Barber Thomas M, Bennett Amanda J, Gloyn Anna L, Groves Christopher J, Sovio Ulla, Ruokonen Aimo, Martikainen Hannu, Pouta Anneli, Taponen Saara, Weedon Michael N, Hartikainen Anna-Liisa, Wass John A H, Järvelin Marjo-Riitta, Zeggini Eleftheria, Franks Stephen, McCarthy Mark I
Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Old Road, Headington, Oxford, UK.
Eur J Hum Genet. 2007 Jun;15(6):679-84. doi: 10.1038/sj.ejhg.5201802. Epub 2007 Mar 7.
Polycystic ovary syndrome (PCOS) is strongly associated with hyperinsulinaemia and type II diabetes (T2D). Sequence variation within KCNJ11 (encoding Kir6.2, the beta-cell inwardly rectifying potassium channel) is implicated in the pathogenesis of neonatal diabetes, hyperinsulinaemia of infancy and multifactorial T2D. Comprehensive tagging studies have demonstrated that the KCNJ11 E23K variant (or ABCC8 A1369S in LD>0.9) is responsible for the known association between KCNJ11 and T2D. Given the phenotypic overlap between PCOS and T2D, we investigated whether E23K is involved in susceptibility to PCOS and related traits. Case-control analyses for the KCNJ11 E23K variant were performed in (a) 374 PCOS cases and 2574 controls of UK British/Irish origin, and (b) 550 women with PCOS symptoms and 1114 controls from a Finnish birth cohort. The relationship between E23K genotype and androgen levels (a key intermediate phenotype relevant to PCOS) in 1380 samples was studied. The UK case-control analysis revealed no association between E23K genotypes and PCOS status (P=0.49; Cochran-Armitage test), and no significant relationship between E23K genotype and androgen measures in the samples for which these phenotypes were available (P=0.19). Similarly, the Finnish case-control analysis showed no association between E23K genotypes and PCOS status (P=0.75; Cochran-Armitage test), and no significant relationship between E23K genotype and androgen measures in the samples for which these phenotypes were available (Finnish controls, P=0.25; Finnish cases, P=0.08). In conclusion, these data (involving >4600 subjects) provide no evidence that common variants of the KCNJ11 E23K polymorphism have a major influence on PCOS susceptibility, though modest effect sizes (OR<1.25) cannot be excluded.
多囊卵巢综合征（PCOS）与高胰岛素血症和2型糖尿病（T2D）密切相关。KCNJ11（编码Kir6.2，即β细胞内向整流钾通道）内的序列变异与新生儿糖尿病、婴儿期高胰岛素血症和多因素T2D的发病机制有关。全面的标签研究表明，KCNJ11 E23K变异（或LD>0.9时的ABCC8 A1369S）是KCNJ11与T2D之间已知关联的原因。鉴于PCOS和T2D之间的表型重叠，我们研究了E23K是否与PCOS易感性及相关性状有关。对KCNJ11 E23K变异进行了病例对照分析，分析对象为：（a）374例英国/爱尔兰裔的PCOS患者和2574例对照；（b）550例有PCOS症状的女性和1114例来自芬兰出生队列的对照。研究了1380个样本中E23K基因型与雄激素水平（与PCOS相关的关键中间表型）之间的关系。英国的病例对照分析显示，E23K基因型与PCOS状态之间无关联（P = 0.49； Cochr an-Armitage检验），在可获得这些表型的样本中，E23K基因型与雄激素指标之间也无显著关系（P = 0.19）。同样，芬兰的病例对照分析显示，E23K基因型与PCOS状态之间无关联（P = 0.75； Cochr an-Armitage检验），在可获得这些表型的样本中，E23K基因型与雄激素指标之间也无显著关系（芬兰对照，P = 0.25；芬兰病例，P = 0.08）。总之，这些数据（涉及>4600名受试者）没有提供证据表明KCNJ11 E23K多态性的常见变异对PCOS易感性有重大影响，不过也不能排除适度的效应大小（OR<1.25）。
