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首页> 外文期刊>Journal of Alzheimer's disease: JAD >Genetic Influences on Plasma Homocysteine Levels in African Americans and Yoruba Nigerians
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Genetic Influences on Plasma Homocysteine Levels in African Americans and Yoruba Nigerians

机译:遗传因素对非洲裔美国人和尼日利亚约鲁巴人血浆同型半胱氨酸水平的影响

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Plasma homocysteine, a metabolite involved in key cellular methylation processes seems to be implicated in cognitive functions and cardiovascular health with its high levels representing a potential modifiable risk factor for Alzheimer's disease (AD) and other dementias. A better understanding of the genetic factors regulating homocysteine levels, particularly in non-white populations, may help in risk stratification analyses of existing clinical trials and may point to novel targets for homocysteine-lowering therapy. To identify genetic influences on plasma homocysteine levels in individuals with African ancestry, we performed a targeted gene and pathway-based analysis using a priori biological information and then to identify new association performed a genome-wide association study. All analyses used combined data from the African American and Yoruba cohorts from the Indianapolis-Ibadan Dementia Project. Targeted analyses demonstrated significant associations of homocysteine and variants within the CBS (Cystathionine beta-Synthase) gene. We identified a novel genome-wide significant association of the AD risk gene CD2AP (CD2-associated protein) with plasma homocysteine levels in both cohorts. Minor allele (T) carriers of identified CD2AP variant (rs6940729) exhibited decreased homocysteine level. Pathway enrichment analysis identified several interesting pathways including the GABA receptor activation pathway. This is noteworthy given the known antagonistic effect of homocysteine on GABA receptors. These findings identify several new targets warranting further investigation in relation to the role of homocysteine in neurodegeneration.
机译:血浆高半胱氨酸是参与关键细胞甲基化过程的代谢产物,似乎与认知功能和心血管健康有关,其高水平代表阿尔茨海默氏病(AD)和其他痴呆症的潜在可修正危险因素。更好地了解调节同型半胱氨酸水平的遗传因素,尤其是在非白人人群中,可能有助于对现有临床试验进行风险分层分析,并可能为降低同型半胱氨酸治疗提供新的靶点。为了确定遗传对非洲血统个体血浆同型半胱氨酸水平的影响,我们使用先验生物学信息进行了针对性的基因和基于途径的分析,然后确定新的关联进行了全基因组关联研究。所有分析均使用来自印第安纳波利斯-伊巴丹痴呆症项目的非裔美国人和约鲁巴人队列的组合数据。有针对性的分析表明高半胱氨酸和CBS(胱氨酸硫代β-合酶)基因中的变体之间的显着关联。我们确定了这两个队列中AD风险基因CD2AP(CD2相关蛋白)与血浆同型半胱氨酸水平的新型全基因组显着关联。鉴定出的CD2AP变体(rs6940729)的次要等位基因(T)携带者的同型半胱氨酸水平降低。途径富集分析确定了几种有趣的途径,包括GABA受体激活途径。鉴于同型半胱氨酸对GABA受体的已知拮抗作用,这一点值得注意。这些发现确定了几个新的靶标,需要就高半胱氨酸在神经变性中的作用进行进一步研究。

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