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- Title
A Genome-Wide Pharmacogenetic Study of Growth Hormone Responsiveness.
- Authors
Dauber, Andrew; Yan Meng; Audi, Laura; Vedantam, Sailaja; Weaver, Benjamin; Carrascosa, Antonio; Albertsson-Wikland, Kerstin; Ranke, Michael B.; Jorge, Alexander A. L.; Cara, Jose; Wajnrajch, Michael P.; Lindberg, Anders; Camacho-Hübner, Cecilia; Hirschhorn, Joel N.; Meng, Yan
- Abstract
<bold>Context: </bold>Individual patients vary in their response to growth hormone (GH). No large-scale genome-wide studies have looked for genetic predictors of GH responsiveness.<bold>Objective: </bold>To identify genetic variants associated with GH responsiveness.<bold>Design: </bold>Genome-wide association study (GWAS).<bold>Setting: </bold>Cohorts from multiple academic centers and a clinical trial.<bold>Patients: </bold>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.<bold>Intervention: </bold>Association of more than 2 million variants was tested.<bold>Main Outcome Measures: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Subjects
SOMATOTROPIN; PITUITARY dwarfism; TRANSFORMING growth factors-beta; SOMATOMEDIN; STATURE; RESEARCH; MOLECULAR chaperones; SEQUENCE analysis; RESEARCH methodology; GENETIC polymorphisms; EVALUATION research; MEDICAL cooperation; HUMAN growth hormone; TREATMENT effectiveness; COMPARATIVE studies; GENOMES; TRANSFERASES; DWARFISM; SMALL for gestational age; LONGITUDINAL method
- Publication
Journal of Clinical Endocrinology & Metabolism, 2020, Vol 105, Issue 10, p1
- ISSN
0021-972X
- Publication type
journal article
- DOI
10.1210/clinem/dgaa443