中国汉族人群2 型糖尿病的遗传关联研究
文献类型：学位论文
| 作者 | 邬莹 |
| 学位类别 | 博士 |
| 答辩日期 | 2009 |
| 授予单位 | 中国科学院上海生命科学研究院营养科学研究所 |
| 授予地点 | 中国科学院上海生命科学研究院 |
| 导师 | 林旭 |
| 关键词 | 遗传关联研究 2型糖尿病 肥胖 中国汉族人群 |
| 其他题名 | Genetic association study on susceptible loci for type 2 diabetes in a Chinese Han population |
| 学位专业 | 生物化学与分子生物学 |
| 中文摘要 | 研究背景：在过去20多年中，随着生活水平的提高和生活方式的改变，2型糖尿病等慢性代谢疾病的患病率在我国急剧上升，对公共卫生构成了很大的威胁。众所周知，2型糖尿病是遗传因素和环境因素长期共同作用的结果。但多年来，关于2型糖尿病遗传易感性的研究进展十分缓慢。而随着近年来全基因组关联研究策略的发展和成熟，法国、英国、芬兰等多个研究组先后发现并证实了位于FTO、CDKAL1、CDKN2A/B、IGF2BP2和SLC30A8等基因附近区域的多个SNP位点与肥胖、2型糖尿病的发病风险显著相关。但由于中国人群相关数据和遗传学资料的缺乏，这些遗传变异在中国汉族人群中的作用尚不清楚。因此了解中国人肥胖、2型糖尿病的遗传学基础，确定这些代谢疾病的易感基因对预防和控制这类慢性代谢性疾病的发生、发展具有非常重要的理论价值和临床意义。 研究目的：本研究拟探讨FTO、CDKAL1、CDKN2A/B、IGF2BP2、SLC30A8和RBP4等基因区域内的遗传变异在中国汉族居民中与肥胖、2型糖尿病、代谢综合征发病风险及这些疾病相关数量性状的关联关系，并考察疾病中间表型和疾病之间的因果关系及其潜在的致病机制。 研究方法：本研究在参加《中国老龄人口营养健康状况》调查的3210名中国汉族居民中，对FTO、CDKAL1和RBP4等10个基因区域内共27个单核苷酸多态性位点（Single Nucleotide Polymorphism，SNP）进行基因分型和遗传关联分析。同时，采用孟德尔随机化方法（Mendelian Randomization）对血浆RBP4水平和代谢综合征之间的关联关系进行因果推断。 研究结果：本研究发现：1）FTO基因上的SNP位点在中国汉族人群中和肥胖、2型糖尿病及其相关数量性状均没有关联关系。次等位基因频率MAF（中国人：0.12~0.20；白种人：0.45~0.48）和连锁不平衡程度（LD）等基因结构上的不同可能是导致遗传易感性在中国人和白种人中存在差异的原因；2）CDKAL1（OR = 1.49 [1.27-1.75], P = 8.91×10－7）和CDKN2A/B（OR = 1.31 [1.12-1.54], P = 1.0×10－3）基因上的多个SNP位点和2型糖尿病风险显著相关， IGF2BP2 （OR = 1.17 [1.03-1.32], P = 0.014）和SLC30A（OR = 1.12 [1.01-1.25], P = 0.033）基因的遗传变异会增加空腹血糖受损的发生风险。研究同时发现这些SNP位点对2型糖尿病的发病风险具有叠加效应（OR = 1.24 [1.14-1.34], P = 2.85×10－7）。另外，上述易感SNP位点与空腹血糖、糖化血红蛋白，尤其是胰岛β细胞功能指标HOMA-B之间存在显著的关联关系；3）RBP4基因的SNP位点rs3758538同时和血浆RPB4水平（z = -0.12SD [-0.24~-0.01]， P = 0.0325）及高甘油三酯血症风险（OR = 0.62 [0.46-0.85]，P = 0.0029）显著相关。但没有证据表明血液中的高RBP4水平是导致高甘油三酯血症发生的直接原因。 结论：本研究在大规模中国汉族人群中确认了CDKAL1等基因的2型糖尿病遗传易感性。同时也发现白种人的“肥胖”基因FTO和中国人的肥胖、2型糖尿病风险无关，提示不同种族人群遗传背景上可能存在差异。与此同时，关于代谢中间表型和疾病发病风险之间是否存在因果关系还亟待更大规模的人群研究或Meta分析来予以证实。总之，本研究为2型糖尿病等慢性代谢疾病的早期发现和预防控制提供了极有价值的遗传学资料。 |
| 索取号 | D2009-059 |
| 英文摘要 | BACKGROUNG: The rapid increase in prevalence of type 2 diabetes, obesity and other metabolic disorders has been a major public health challenge in China. Besides the important contribution of environmental factors, genetic determinants also play a major role in the susceptibility to the diseases. Recent advances in genome-wide association studies identified several genetic loci consistently associated with type 2 diabetes and obesity in European populations. However, it remains unclear whether these variants have the same effects in Chinese Hans. In addition, little has been known about the causal relationship underlying the observational associations between diseases and their intermediate phenotypes. OBJECTIVES: This study aimed to investigate whether the variants in the genes of FTO, CDKAL1 and IGF2BP2 are associated type 2 diabetes, obesity or their related traits in Chinese Hans, and to explore the potential causality to these metabolic disorders. METHODS: We genotyped a total of 27 