一种变异对囊性纤维化纯合子患者临床疾病表型的影响。
Impact of a Variant on Clinical Disease Phenotype in Homozygous Patients With Cystic Fibrosis.
作者信息
Horn Tabea, Ludwig Michael, Eickmeier Olaf, Neerinex Anne H, Maitland-van der Zee Anke H, Smaczny Christina, Wagner Thomas O F, Schubert Ralf, Zielen Stefan, Majoor Christof, Bos Lieuwe D, Schmitt-Grohé Sabina
机构信息
Abt. Allgemeine Pädiatrie, Zentrum für Kinderheilkunde des Universitätsklinikums Bonn, Bonn, Germany.
Institut für Klinische Chemie und Klinische Pharmakologie des Universitätsklinikums Bonn, Bonn, Germany.
出版信息
Front Genet. 2020 Oct 28;11:570403. doi: 10.3389/fgene.2020.570403. eCollection 2020.
BACKGROUND
Lung disease phenotype varies widely even in the (homozygous) genotype. Leukocyte-driven inflammation is important for pulmonary disease pathogenesis in cystic fibrosis (CF). Blood cytokines correlate negatively with pulmonary function homozygous patients, and gap junction proteins (GJA) might be related to the influx of blood cells into the lung and influence disease course. We aimed to assess the relationship between genotypes and the clinical disease phenotype.
METHODS
One-hundred-and-sixteen homozygous patients (mean age 27 years, m/f 66/50) were recruited from the CF centers of Bonn, Frankfurt, and Amsterdam. Sequence analysis was performed for and . The clinical disease course was assessed over 3 years using pulmonary function tests, body mass index, colonization, diabetes mellitus, survival to end-stage lung disease, blood and sputum inflammatory markers.
RESULTS
Sequence analysis revealed one clinically relevant single nucleotide polymorphism. In this variant (rs41266431), homozygous G variant carriers ( = 84/116; 72.4%) had poorer pulmonary function (FVC% pred: mean 78/86, < 0.040) and survival to end-stage lung disease was lower ( < 0.029). The frequency of colonization was not influenced by the genotype, but in those chronically colonized, those with the G/G genotype had reduced pulmonary function (FVC% pred: mean 67/80, < 0.049). Serum interleukin-8 (median: 12.4/6.7 pg/ml, < 0.052) and sputum leukocytes (2305/437.5 pg/ml, < 0.025) were higher for the G/G genotype.
CONCLUSIONS
In carriers of the A allele (27.6%) the variant is associated with significantly better protection against end-stage lung disease and superior pulmonary function test results in homozygous patients. This SNP has the potential of a modifier gene for phenotyping severity of CF lung disease, in addition to the genotype.
CLINICAL TRIAL REGISTRATION
The study was registered with ClinicalTrials.gov, number NCT04242420, retrospectively on January 24th, 2020.
背景
即使在（纯合子）基因型中，肺部疾病表型也存在很大差异。白细胞驱动的炎症在囊性纤维化（CF）的肺部疾病发病机制中起重要作用。在纯合子患者中，血液细胞因子与肺功能呈负相关，而间隙连接蛋白（GJA）可能与血细胞流入肺部有关，并影响疾病进程。我们旨在评估基因型与临床疾病表型之间的关系。
方法
从波恩、法兰克福和阿姆斯特丹的CF中心招募了116名纯合子患者（平均年龄27岁，男/女66/50）。对[基因名称]和[基因名称]进行序列分析。使用肺功能测试、体重指数、[细菌名称]定植、糖尿病、终末期肺病生存率、血液和痰液炎症标志物对临床疾病进程进行了3年的评估。
结果
序列分析揭示了一个具有临床相关性的单核苷酸多态性。在这个[基因名称]变体（rs41266431）中，纯合G变体携带者（n = 84/116；72.4%）的肺功能较差（预测FVC%：平均78/86，P < 0.040），终末期肺病的生存率较低（P < 0.029）。[细菌名称]定植频率不受基因型影响，但在那些长期定植的患者中，G/G基因型患者的肺功能降低（预测FVC%：平均67/80，P < 0.049）。G/G基因型的血清白细胞介素-8（中位数：12.4/6.7 pg/ml，P < 0.052）和痰液白细胞（2305/437.5 pg/ml，P < 0.025）较高。
结论
在A等位基因携带者（27.6%）中，[基因名称]变体与纯合子患者终末期肺病的显著更好保护和更好的肺功能测试结果相关。除了[主要基因名称]基因型外，这个单核苷酸多态性有潜力作为CF肺病表型严重程度的修饰基因。
临床试验注册
该研究于2020年1月24日追溯性地在ClinicalTrials.gov上注册，编号为NCT04242420。
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