Aims Wernicke–Korsakoff syndrome (WKS) is commonly associated with chronic alcohol misuse, a condition known to have multiple detrimental effects on thiamine metabolism. This study was conducted to identify genetic variants that may contribute to the development of WKS in individuals with alcohol dependence syndrome through alteration of thiamine transport into cells. Methods Exome sequencing data from a panel of genes related to alcohol metabolism and thiamine pathways were analysed in a discovery cohort of 29 individuals with WKS to identify possible genetic risk variants associated with its development. Variant frequencies in this discovery cohort were compared with European frequencies in the Genome Aggregation Database browser, and those present at significantly higher frequencies were genotyped in an additional cohort of 87 alcohol-dependent cases with WKS and 197 alcohol-dependent cognitively intact controls. Results Thirty non-synonymous variants were identified in the discovery cohort and, after filtering, 23 were taken forward and genotyped in the case–control cohort. Of these SLC19A1:rs1051266:G was nominally associated with WKS. SLC19A1 encodes the reduced folate carrier, a major transporter for physiological folate in plasma; rs1051266 is reported to impact folate transport. Thiamine pyrophosphate (TPP) efflux was significantly decreased in HEK293 cells, stably transfected with rs1051266:G, under thiamine deficient conditions when compared with the efflux from cells transfected with rs1051266:A (P = 5.7 × 10−11). Conclusion This study provides evidence for the role of genetic variation in the SLC19A1 gene, which may contribute to the development of WKS in vivo through modulation of TPP transport in cells.

中文翻译：

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SLC19A1 基因变异导致硫胺素二磷酸转运改变：对发生 Wernicke-Korsakoff 综合征风险的影响

目的 Wernicke-Korsakoff 综合征 (WKS) 通常与慢性酒精滥用有关，这种情况已知对硫胺素代谢有多种不利影响。本研究旨在通过改变硫胺素转运到细胞中来确定可能有助于酒精依赖综合征患者发生 WKS 的遗传变异。方法 在 29 名 WKS 患者的发现队列中分析了一组与酒精代谢和硫胺素途径相关的基因的外显子组测序数据，以确定与其发展相关的可能的遗传风险变异。将该发现队列中的变异频率与基因组聚合数据库浏览器中的欧洲频率进行了比较，并且那些以显着更高频率出现的人在另外一个队列中进行基因分型，该队列由 87 名酒精依赖的 WKS 病例和 197 名酒精依赖的认知完整对照病例组成。结果 在发现队列中鉴定出 30 个非同义变体，过滤后，在病例对照队列中对 23 个进行了基因分型。在这些 SLC19A1:rs1051266:G 中，名义上与 WKS 相关。SLC19A1 编码还原型叶酸载体，这是血浆中生理叶酸的主要转运蛋白；据报道 rs1051266 会影响叶酸转运。在硫胺素缺乏条件下，与用 rs1051266:A 转染的细胞的流出量相比，在用 rs1051266:G 稳定转染的 HEK293 细胞中，硫胺素焦磷酸 (TPP) 流出量显着降低（P = 5.7 × 10-11）。