SNPs within ten gene regions of FTO, CDKAL1 and RBP4 etc., and examined their associations with obesity, type 2 diabetes and other metabolic disorders in a population-based sample including 3,210 unrelated Chinese Hans. We applied the Mendelian randomization approach to evaluate the possible causal relationship between plasma RBP4 levels and hypertriglyceridemia. RESULTS: In this Chinese Han population, 1) we did not replicate the significant associations for the FTO gene variants with obesity, type 2 diabetes and their related phenotypes. The relatively lower minor allele frequencies (MAFs) of the three FTO variants in Chinese as well as their different LD patterns from Caucasians might account for the inconsistent findings. 2) we confirmed the strong associations between type 2 diabetes and variants near CDKAL1 (OR = 1.49 [1.27-1.75], P = 8.91×10－7) and CDKN2A/B (OR = 1.31 [1.12-1.54], P = 1.0×10－3). We observed significant association of SNPs in IGF2BP2 (OR = 1.17 [1.03-1.32], P = 0.014) and SLC30A8 (OR = 1.12 [1.01-1.25], P = 0.033) with combined impaired fasting glucose / type 2 diabetes. These variants were also associated with impaired βcell functions estimated by HOMA-B. When combined, each additional risk allele from these susceptible loci significantly increased the risk for type 2 diabetes (OR = 1.24 [1.14-1.34], P = 2.85×10－7). 3) The SNP rs3758538 in the gene of RBP4 was significantly associated with both plasma RBP4 levels (z = -0.12SD [-0.24~-0.01]， P = 0.0325) and risk of hypertriglyceridemia (OR = 0.62 [0.46-0.85]，P = 0.0029). However, mendelian randomization analysis found that the observed effect size of association between rs3758538 and hypertriglyceridemia was significantly different from the expected effect size (P for difference = 0.0213), suggesting that the increased RBP4 levels are not causally related to hypertriglyceridemia risk. CONCLUSION: This study confirmed the strong associations of type 2 diabetes with SNPs in CDKAL1 and CDKN2A/B, but failed to replicate the associations between FTO variants and obesity in a Chinese Han population. The different genetic architecture among ethnics may contribute to the discrepancy between our results and previous findings in Caucasians. Besides, we found no evidence for the hypothesis that plasma RBP4 levels are causally related to hypertriglyceridemia risk. Therefore, further studies with larger sample size or meta-analyses are warranted to examine the genetic susceptibility and the potential mechanisms for type 2 diabetes, obesity and other metabolic disorders. |
| 语种 | 中文 |
| 公开日期 | 2015-12-24 |
| 源URL | [http://202.127.25.144/handle/331004/256]  |
| 专题 | 中国科学院上海生命科学研究院营养科学研究所_人类营养与疾病研究组 |
| 推荐引用方式 GB/T 7714 | 邬莹. 中国汉族人群2 型糖尿病的遗传关联研究[D]. 中国科学院上海生命科学研究院. 中国科学院上海生命科学研究院营养科学研究所. 2009. |
入库方式： OAI收割
来源：上海营养与健康研究所
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