者：
Danesh, John;Kaptoge, Stephen;Mann, Andrea G.;Sarwar, Nadeem;Wood, Angela;Angleman, Sara B.;Wensley, Frances;Higgins, Julian P. T.;Lennon, Lucy;Eiriksdottir, Gudny;Rumley, Ann;Whincup, Peter H.;Lowe, Gordon D. O.;Gudnason, Vilmundur
通讯作者：
Gudnason, Vilmundur
DOI：
10.1016/j.bbi.2015.06.001
发表时间：
2015-10
期刊：
Brain, behavior, and immunity
影响因子：
--
作者：
Haapakoski R;Mathieu J;Ebmeier KP;Alenius H;Kivimäki M
通讯作者：
Kivimäki M
影响因子：
25.8
作者：
Khandaker GM;Pearson RM;Zammit S;Lewis G;Jones PB
通讯作者：
Jones PB
影响因子：
10.6
作者：
Dowlati, Yekta;Herrmann, Nathan;Lanctot, Krista L.
通讯作者：
Lanctot, Krista L.
影响因子：
3.4
作者：
Khandaker GM;Dantzer R
通讯作者：
Dantzer R