单氨基酸多态性与2型糖尿病发生发展及影响因素研究

Identifying novel early sensitive biomarkers of type 2 diabetes mellitus (T2DM) is critical to improve the capability to screen high-risk individuals for this disease. Although genome-wide association studies for T2DM found multiple single nucleotide polymorphism risk loci, ability of these loci to predict T2DM is limited. Concentrations of a pair of peptides with single amino acid polymorphisms (SAP), of two individual SAP peptides and their ratio have been related to biological phenotypes. To our knowledge, population-based studies relating SAP peptides to the development of T2DM have not been carried out. Based on a prospective population cohort sample, this study aims to adopt a high-throughput quantitative proteomic approach to detecting human plasma SAP peptides, to screen and identify SAP peptides with ability to predict those with normal fasting blood glucose at baseline progressed to impaired fasting glucose and to T2DM after 6-year follow-up, respectively, as well as those with impaired fasting glucose at baseline progressed to T2DM; and to determine the ability of these identified SAP peptides to predict blood glucose control among those with T2DM. Potential factors associated with concentrations of these identified SAP peptides, including genetics, lifestyle, obesity and lipid disorders and other relevant factors, will be also identified. This study will not only improve the screening of individuals with high-risk for T2DM, but will also provide new insights into mechanism investigation and development of population intervention program for this disease.

寻找新的2型糖尿病早期敏感标志物对改善该病高风险人群的筛查能力具有至关重要的作用。尽管目前有关该病的全基因组关联研究发现了多个单核苷酸多态性风险位点，但这些位点对患该病风险预测能力及其有限。据报道,含单氨基酸多态性(SAP)的单条肽段浓度，成对SAP肽段的浓度之和及其比值均与生物学表型有关联。而有关SAP肽段与2型糖尿病发生发展的人群研究尚未开展。本研究拟在前瞻性人群队列样本的基础上，通过高通量蛋白质组学技术定量检测人血浆SAP肽段。筛查和鉴定对由空腹血糖正常6年后分别发展为空腹血糖受损和2型糖尿病，以及由空腹血糖受损发展为2型糖尿病具有预测作用的SAP肽段；并确定其对2型糖尿病个体血糖控制的预示作用；以及确定影响SAP肽段水平的遗传、生活方式、肥胖和血脂紊乱等因素。本研究的开展不仅有助于更好的筛选2型糖尿病高风险人群，也为后续该病发生发展相关机理研究和人群干预方案制定提供新的线索和思路。

寻找新的2型糖尿病早期敏感标志物对改善该病高风险人群的筛查能力具有至关重要的作用。尽管目前有关该病的全基因组关联研究发现了多个单核苷酸多态性风险位点，但这些位点对患该病风险预测能力及其有限。据报道,含单氨基酸多态性(SAP)的单条肽段浓度，成对SAP 肽段的浓度之和及其比值均与生物学表型有关联。而有关SAP 肽段与2 型糖尿病发生发展的人群研究尚未开展。本研究拟在前瞻性人群队列样本的基础上，通过高通量蛋白质组学技术定量检测人血浆SAP 肽段。本项目在国际上首次发现apoA4的SAP肽段（apoA4_N147S）与2型糖尿风险密切相关。与其在APOA4基因水平对应的SNP rs5104位点相比，是更好的疾病风险预测指标。此外，apoA4_N147S与糖尿病风险的关联可能主要是基于血脂异常的作用通路。本研究的开展不仅有助于更好的筛选2型糖尿病高风险人群，也为后续该病发生发展相关机理研究和人群干预方案制定提供新的线索和思路。