Division of Endocrinology, Children's National Hospital, Washington, DC.
Division of Endocrinology, Boston Children's Hospital, and Program in Medical and Population Genetics, Broad Institute, Harvard Medical School, Boston, Massachusetts.
J Clin Endocrinol Metab. 2020 Oct 1;105(10):3203-14. doi: 10.1210/clinem/dgaa443.
Individual patients vary in their response to growth hormone (GH). No large-scale genome-wide studies have looked for genetic predictors of GH responsiveness.
To identify genetic variants associated with GH responsiveness.
Genome-wide association study (GWAS).
Cohorts from multiple academic centers and a clinical trial.
A total of 614 individuals from 5 short stature cohorts receiving GH: 297 with idiopathic short stature, 276 with isolated GH deficiency, and 65 born small for gestational age.
Association of more than 2 million variants was tested.
Primary analysis: individual single nucleotide polymorphism (SNP) association with first-year change in height standard deviation scores. Secondary analyses: SNP associations in clinical subgroups adjusted for clinical variables; association of polygenic score calculated from 697 genome-wide significant height SNPs with GH responsiveness.
No common variant associations reached genome-wide significance in the primary analysis. The strongest suggestive signals were found near the B4GALT4 and TBCE genes. After meta-analysis including replication data, signals at several loci reached or retained genome-wide significance in secondary analyses, including variants near ST3GAL6. There was no significant association with variants previously reported to be associated with GH response nor with a polygenic predicted height score.
We performed the largest GWAS of GH responsiveness to date. We identified 2 loci with a suggestive effect on GH responsiveness in our primary analysis and several genome-wide significant associations in secondary analyses that require further replication. Our results are consistent with a polygenic component to GH responsiveness, likely distinct from the genetic regulators of adult height.
个体患者对生长激素（GH）的反应存在差异。目前还没有大规模的全基因组研究寻找 GH 反应的遗传预测因子。
确定与 GH 反应性相关的遗传变异。
全基因组关联研究（GWAS）。
来自多个学术中心和临床试验的队列。
共纳入 614 名接受 GH 治疗的身材矮小患者：297 名特发性身材矮小，276 名孤立性 GH 缺乏症，65 名出生时小于胎龄。
检测了超过 200 万个变体的关联。
主要分析：个体单核苷酸多态性（SNP）与第一年身高标准差评分变化的关联。次要分析：调整临床变量后，临床亚组中 SNP 的关联；从 697 个全基因组显著身高 SNP 计算的多基因评分与 GH 反应性的关联。
在主要分析中，没有常见变异与全基因组显著相关。在 B4GALT4 和 TBCE 基因附近发现了最强的提示信号。包括复制数据的荟萃分析后，在次要分析中，包括 ST3GAL6 附近的几个位点的信号达到或保留了全基因组的显著性，包括附近的变体。与先前报道与 GH 反应相关的变体或与多基因预测身高评分无显著关联。
我们进行了迄今为止最大规模的 GH 反应性 GWAS。我们在主要分析中确定了 2 个与 GH 反应性有提示作用的位点，在次要分析中确定了几个全基因组显著相关的位点，这些结果需要进一步复制。我们的结果与 GH 反应的多基因成分一致，可能与成人身高的遗传调节因子不同。
