Abstract：
BACKGROUND: Pseudoxanthoma elasticum (PXE), a monogenic disorder resulting in calcification affecting the skin, eyes and peripheral arteries, is caused by mutations in the ABCC6 gene, and is associated with low plasma inorganic pyrophosphate (PPi). It is unknown how ABCC6 genotype affects plasma PPi.
METHODS: We studied the association of ABCC6 genotype (192 patients with biallelic pathogenic ABCC6 mutations) and PPi levels, and its association with the severity of arterial and ophthalmological phenotypes. ABCC6 variants were classified as truncating or non-truncating, and three groups of the 192 patients were formed: those with truncating mutations on both chromosomes (n = 121), those with two non-truncating mutations (n = 10), and a group who had one truncating and one non-truncating ABCC6 mutation (n = 61). The hypothesis formulated before this study was that there was a negative association between PPi level and disease severity.
RESULTS: Our findings confirm low PPi in PXE compared with healthy controls (0.53 ± 0.15 vs. 1.13 ± 0.29 µM, p < 0.01). The PPi of patients correlated with increasing age (β: 0.05 µM, 95% CI: 0.03-0.06 per 10 years) and was higher in females (0.55 ± 0.17 vs. 0.51 ± 0.13 µM in males, p = 0.03). However, no association between PPi and PXE phenotypes was found. When adjusted for age and sex, no association between PPi and ABCC6 genotype was found.
CONCLUSIONS: Our data suggest that the relationship between ABCC6 mutations and reduced plasma PPi may not be as direct as previously thought. PPi levels varied widely, even in patients with the same ABCC6 mutations, further suggesting a lack of direct correlation between them, even though the ABCC6 protein-mediated pathway is responsible for ~60% of this metabolite in the circulation. We discuss potential factors that may perturb the expected associations between ABCC6 genotype and PPi and between PPi and disease severity. Our findings support the argument that predictions of pathogenicity made on the basis of mutations (or on the structure of the mutated protein) could be misleading.
METHODS: We studied the association of ABCC6 genotype (192 patients with biallelic pathogenic ABCC6 mutations) and PPi levels, and its association with the severity of arterial and ophthalmological phenotypes. ABCC6 variants were classified as truncating or non-truncating, and three groups of the 192 patients were formed: those with truncating mutations on both chromosomes (n = 121), those with two non-truncating mutations (n = 10), and a group who had one truncating and one non-truncating ABCC6 mutation (n = 61). The hypothesis formulated before this study was that there was a negative association between PPi level and disease severity.
RESULTS: Our findings confirm low PPi in PXE compared with healthy controls (0.53 ± 0.15 vs. 1.13 ± 0.29 µM, p < 0.01). The PPi of patients correlated with increasing age (β: 0.05 µM, 95% CI: 0.03-0.06 per 10 years) and was higher in females (0.55 ± 0.17 vs. 0.51 ± 0.13 µM in males, p = 0.03). However, no association between PPi and PXE phenotypes was found. When adjusted for age and sex, no association between PPi and ABCC6 genotype was found.
CONCLUSIONS: Our data suggest that the relationship between ABCC6 mutations and reduced plasma PPi may not be as direct as previously thought. PPi levels varied widely, even in patients with the same ABCC6 mutations, further suggesting a lack of direct correlation between them, even though the ABCC6 protein-mediated pathway is responsible for ~60% of this metabolite in the circulation. We discuss potential factors that may perturb the expected associations between ABCC6 genotype and PPi and between PPi and disease severity. Our findings support the argument that predictions of pathogenicity made on the basis of mutations (or on the structure of the mutated protein) could be misleading.
摘要：
背景：弹性假性黄瘤（PXE），导致钙化影响皮肤的单基因疾病，眼睛和外周动脉，是由ABCC6基因突变引起的,并与低血浆无机焦磷酸盐（PPi）有关。目前尚不清楚ABCC6基因型如何影响血浆PPi。
方法：我们研究了ABCC6基因型（192例具有双等位基因致病性ABCC6突变的患者）与PPi水平的关联，及其与动脉和眼科表型严重程度的关系。ABCC6变体分为截短或非截短，192例患者中形成了三组：两条染色体上都有截断突变的患者（n=121），那些有两个非截断突变（n=10），和一组有一个截短和一个非截短的ABCC6突变（n=61）。在这项研究之前提出的假设是PPi水平与疾病严重程度之间存在负相关。
结果：我们的发现证实，与健康对照组相比，PXE的PPi较低（0.53±0.15vs.1.13±0.29µM，p<0.01)。患者的PPi与年龄增长相关(β：0.05µM，95％CI：每10年0.03-0.06），女性更高（0.55±0.17vs.男性为0.51±0.13µM，p=0.03)。然而,未发现PPi和PXE表型之间存在关联.当调整年龄和性别时，未发现PPi和ABCC6基因型之间存在关联.
结论：我们的数据表明，ABCC6突变与血浆PPi降低之间的关系可能不像以前认为的那么直接。PPI水平差异很大，即使在具有相同ABCC6突变的患者中，进一步表明它们之间缺乏直接的相关性，即使ABCC6蛋白介导的途径负责约60％的这种代谢物在循环中。我们讨论了可能扰乱ABCC6基因型与PPi之间以及PPi与疾病严重程度之间预期关联的潜在因素。我们的发现支持这样的论点，即基于突变（或突变蛋白的结构）做出的致病性预测可能会产生误导。
方法：我们研究了ABCC6基因型（192例具有双等位基因致病性ABCC6突变的患者）与PPi水平的关联，及其与动脉和眼科表型严重程度的关系。ABCC6变体分为截短或非截短，192例患者中形成了三组：两条染色体上都有截断突变的患者（n=121），那些有两个非截断突变（n=10），和一组有一个截短和一个非截短的ABCC6突变（n=61）。在这项研究之前提出的假设是PPi水平与疾病严重程度之间存在负相关。
结果：我们的发现证实，与健康对照组相比，PXE的PPi较低（0.53±0.15vs.1.13±0.29µM，p<0.01)。患者的PPi与年龄增长相关(β：0.05µM，95％CI：每10年0.03-0.06），女性更高（0.55±0.17vs.男性为0.51±0.13µM，p=0.03)。然而,未发现PPi和PXE表型之间存在关联.当调整年龄和性别时，未发现PPi和ABCC6基因型之间存在关联.
结论：我们的数据表明，ABCC6突变与血浆PPi降低之间的关系可能不像以前认为的那么直接。PPI水平差异很大，即使在具有相同ABCC6突变的患者中，进一步表明它们之间缺乏直接的相关性，即使ABCC6蛋白介导的途径负责约60％的这种代谢物在循环中。我们讨论了可能扰乱ABCC6基因型与PPi之间以及PPi与疾病严重程度之间预期关联的潜在因素。我们的发现支持这样的论点，即基于突变（或突变蛋白的结构）做出的致病性预测可能会产生误导。
