Vartiainen Johanna, Kesäniemi Y Antero, Ukkola Olavi
Department of Internal Medicine and Biocenter Oulu, University of Oulu, P.O. Box 5000, 90014 Oulu, Finland.
Metabolism. 2006 Oct;55(10):1420-5. doi: 10.1016/j.metabol.2006.06.014.
Ghrelin is a 28-amino-acid peptide with several functions linked to energy metabolism. Low ghrelin plasma concentrations are associated with obesity, hypertension, and type 2 diabetes mellitus, whereas high concentrations reflect states of negative energy balance. Several studies addressing the hormonal and neural regulation of ghrelin gene expression have been carried out, but the role of genetic factors in the regulation of ghrelin plasma levels remains unclear. To elucidate the role of genetic factors in the regulation of ghrelin expression, we screened 1657 nucleotides of the ghrelin gene 5' flanking region (promoter and possible regulatory sites) for new sequential variations from patient samples with low (n = 50) and high (n = 50) fasting plasma total ghrelin concentrations (low- and high-ghrelin groups). Eleven single nucleotide polymorphisms (SNPs), 3 of which were rare variants (allelic frequency less than 1%) were found in our population. The genotype distribution patterns of the SNPs did not differ between the study groups, except for SNP-501A>C (P = .039). In addition, the SNP-01A>C was associated with body mass index (BMI) (P = .018). This variant was studied further in our large and well-defined Oulu Project Elucidating Risk for Atherosclerosis (OPERA) cohort (n = 1045) by the restriction fragment length polymorphism (RFLP) technique. No significant association of SNP-501A>C genotypes with fasting ghrelin plasma concentrations was found in the whole OPERA population. However, the association of this SNP with BMI and with waist circumference reached statistical significance in OPERA (P = .047 and .049, respectively), remaining of borderline significance for BMI after adjustments (P = .055). The results indicate that factors other than the 11 SNPs found in this study in the 5' flanking region of ghrelin gene are the main determinants of ghrelin plasma levels. However, SNP-501 A>C genotype distribution seems to be different in subjects having the highest compared with those with the lowest ghrelin levels, and the SNP may be associated with BMI and waist circumference.
胃饥饿素是一种由28个氨基酸组成的肽，具有多种与能量代谢相关的功能。胃饥饿素血浆浓度低与肥胖、高血压和2型糖尿病有关，而高浓度则反映负能量平衡状态。已经开展了多项关于胃饥饿素基因表达的激素和神经调节的研究，但遗传因素在胃饥饿素血浆水平调节中的作用仍不清楚。为了阐明遗传因素在胃饥饿素表达调节中的作用，我们从空腹血浆总胃饥饿素浓度低（n = 50）和高（n = 50）的患者样本（低胃饥饿素组和高胃饥饿素组）中筛选了胃饥饿素基因5'侧翼区域（启动子和可能的调控位点）的1657个核苷酸，以寻找新的序列变异。在我们的人群中发现了11个单核苷酸多态性（SNP），其中3个是罕见变异（等位基因频率小于1%）。除了SNP-501A>C（P = 0.039）外，各研究组之间SNP的基因型分布模式没有差异。此外，SNP-01A>C与体重指数（BMI）相关（P = 0.018）。通过限制性片段长度多态性（RFLP）技术，在我们规模大且定义明确的奥卢动脉粥样硬化风险研究项目（OPERA）队列（n = 1045）中对该变异进行了进一步研究。在整个OPERA人群中，未发现SNP-501A>C基因型与空腹胃饥饿素血浆浓度有显著关联。然而，在OPERA中，该SNP与BMI和腰围的关联达到统计学显著性（分别为P = 0.047和0.049），调整后BMI仍具有临界显著性（P = 0.055）。结果表明，本研究在胃饥饿素基因5'侧翼区域发现的11个SNP以外的因素是胃饥饿素血浆水平的主要决定因素。然而，与胃饥饿素水平最低的受试者相比，胃饥饿素水平最高的受试者中SNP-501 A>C基因型分布似乎不同，并且该SNP可能与BMI和腰围有关。
