Nitz Inke, Fisher Eva, Weikert Cornelia, Burwinkel Barbara, Li Yun, Möhlig Matthias, Boeing Heiner, Schreiber Stefan, Schrezenmeir Jürgen, Döring Frank
Department of Molecular Nutrition, Institute of Human Nutrition and Food Science, Christian-Albrechts University, Kiel, Germany.
Mol Nutr Food Res. 2007 Aug;51(8):1046-52. doi: 10.1002/mnfr.200700048.
Glucose-dependent insulinotropic polypeptide (GIP) stimulates insulin release via interaction with its pancreatic receptor (GIP receptor (GIPR)). GIP also acts as vasoactive protein. To investigate whether variations in GIP and GIPR genes are associated with risk factors of the metabolic syndrome we sequenced gene regions and identified two coding SNPs (GIP Ser103Gly, GIPR Glu354Gln) and one splice site SNP (GIP rs2291726) in 47 subjects. Interestingly, in silico analyses revealed that splice site SNP rs2291726 results in a truncated protein and classified GIPR variant Glu354Gln as a functional amino acid change. Association analyses were performed in a case-cohort study of incident cardiovascular disease (CVD) nested in the EPIC-Potsdam cohort. No significant associations between incident CVD and GIP Ser103Gly and rs2291726 were found. For GIPR Glu354Gln, we obtained a nominal association of heterozygous minor allele carrier with CVD in a codominant model adjusted for BMI, sex, and age (OR: 0.67, CI: 0.50-0.91, p = 0.01) or additional covariates of CVD (OR: 0.72, CI: 0.52-0.97, p = 0.03). In conclusion, we identified a common splice site mutation (rs2291726) of the GIP gene which results in a truncated protein and provide preliminary evidence for an association of the heterozygous GIPR Glu354Gln genotype with CVD.
葡萄糖依赖性促胰岛素多肽（GIP）通过与其胰腺受体（GIP受体（GIPR））相互作用来刺激胰岛素释放。GIP还作为血管活性蛋白发挥作用。为了研究GIP和GIPR基因的变异是否与代谢综合征的危险因素相关，我们对47名受试者的基因区域进行了测序，并鉴定出两个编码单核苷酸多态性（GIP Ser103Gly、GIPR Glu354Gln）和一个剪接位点单核苷酸多态性（GIP rs2291726）。有趣的是，计算机分析显示，剪接位点单核苷酸多态性rs2291726会导致蛋白质截短，并将GIPR变体Glu354Gln归类为功能性氨基酸变化。在嵌套于EPIC-波茨坦队列中的心血管疾病（CVD）发病病例队列研究中进行了关联分析。未发现CVD发病与GIP Ser103Gly和rs2291726之间存在显著关联。对于GIPR Glu354Gln，在针对体重指数、性别和年龄进行调整的共显性模型中（比值比：0.67，可信区间：0.50 - 0.91，p = 0.01）或针对CVD的其他协变量进行调整时（比值比：0.72，可信区间：0.52 - 0.97，p = 0.03），我们发现杂合子次要等位基因携带者与CVD存在名义上的关联。总之，我们鉴定出了GIP基因的一个常见剪接位点突变（rs2291726），该突变会导致蛋白质截短，并为杂合GIPR Glu354Gln基因型与CVD之间的关联提供了初步证据。
