遗传潜力和儿童及青少年时期的身高增长速度并不能完全解释囊性纤维化患者身材矮小的原因。

Genetic potential and height velocity during childhood and adolescence do not fully account for shorter stature in cystic fibrosis.

机构信息

Division of Pulmonary Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

出版信息

Pediatr Res. 2021 Feb;89(3):653-659. doi: 10.1038/s41390-020-0940-4. Epub 2020 May 9.

DOI:10.1038/s41390-020-0940-4

PMID:32386398

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7649126/

Abstract

BACKGROUND

Despite improved health, shorter stature is common in cystic fibrosis (CF). We aimed to describe height velocity (HV) and contribution of height-related genetic variants to height (HT) in CF.

METHODS

HV cohort: standard deviation scores (-Z) for HT, mid-parental height-adjusted HT (MPAH), and HV were generated using our Pediatric Center's CF Foundation registry data. HV-Z was compared with population means at each age (5-17 y), the relationship of HV-Z with HT-Z assessed, and HT-Z compared with MPAH-Z. GRS cohort: HT genetic risk-Z (HT-GRS-Z) were determined for pancreatic exocrine sufficient (PS) and insufficient (PI) youth and adults from our CF center and their relationships with HT-Z assessed.

RESULTS

HV cohort: average HV-Z was normal across ages in our cohort but was 1.5× lower (p < 0.01) for each SD decrease in HT-Z. MPAH-Z was lower than HT-Z (p < 0.001). GRS cohort: HT-GRS-Z more strongly correlated with HT-Z and better explained height variance in PS (rho = 0.42; R= 0.25) vs. PI (rho = 0.27; R = 0.11).

CONCLUSIONS

Despite shorter stature compared with peers and mid-parental height, youth with CF generally have normal linear growth in mid- and late childhood. PI tempered the heritability of height. These results suggest that, in CF, final height is determined early in life in CF and genetic potential is attenuated by other factors.

IMPACT

Children with CF remain shorter than their healthy peers despite advances in care. Our study demonstrates that children with CF have persistent shorter stature from an early age and fail to reach their genetic potential despite height velocities comparable to those of average maturing healthy peers and similar enrichment in known height increasing single-nucleotide polymorphisms (SNPs). Genetic risk scores better explained variability in pancreatic sufficient than in pancreatic insufficient individuals, suggesting that other modifying factors are in play for pancreatic insufficient individuals with CF. Given the CF Foundation's recommendation to target not only normal body mass index, but normal height percentiles as well, this study adds valuable insight to this discussion.

摘要

背景

尽管健康状况有所改善，但身材矮小在囊性纤维化（CF）中很常见。我们旨在描述 CF 中的身高速度（HV）和与身高相关的遗传变异对身高（HT）的贡献。

方法

HV 队列：使用我们的儿科中心 CF 基金会注册数据生成 HT、中亲身高调整后的 HT（MPAH）和 HV 的标准偏差分数（-Z）。在每个年龄（5-17 岁）比较 HV-Z 与人群平均值，评估 HV-Z 与 HT-Z 的关系，并比较 HT-Z 与 MPAH-Z。GRS 队列：从我们的 CF 中心确定胰腺外分泌充足（PS）和不足（PI）青少年和成年人的 HT 遗传风险-Z（HT-GRS-Z），并评估它们与 HT-Z 的关系。

结果

HV 队列：我们队列中各年龄段的平均 HV-Z 均正常，但 HT-Z 每降低一个标准差，HV-Z 就降低 1.5 倍（p<0.01）。MPAH-Z 低于 HT-Z（p<0.001）。GRS 队列：HT-GRS-Z 与 HT-Z 的相关性更强，并且在 PS 中更好地解释了身高变异（rho=0.42；R=0.25），而在 PI 中则相关性较弱（rho=0.27；R=0.11）。

结论

尽管与同龄人相比身材矮小，中亲身高也较低，但 CF 青少年在儿童中期和晚期通常具有正常的线性生长。PI 缓和了身高的遗传性。这些结果表明，在 CF 中，最终身高在 CF 生命早期就已确定，并且遗传潜力被其他因素削弱。

影响

尽管 CF 的治疗有了进步，但儿童 CF 患者仍然比健康同龄人矮小。我们的研究表明，CF 儿童从很小的时候就一直身材矮小，尽管 HV 与健康同龄人成熟的速度相当，并且已知增加身高的单核苷酸多态性（SNP）的富集程度相似，但他们未能达到遗传潜力。对于 CF 中胰腺功能不全的个体，遗传风险评分可以更好地解释个体间的变异性，这表明对于胰腺功能不全的个体，还有其他调节因素在起作用。鉴于 CF 基金会不仅建议针对正常体重指数，还建议针对正常身高百分位数，因此，这项研究为这一讨论提供了有价值的见解。