Department of Public Health and Clinical Medicine, Umeå University Hospital, Sweden.
Diabetes. 2011 Jan;60(1):345-54. doi: 10.2337/db10-0933. Epub 2010 Sep 24.
To assess whether recently discovered genetic loci associated with hyperglycemia also predict long-term changes in glycemic traits.
Sixteen fasting glucose-raising loci were genotyped in middle-aged adults from the Gene x Lifestyle interactions And Complex traits Involved in Elevated disease Risk (GLACIER) Study, a population-based prospective cohort study from northern Sweden. Genotypes were tested for association with baseline fasting and 2-h postchallenge glycemia (N = 16,330), and for changes in these glycemic traits during a 10-year follow-up period (N = 4,059).
Cross-sectional directionally consistent replication with fasting glucose concentrations was achieved for 12 of 16 variants; 10 variants were also associated with impaired fasting glucose (IFG) and 7 were independently associated with 2-h postchallenge glucose concentrations. In prospective analyses, the effect alleles at four loci (GCK rs4607517, ADRA2A rs10885122, DGKB-TMEM195 rs2191349, and G6PC2 rs560887) were nominally associated with worsening fasting glucose concentrations during 10-years of follow-up. MTNR1B rs10830963, which was predictive of elevated fasting glucose concentrations in cross-sectional analyses, was associated with a protective effect on postchallenge glucose concentrations during follow-up; however, this was only when baseline fasting and 2-h glucoses were adjusted for. An additive effect of multiple risk alleles on glycemic traits was observed: a weighted genetic risk score (80th vs. 20th centiles) was associated with a 0.16 mmol/l (P = 2.4 × 10⁻⁶) greater elevation in fasting glucose and a 64% (95% CI: 33-201%) higher risk of developing IFG during 10 years of follow-up.
Our findings imply that genetic profiling might facilitate the early detection of persons who are genetically susceptible to deteriorating glucose control; studies of incident type 2 diabetes and discrete cardiovascular end points will help establish whether the magnitude of these changes is clinically relevant.
评估最近发现的与高血糖相关的遗传位点是否也能预测血糖特征的长期变化。
在来自瑞典北部的基于人群的前瞻性队列研究 Gene x 生活方式相互作用和升高疾病风险的复杂特征（GLACIER）研究中，对 16 个空腹血糖升高的基因座进行了基因型分析。对 16330 名成年人的基线空腹和 2 小时餐后血糖进行了基因型与血糖的关联分析，对 4059 名成年人的 10 年随访期间的血糖变化进行了分析。
16 个变体中有 12 个与空腹血糖浓度呈横向一致的复制；10 个变体与空腹血糖受损（IFG）相关，7 个变体与 2 小时餐后血糖浓度独立相关。在前瞻性分析中，4 个基因座（GCK rs4607517、ADRA2A rs10885122、DGKB-TMEM195 rs2191349 和 G6PC2 rs560887）的效应等位基因与 10 年随访期间空腹血糖浓度的恶化呈名义相关。在横断面分析中，MTNR1B rs10830963 预测空腹血糖升高，与随访期间餐后血糖浓度的保护作用相关；然而，这仅在调整了基线空腹和 2 小时血糖时才会出现。在血糖特征方面观察到多个风险等位基因的累加效应：80 百分位与 20 百分位的加权遗传风险评分（weighted genetic risk score）与空腹血糖升高 0.16mmol/l（P = 2.4×10⁻⁶）相关，并且在 10 年随访期间 IFG 的发病风险增加 64%（95%CI：33-201%）。
我们的研究结果表明，基因谱分析可能有助于早期发现那些在遗传上易发生血糖控制恶化的人；对新发 2 型糖尿病和离散心血管终点的研究将有助于确定这些变化的幅度是否具有临床意义。
