Analysis of protein-altering variants in telomerase genes and their association with MUC5B common variant status in patients with idiopathic pulmonary fibrosis: a candidate gene sequencing study.
Analysis of protein-altering variants in telomerase genes and their association with MUC5B common variant status in patients with idiopathic pulmonary fibrosis: a candidate gene sequencing study.
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分析特发性肺纤维化患者中端粒酶基因中蛋白质改变的变体及其与MUC5B共同变异状态的关联：候选基因测序研究。
DOI：
10.1016/s2213-2600(18)30135-8
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发表时间：
2018-08
期刊：
影响因子：
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通讯作者：
Yaspan BL
中科院分区：
文献类型：
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作者：
Dressen A;Abbas AR;Cabanski C;Reeder J;Ramalingam TR;Neighbors M;Bhangale TR;Brauer MJ;Hunkapiller J;Reeder J;Mukhyala K;Cuenco K;Tom J;Cowgill A;Vogel J;Forrest WF;Collard HR;Wolters PJ;Kropski JA;Lancaster LH;Blackwell TS;Arron JR;Yaspan BL
特发性肺纤维化（IPF）风险具有很强的遗传成分。研究表明，包括端粒酶逆转录酶（TERT），表面活性剂基因，和一个单核苷酸多态性（SNP）在chr 11 p15，rs35705950之间的基因间区域TOLLIP和MUC 5 B的几个位点的变化。具有rs35705950风险等位基因的IPF患者从IPF诊断时起的生存期长于非风险等位基因纯合子患者，而端粒较短的患者生存期较短。我们假设，在rs35705950处缺乏风险等位基因的IPF患者中，端粒长度调节基因中罕见的蛋白质改变变体富集。使用来自III期临床试验和观察性研究的1，510例散发性IPF患者的全基因组测序来评估端粒长度并鉴定罕见的蛋白质改变变体。我们通过rs35705950基因型对患者进行了分离，并评估了TERT外显子中罕见的功能变异，并将基因型与端粒长度和疾病进展率进行了比较。2.9%的rs35705950风险等位基因携带者携带一种罕见的蛋白质改变变体（RV），而非风险等位基因携带者为7.3%（比值比[OR] 0.40 [95%CI 0.24 - 0.66]，p= 3.99 × 10−4）。随后的分析确定了与非IPF对照相比，IPF患者中PARN、RTEL 1中罕见蛋白质改变变体的富集和TERC中罕见变异。总体而言，IPF患者在TERT、PARN、TERC或RTEL 1中至少存在一种罕见变异的频率高于其他临床试验中的非IPF患者（IPF患者为8.57%，其他患者为2.37%，p= 2.44 × 10−8）。在四个已确定的端粒酶组成基因中的任何一个中具有变异的患者比没有的患者（67 ± 1岁; p= 0.004）具有4 ± 78%-16 ± 10%的短端粒和更早的发病年龄（65 ± 1岁）。在临床试验的安慰剂组中，端粒较短的患者的肺功能下降速度更快（1 ~ 7% FVC/kb/年，p=0 ~ 0002）。尽管存在上述差异，但我们发现无论端粒长度状态如何，吡非尼酮均显示出治疗益处。与非IPF对照相比，IPF患者中TERT、PARN、TERC和RTEL 1的罕见蛋白质改变变体富集，并且在TERT的情况下，特别是在rs35705950位点不携带风险等位基因的患者中，表明散发性IPF存在多种遗传因素，可能涉及不同的发病机制和进展速率。NCT 00287716、NCT 01366209、NCT 00075998、NCT 01872689。
Idiopathic Pulmonary Fibrosis (IPF) risk has a strong genetic component. Studies have implicated variation at several loci, including telomerase reverse transcriptase (TERT), surfactant genes, and a single nucleotide polymorphism (SNP) at chr11p15, rs35705950 in the intergenic region between TOLLIP and MUC5B. IPF patients with risk alleles at rs35705950 have longer survival from the time of IPF diagnosis than patients homozygous for the non-risk allele, while patients with shorter telomeres have shorter survival times. We hypothesized that rare protein altering variants in genes regulating telomere length are enriched in IPF patients lacking risk alleles at rs35705950. Whole genome sequencing of 1,510 patients with sporadic IPF from phase 3 clinical trials and observational studies was used to assess telomere length and identify rare protein altering variants. We separated patients by rs35705950 genotype and assessed rare functional variation in TERT exons and compared genotypes to telomere length and rates of disease progression. 2⋅9% of patients with an rs35705950 risk allele carried a rare protein-altering variant (RV) in TERT compared to 7⋅3% of non-risk allele carriers (odds ratio [OR] 0⋅40 [95% CI 0⋅24-0⋅66], p=3⋅9 × 10−4). Subsequent analyses identified enrichment of rare protein-altering variants in PARN, RTEL1 and rare variation in TERC in IPF patients compared to non-IPF controls. In total, IPF patients harbored at least one rare variant in TERT, PARN, TERC or RTEL1 more frequently than non-IPF patients from other clinical trials (8⋅57% in IPF vs. 2⋅37% for others p=2⋅44 × 10−8). Patients with a variant in any of the four identified telomerase component genes had 4⋅78%-16⋅10% shorter telomeres and an earlier age of onset (65⋅1 years) than patients without (67⋅1 years; p=0⋅004). Patients with shorter telomeres had more rapid rates of lung function decline in the placebo arms of clinical trials (1⋅7% FVC/kb/year, p=0⋅002). Despite the aforementioned differences, we found pirfenidone demonstrated treatment benefit regardless of telomere length status. Rare protein-altering variants in TERT, PARN, TERC and RTEL1 are enriched in IPF patients compared to non-IPF controls, and, in the case of TERT, particularly in those not carrying a risk allele at the rs35705950 locus, suggesting that there are multiple genetic factors underlying sporadic IPF that may implicate distinct mechanisms of pathogenesis and rates of progression. NCT00287716, NCT01366209, NCT00075998, NCT01872689.