Vaxillaire M, Dina C, Lobbens S, Dechaume A, Vasseur-Delannoy V, Helbecque N, Charpentier G, Froguel P
CNRS 8090-Institut de Biologie, Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 245, 59019, Lille, France.
Diabetologia. 2005 Mar;48(3):440-4. doi: 10.1007/s00125-004-1665-3. Epub 2005 Feb 25.
AIMS/HYPOTHESIS: The gene encoding HNF-4alpha, an orphan nuclear receptor playing critical roles in embryogenesis and metabolism by regulating gene expression in pancreatic beta cells, liver, and other tissues, is localised to chromosome 20q13, where linkage to type 2 diabetes has been shown in multiple studies. As two reports have independently demonstrated a convincing association with variants adjacent to the HNF-4alpha P2 promoter in Finnish and Ashkenazi Jewish populations, we evaluated their contribution to diabetes risk in the French Caucasian population.
Genotypes for four haplotype tag SNPs were analysed for association with diabetes in a case-control study of 744 unrelated type 2 diabetic patients and 686 normoglycaemic subjects, and for linkage in 148 diabetic families in whom significant linkage to the HNF4alpha region had been shown.
The association seen in the Finnish and Ashkenazi studies for SNPs rs2144908 and rs1884614 located within a haplotype block encompassing the beta cell promoter P2 of HNF-4alpha was not replicated in our study; in French Caucasians the minor allele prevalence was increased in control subjects [odds ratio (OR) 0.80, uncorrected p=0.022 for rs2144908; OR 0.82 uncorrected p=0.058 for rs1884614]. Furthermore, none of the SNPs tested in the French familial sample was associated with diabetes, nor do they appear to contribute to the linkage.
CONCLUSIONS/INTERPRETATION: None of the previously associated SNPs confer an increased risk for diabetes in French Caucasians. A large meta-analysis of association studies will determine whether there is a consistent association between particular SNPs upstream of HNF-4alpha and type 2 diabetes in several ethnic groups.
目的/假设：编码肝细胞核因子-4α（HNF-4α）的基因定位于20号染色体q13区域，多项研究表明该区域与2型糖尿病存在连锁关系。HNF-4α是一种孤儿核受体，通过调节胰腺β细胞、肝脏及其他组织中的基因表达，在胚胎发育和新陈代谢中发挥关键作用。由于有两份报告分别在芬兰和德系犹太人群体中独立证实了与HNF-4α P2启动子附近变异存在令人信服的关联，我们评估了这些变异对法国白种人群体糖尿病风险的影响。
在一项病例对照研究中，对744例无亲缘关系的2型糖尿病患者和686例血糖正常的受试者进行了4个单倍型标签单核苷酸多态性（SNP）的基因型分析，以确定其与糖尿病的关联；并对148个已显示与HNF4α区域存在显著连锁的糖尿病家族进行了连锁分析。
在芬兰和德系犹太人群体研究中观察到的位于包含HNF-4αβ细胞启动子P2的单倍型区域内的SNP rs2144908和rs1884614的关联，在我们的研究中未得到重复验证；在法国白种人群体中，对照受试者的次要等位基因频率增加[rs2144908的优势比（OR）为0.80，未校正p = 0.022；rs1884614的OR为0.82，未校正p = 0.058]。此外，在法国家族样本中检测的任何SNP均与糖尿病无关，它们似乎也不影响连锁关系。
结论/解读：在法国白种人群体中，先前相关的SNP均未增加糖尿病风险。一项大型关联研究的荟萃分析将确定在几个种族群体中，HNF-4α上游特定SNP与2型糖尿病之间是否存在一致的关联。
