Purpose

Phenylketonuria (PKU) can be effectively treated with the use of a low-phenylalanine diet. However, some patients become overweight despite proper dietary treatment. We hypothesized that this phenomenon could be explained by the presence of specific variants within the genes involved in phenylalanine transport or in the phenylalanine transamination/oxygenation pathway.

Methods

We selected a clinically homogenous group of 100 infants with PKU and assessed their growth patterns in the context of dietary phenylalanine tolerance. Next, within the sample, we performed exome sequencing and assessed a potential relationship between the observed phenotypical variability and the presence of structural variants in a priori selected genes of interest.

Results

We detected a highly significant association between overweight and carriership of the rs113883650/rs2287120 haplotype of the SLC7A5 (LAT1) gene, which encodes the main transmembrane transporter of large neutral amino acids and of thyroid hormones.

Conclusions

Our findings suggest a pharmacogenetic effect of the relatively common rs113883650/rs2287120 haplotype of the SLC7A5 gene. This can have practical implications for patients with PKU, since treatment protocols need to be reassessed to better prevent overweight in the carriers of the above variant.

中文翻译：

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携带 SLC7A5 (LAT1) 基因的 rs113883650/rs2287120 单倍型会增加苯丙酮尿症婴儿肥胖的风险。

目的

使用低苯丙氨酸饮食可以有效治疗苯丙酮尿症 (PKU)。然而，尽管进行了适当的饮食治疗，一些患者仍会超重。我们假设这种现象可以通过参与苯丙氨酸转运或苯丙氨酸转氨/氧化途径的基因内存在特定变体来解释。

方法

我们选择了一组临床同质的 100 名 PKU 婴儿，并在饮食苯丙氨酸耐受性的背景下评估了他们的生长模式。接下来，在样本中，我们进行了外显子组测序，并评估了观察到的表型变异性与先验选择的感兴趣基因中结构变异的存在之间的潜在关系。

结果

我们检测到超重与SLC7A5 ( LAT1 ) 基因的 rs113883650/rs2287120 单倍型的携带之间存在高度显着的关联，该基因编码大中性氨基酸和甲状腺激素的主要跨膜转运蛋白。

结论

我们的研究结果表明SLC7A5基因的相对常见的 rs113883650/rs2287120 单倍型具有药物遗传学作用。这对 PKU 患者可能具有实际意义，因为需要重新评估治疗方案以更好地防止上述变异携带者的超重。