From the Department of Clinical Sciences, Lund University, Malmö, Sweden.
Department of Internal Medicine, Skåne University Hospital, 205 02, Malmö, SE, Sweden.
BMC Genomics. 2017 Oct 24;18(1):822. doi: 10.1186/s12864-017-4219-z.
Higher fasting Growth Hormone (GH) has been associated with increased cardiovascular morbidity and mortality. Our objective was to find genetic determinants of fasting GH in order to facilitate future efforts of analyzing the association between fasting growth hormone and cardiovascular disease. A genome-wide association study (GWAS) was performed in a discovery cohort of 4134 persons (58% females; age 46-68 yrs), linking SNPs to fasting hs-GH. Fifteen SNPs were replicated in an independent cohort of 5262 persons (28.9% females; age 56-85 yrs). The best performing SNP was analyzed vs GH-related variables in a third independent cohort (n = 24,047; 61% females; age 44-73 yrs). A candidate gene approach searched for significant SNPs in the genes GH1 and GHR in the discovery cohort and was replicated as previously described.
In the GWAS, the minor allele of rs7208736 was associated with lower GH in the discovery cohort (p = 5.15*10^-6) and the replication cohort (p = 0.005). The GH reducing allele was associated with lower BMI (P = 0.026) and waist (P = 0.021) in males only. In the candidate gene approach rs13153388 in the GHR-gene was associated with elevated GH-levels (P = 0.003) in the discovery cohort only and reduced height (P = 0.003).
In the first GWAS ever for GH, we identify a novel locus on chromosome 17 associated with fasting GH levels, suggesting novel biological mechanisms behind GH secretion and GH-related traits. The candidate gene approach identified a genetic variant in the GHR, which was associated with an elevation of fasting hs-GH and lower height suggesting reduced GHR ligand sensitivity. Our findings need further replication.
较高的空腹生长激素（GH）与心血管发病率和死亡率的增加有关。我们的目的是找到空腹 GH 的遗传决定因素，以便于未来分析空腹生长激素与心血管疾病之间的关系。在一个包含 4134 人的发现队列中进行了全基因组关联研究（GWAS），将 SNPs 与空腹 hs-GH 联系起来。在一个包含 5262 人的独立队列中对 15 个 SNPs 进行了复制（女性占 28.9%；年龄 56-85 岁）。在第三个独立队列（n=24047；女性占 61%；年龄 44-73 岁）中，对表现最好的 SNP 进行了与 GH 相关变量的分析。在发现队列中采用候选基因方法在 GH1 和 GHR 基因中搜索显著的 SNPs，并按之前的描述进行了复制。
在 GWAS 中，rs7208736 的次要等位基因与发现队列中 GH 降低相关（p=5.15*10^-6）和复制队列（p=0.005）。只有男性中，GH 降低等位基因与较低的 BMI（P=0.026）和腰围（P=0.021）相关。在候选基因方法中，仅在发现队列中，GHR 基因中的 rs13153388 与 GH 水平升高（P=0.003）相关，与身高降低（P=0.003）相关。
在首次针对 GH 的全基因组关联研究中，我们确定了一个与空腹 GH 水平相关的 17 号染色体上的新位点，提示 GH 分泌和 GH 相关特征背后存在新的生物学机制。候选基因方法在 GHR 中发现了一个与空腹 hs-GH 升高和身高降低相关的遗传变异，提示 GHR 配体敏感性降低。我们的发现需要进一步复制。
