Study of the associations between short telomeres, sex hormones and pulmonary fibrosis
Study of the associations between short telomeres, sex hormones and pulmonary fibrosis
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DOI：
10.1101/2022.09.29.22280270
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发表时间：
2022-09
期刊：
影响因子：
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通讯作者：
A. Duckworth;K. Ruth;J. Prague;A. Russell;H. Almond;J. Conway;R. Beaumont;A. Wood;S. Martin;K. Lunnon;M. Lindsay;A. Murray;M. Gibbons;J. Tyrrell;C. Scotton
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作者：
A. Duckworth;K. Ruth;J. Prague;A. Russell;H. Almond;J. Conway;R. Beaumont;A. Wood;S. Martin;K. Lunnon;M. Lindsay;A. Murray;M. Gibbons;J. Tyrrell;C. Scotton
背景肺纤维化（PF）是一种无法治愈的纤维化肺部疾病，治疗选择有限，死亡率高。越来越多的证据表明，短端粒导致遗传性和特发性肺纤维化（IPF）。基于生存数据，我们假设性激素对端粒过早磨损具有保护作用，并可能影响PF疾病的发作和/或进展。方法对诊断为IPF的欧洲血统的无关英国生物样本库参与者（415名女性，718名男性）与对照组（204，321名女性，174，254名男性）进行IPF、性激素浓度和测量的白细胞端粒长度（LTL）之间的相关性检查。多基因风险评分用于探讨性激素指数、LTL和疾病之间的因果关系。结果IPF和LTL之间存在强相关性。对于女性，IPF发生率较高与绝经早期和卵巢早衰相关。绝经年龄与IPF诊断年龄和死亡年龄呈正相关。对于男性，IPF患病率和疾病分期与血清生物可利用睾酮浓度相关。对于两种性别，性激素浓度较低的证据与较短的LTL。遗传分析还推断了性激素结合球蛋白浓度（影响游离睾酮浓度）与男性LTL之间的双向因果关系。我们的研究结果表明，较高的性激素浓度可能通过减缓端粒缩短来防止IPF的发作和进展。补充激素可以延迟或预防端粒相关PF风险患者的疾病发作，并改善疾病预后。这需要在随机对照试验中进一步探索。
Background Pulmonary fibrosis (PF) is an incurable fibrotic lung disease with limited treatment options and a high mortality. Evidence is growing that short telomeres cause both heritable and idiopathic pulmonary fibrosis (IPF). Based on survival data, we hypothesised that sex hormones are protective against premature telomere attrition and could influence PF disease onset and/or progression. Methods Associations between IPF, sex hormone concentrations and measured leukocyte telomere length (LTL) were examined for unrelated UK Biobank participants of European ancestry with a diagnosis of IPF (415 females, 718 males) against controls (204,321 females, 174,254 males). Polygenic risk scores were used to explore causality between sex hormone indices, LTL and disease. Findings Strong associations were found between IPF and LTL. For females, higher odds of having IPF was associated with early menopause and premature ovarian failure. Menopause age correlated positively with both age of IPF diagnosis and age of death. For males, IPF prevalence and stages of disease were associated with serum bioavailable testosterone concentrations. For both sexes, evidence of lower concentrations of sex hormones was associated with shorter LTL. Genetic analysis also inferred bi-directional causal links between sex hormone binding globulin concentration, which impacts free testosterone concentration, and LTL in males. Interpretation Our findings suggest that higher sex hormone concentrations protect against IPF onset and progression, possibly by slowing telomere shortening. Hormonal supplementation may delay or prevent disease onset for those with telomere-associated PF risk and improve disease prognosis. This warrants further exploration in a randomised controlled trial.