Cauchi Stéphane, Meyre David, Durand Emmanuelle, Proença Christine, Marre Michel, Hadjadj Samy, Choquet Hélène, De Graeve Franck, Gaget Stefan, Allegaert Frederic, Delplanque Jérôme, Permutt Marshall Alan, Wasson Jon, Blech Ilana, Charpentier Guillaume, Balkau Beverley, Vergnaud Anne-Claire, Czernichow Sébastien, Patsch Wolfgang, Chikri Mohamed, Glaser Benjamin, Sladek Robert, Froguel Philippe
CNRS 8090-Institute of Biology, Pasteur Institute, Lille, France.
PLoS One. 2008 May 7;3(5):e2031. doi: 10.1371/journal.pone.0002031.
BACKGROUND: Recently, several Genome Wide Association (GWA) studies in populations of European descent have identified and validated novel single nucleotide polymorphisms (SNPs), highly associated with type 2 diabetes (T2D). Our aims were to validate these markers in other European and non-European populations, then to assess their combined effect in a large French study comparing T2D and normal glucose tolerant (NGT) individuals. METHODOLOGY/PRINCIPAL FINDINGS: In the same French population analyzed in our previous GWA study (3,295 T2D and 3,595 NGT), strong associations with T2D were found for CDKAL1 (OR(rs7756992) = 1.30[1.19-1.42], P = 2.3x10(-9)), CDKN2A/2B (OR(rs10811661) = 0.74[0.66-0.82], P = 3.5x10(-8)) and more modestly for IGFBP2 (OR(rs1470579) = 1.17[1.07-1.27], P = 0.0003) SNPs. These results were replicated in both Israeli Ashkenazi (577 T2D and 552 NGT) and Austrian (504 T2D and 753 NGT) populations (except for CDKAL1) but not in the Moroccan population (521 T2D and 423 NGT). In the overall group of French subjects (4,232 T2D and 4,595 NGT), IGFBP2 and CXCR4 synergistically interacted with (LOC38776, SLC30A8, HHEX) and (NGN3, CDKN2A/2B), respectively, encoding for proteins presumably regulating pancreatic endocrine cell development and function. The T2D risk increased strongly when risk alleles, including the previously discovered T2D-associated TCF7L2 rs7903146 SNP, were combined (8.68-fold for the 14% of French individuals carrying 18 to 30 risk alleles with an allelic OR of 1.24). With an area under the ROC curve of 0.86, only 15 novel loci were necessary to discriminate French individuals susceptible to develop T2D. CONCLUSIONS/SIGNIFICANCE: In addition to TCF7L2, SLC30A8 and HHEX, initially identified by the French GWA scan, CDKAL1, IGFBP2 and CDKN2A/2B strongly associate with T2D in French individuals, and mostly in populations of Central European descent but not in Moroccan subjects. Genes expressed in the pancreas interact together and their combined effect dramatically increases the risk for T2D, opening avenues for the development of genetic prediction tests.
背景：最近，几项针对欧洲裔人群的全基因组关联（GWA）研究已经识别并验证了与2型糖尿病（T2D）高度相关的新型单核苷酸多态性（SNP）。我们的目标是在其他欧洲和非欧洲人群中验证这些标记，然后在一项比较T2D和糖耐量正常（NGT）个体的大型法国研究中评估它们的联合效应。 方法/主要发现：在我们之前的GWA研究中分析的同一法国人群（3295例T2D和3595例NGT）中，发现CDKAL1（OR(rs7756992)=1.30[1.19 - 1.42]，P = 2.3×10⁻⁹）、CDKN2A/2B（OR(rs10811661)=0.74[0.66 - 0.82]，P = 3.5×10⁻⁸）与T2D有强关联，IGFBP2（OR(rs1470579)=1.17[1.07 - 1.27]，P = 0.0003）SNP的关联较弱。这些结果在以色列德系犹太人（577例T2D和552例NGT）和奥地利人群（504例T2D和753例NGT）中得到重复（CDKAL1除外），但在摩洛哥人群（521例T2D和423例NGT）中未得到重复。在法国受试者的总体组（4232例T2D和4595例NGT）中，IGFBP2和CXCR4分别与（LOC38776、SLC30A8、HHEX）和（NGN3、CDKN2A/2B）协同相互作用，这些基因分别编码可能调节胰腺内分泌细胞发育和功能的蛋白质。当包括先前发现的与T2D相关的TCF7L2 rs7903146 SNP在内的风险等位基因组合时，T2D风险大幅增加（对于携带18至30个风险等位基因且等位基因OR为1.24的14%法国个体，风险增加8.68倍）。ROC曲线下面积为0.86，仅需15个新位点就能区分易患T2D的法国个体。 结论/意义：除了最初由法国GWA扫描识别的TCF7L2、SLC30A8和HHEX外，CDKAL1、IGFBP2和CDKN2A/2B在法国个体中与T2D密切相关，主要在中欧血统人群中相关，而在摩洛哥受试者中不相关。在胰腺中表达的基因相互作用，它们的联合效应显著增加T2D风险，为基因预测测试的开发开辟了道路。
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