Konheim Yasmine L, Wolford Johanna K
Clinical Diabetes and Nutrition Section, Phoenix Epidemiology and Research Branch, National Institutes of Health, 4212 North 16th Street, Phoenix, AZ 85016, USA.
Hum Genet. 2003 Oct;113(5):377-81. doi: 10.1007/s00439-003-1000-y. Epub 2003 Aug 14.
Recent studies have suggested that prostaglandin-endoperoxide synthase-2 (PTGS2), also known as cyclo-oxygenase 2, plays an etiological role in the development of type 2 diabetes mellitus (T2DM). PTGS2 generates prostaglandins, which negatively modulate glucose-stimulated insulin secretion, and functions as a mediator of the inflammatory response, which is associated with decreased insulin sensitivity. Moreover, the gene encoding this enzyme, PTGS2, is located on 1q25.2, a region that has been linked with early onset T2DM in Pima Indians. To determine the possible role played by PTGS2 in modulating susceptibility to T2DM, we screened approximately 7.0 kb of the gene, corresponding to the promoter, coding sequence, and flanking exon-intron boundaries, and identified five variants, including three single nucleotide polymorphisms (SNPs) in the promoter, one intronic SNP, and one in the 3' untranslated region. With the exception of one rare promoter SNP (minor allele frequency <0.03), all SNPs were typed in approximately 1000 Pima Indians. The range of frequencies for the more common alleles was 0.65-0.88, and we found substantial linkage disequilibrium between all PTGS2 SNP pairs (D'>/=0.95). Variant alleles at two markers, rs20417 and rs2066826, which are located in the promoter and intron 6, respectively, were in strong linkage disequilibrium with each other (D'=0.97) and were associated with a higher prevalence of T2DM. For marker rs20417, individuals with the variant CC genotype had a 30% higher T2DM prevalence compared with subjects with the GG genotype (odds ratio=1.6 per copy of C allele; P=0.01). The variant C allele of rs20417 has been associated with decreased PTGS2 promoter activity, thereby suggesting a possible biological consequence attributable to this polymorphism. These findings indicate that genetic variants in PTGS2 may play a role in mediating susceptibility to T2DM in Pima Indians and are consistent with the hypothesis that chronic inflammation may contribute to the development of T2DM in some individuals.
近期研究表明，前列腺素内过氧化物合酶-2（PTGS2），也称为环氧化酶2，在2型糖尿病（T2DM）的发生发展中起病因学作用。PTGS2可生成前列腺素，其对葡萄糖刺激的胰岛素分泌起负调节作用，并且作为炎症反应的介质，与胰岛素敏感性降低相关。此外，编码该酶的基因PTGS2位于1q25.2，该区域与皮马印第安人早发T2DM有关。为了确定PTGS2在调节T2DM易感性中可能发挥的作用，我们筛查了该基因约7.0 kb的区域，对应于启动子、编码序列以及侧翼外显子-内含子边界，并鉴定出5个变异，包括启动子中的3个单核苷酸多态性（SNP）、1个内含子SNP和1个位于3'非翻译区的SNP。除了一个罕见的启动子SNP（次要等位基因频率<0.03）外，所有SNP均在约1000名皮马印第安人中进行了分型。较常见等位基因的频率范围为0.65 - 0.88，并且我们发现所有PTGS2 SNP对之间存在显著的连锁不平衡（D'>/=0.95）。分别位于启动子和内含子6中的两个标记rs20417和rs2066826的变异等位基因彼此之间存在强连锁不平衡（D' = 0.97），并且与T2DM的较高患病率相关。对于标记rs20417，具有变异CC基因型的个体与具有GG基因型的个体相比，T2DM患病率高30%（每拷贝C等位基因的优势比 = 1.6；P = 0.01）。rs20417的变异C等位基因与PTGS2启动子活性降低相关，从而提示该多态性可能产生的生物学后果。这些发现表明，PTGS2中的基因变异可能在介导皮马印第安人对T2DM的易感性中发挥作用，并且与慢性炎症可能促成某些个体发生T2DM的假说一致。
