Association of a long-chain fatty acid-CoA ligase 4 gene polymorphism with depression and with enhanced niacin-induced dermal erythema
Association of a long-chain fatty acid-CoA ligase 4 gene polymorphism with depression and with enhanced niacin-induced dermal erythema
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DOI：
10.1002/ajmg.b.20156
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发表时间：
2004-05-15
影响因子：
2.8
通讯作者：
Kranzler, HR
中科院分区：
文献类型：
--
作者：
Covault, J;Pettinati, H;Kranzler, HR
关于膜脂质变化与精神疾病之间关系的假设主要集中在三种长链多不饱和脂肪酸：花生四烯酸（AA），二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）。这些脂肪酸的膜缺陷已被报道在精神分裂症（AA，EPA和DHA）和抑郁症（EPA和DHA）。长链脂肪酸-CoA连接酶4型（FACL 4; MIM 300157）是参与AA、EPA和DHA代谢的关键酶。FACL 4用辅酶A选择性地使这些脂肪酸变性，形成酰基-co-A，然后可以将其掺入膜磷脂中。我们使用烟酸诱导的皮肤红斑作为AA代谢的一个指标，以确定FACL 4基因（Xq22.3）第一内含子中常见的C到T单核苷酸多态性（SNP），这与精神分裂症和对照组的皮肤红斑增强有关。TO基因型的男性受试者表现出更大的皮肤红斑后，局部应用甲基烟酸，这表明，这种多态性可能是在连锁不平衡与FACL 4基因的功能多态性，调节激动剂释放游离AA的再隔离。我们还检查了这种多态性的等位基因频率。555名欧洲裔美国人（EA），包括229名对照组，198名抑郁症患者，58名精神分裂症或情感障碍患者，70名无共病精神疾病的酒精依赖患者。我们观察到，与对照组相比，抑郁症患者的T等位基因显著过量（49% vs. 38%; P = 0.003），精神分裂症患者的T等位基因不显著过量（44%; P = 0.29）。酒精依赖受试者的等位基因频率与对照组没有差异。(C)2004 Wiley-Liss，Inc.
Hypotheses about relationships between changes in membrane lipids and mental illness have focused primarily on three long-chain polyunsaturated fatty acids: arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Membrane deficiencies of these fatty acids have been reported in schizophrenia (AA, EPA, and DHA) and in depression (EPA and DHA). Long-chain fatty acid-CoA ligase type 4 (FACL4; MIM 300157) is a key enzyme involved in the metabolism of AA, EPA, and DHA. FACL4 selectively esterifies these fatty acids with co-enzyme A, forming acyl-co-A, which can then be incorporated into membrane phospholipid. We used niacin-induced dermal erythema as one index of AA metabolism to identify a common C to T single nucleotide polymorphism (SNP) in the first intron of the FACL4 gene (Xq22.3), which is associated with enhanced dermal erythema in both schizophrenia and control subjects. Male subjects with the TO genotype showed greater dermal erythema following topical application of methylnicotinate, suggesting that this polymorphism may be in linkage disequilibrium with a functional polymorphism of the FACL4 gene that modulates re-sequestration of agonist-released free AA. We also examined the allele frequency of this polymorphism. in 555 European-Americans (EA), including 229 control subjects, 198 subjects with major depression, 58 with schizophrenia or schizoaffective disorder, and 70 with alcohol dependence without co-morbid psychiatric illness. We observed a significant excess of the T allele in subjects with major depression, as compared with controls (49% vs. 38%; P = 0.003) and a non-significant excess of the T allele in schizophrenia (44%; P = 0.29). The allele frequency for subjects with alcohol dependence did not differ from controls. (C) 2004 Wiley-Liss, Inc.