西班牙一个先证者突变人群中急性间歇性血卟啉症的高外显率和 CYP2D6 基因型作为一个易感性因素。
High penetrance of acute intermittent porphyria in a Spanish founder mutation population and CYP2D6 genotype as a susceptibility factor.
机构信息
Cátedra de Genética (Pabellón 9), Facultad de Ciencias de la Salud, Universidad Católica de Murcia (UCAM), Avda. Los Jerónimos s/n, CP 30107, Guadalupe, Murcia, Spain.
Servicio de Neurología, Hospital Comarcal del Noroeste, Caravaca, Murcia, Spain.
出版信息
Orphanet J Rare Dis. 2019 Feb 26;14(1):59. doi: 10.1186/s13023-019-1031-7.
BACKGROUND
Acute intermittent porphyria (AIP) is a low-penetrant genetic metabolic disease caused by a deficiency of hydroxymethylbilane synthase (HMBS) in the haem biosynthesis. Manifest AIP (MAIP) is considered when carriers develop typical acute neurovisceral attacks with elevation of porphyrin precursors, while the absence of attacks is referred to as latent AIP (LAIP). Attacks are often triggered by drugs, endocrine factors, fasting or stress. Although AIP penetrance is traditionally considered to be around 10-20%, it has been estimated to be below 1% in general population studies and a higher figure has been found in specific AIP populations. Genetic susceptibility factors underlying penetrance are still unknown. Drug-metabolizing cytochrome P450 enzymes (CYP) are polymorphic haem-dependent proteins which play a role in haem demand, so they might modulate the occurrence of AIP attacks. Our aim was to determine the prevalence and penetrance of AIP in our population and analyse the main hepatic CYP genes to assess their association with acute attacks. For this, CYP2C92, 3; CYP2C192; CYP2D64, 5; CYP3A41B and CYP3A5*3 defective alleles were genotyped in fifty AIP carriers from the Region of Murcia, a Spanish population with a high frequency of the HMBS founder mutation c.669_698del30.
RESULTS
AIP penetrance was 52%, and prevalence was estimated as 17.7 cases/million inhabitants. The frequency of defective CYP2D6 alleles was 3.5 times higher in LAIP than in MAIP. MAIP was less frequent among CYP2D6*4 and *5 carriers (p < 0.05). The urine porphobilinogen (PBG)-to-creatinine ratio was lower in these individuals, although it was associated with a lower prevalence of attacks (p < 0.05) rather than with the CYP2D6 genotype.
CONCLUSIONS
AIP prevalence in our region is almost 3 times higher than that estimated for the rest of Spain. The penetrance was high, and similar to other founder mutation AIP populations. This is very relevant for genetic counselling and effective health care. CYP2D6*4 and *5 alleles may be protective factors for acute attacks, and CYP2D6 may constitute a penetrance-modifying gene. Further studies are needed to confirm these findings, which would allow a further progress in clinical risk profile assessment based on the CYP genotype, leading to predictive personalized medicine for each AIP carrier in the future.
背景
急性间歇性卟啉症（AIP）是一种低外显率的遗传性代谢疾病，由血红素生物合成中羟甲基胆素合酶（HMBS）缺乏引起。有症状的 AIP（MAIP）被认为是当携带者出现典型的急性神经内脏发作并伴有卟啉前体升高时，而无发作则称为潜伏性 AIP（LAIP）。发作通常由药物、内分泌因素、禁食或应激引发。尽管 AIP 的外显率传统上被认为在 10-20%左右，但在一般人群研究中估计不到 1%，在特定的 AIP 人群中发现的外显率更高。导致外显率的遗传易感性因素仍不清楚。药物代谢细胞色素 P450 酶（CYP）是多态性血红素依赖性蛋白，在血红素需求中起作用，因此它们可能调节 AIP 发作的发生。我们的目的是确定我们人群中 AIP 的患病率和外显率，并分析主要的肝 CYP 基因，以评估它们与急性发作的关系。为此，在来自西班牙穆尔西亚地区的 50 名 AIP 携带者中检测了 CYP2C92、3；CYP2C192；CYP2D64、5；CYP3A41B 和 CYP3A5*3 缺陷等位基因，该人群中 HMBS 启动子突变 c.669_698del30 的频率很高。
结果
AIP 的外显率为 52%，患病率估计为每百万居民 17.7 例。LAIP 中 CYP2D6 缺陷等位基因的频率比 MAIP 高 3 倍。MAIP 在 CYP2D64 和5 携带者中较少见（p<0.05）。这些个体的尿卟胆原（PBG）-肌酐比值较低，尽管它与发作频率较低有关（p<0.05），而与 CYP2D6 基因型无关。
结论
我们地区的 AIP 患病率几乎是西班牙其他地区估计值的 3 倍。外显率高，与其他启动子突变 AIP 人群相似。这对于遗传咨询和有效的医疗保健非常重要。CYP2D64 和5 等位基因可能是急性发作的保护因素，CYP2D6 可能是外显率修饰基因。需要进一步研究来证实这些发现，这将允许根据 CYP 基因型进一步评估临床风险概况，从而为未来的每个 AIP 携带者提供预测性个体化医学。
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