Endocrine and Metabolism Unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Rama 6 Road, Mahidol University, Bangkok, Thailand.
J Hum Genet. 2012 May;57(5):301-4. doi: 10.1038/jhg.2012.20. Epub 2012 Mar 8.
Several lines of evidence have pointed out that genetic components have roles in thyrotoxic hypokalemic periodic paralysis (TTPP). In this study, for the first time we performed genome-wide association study (GWAS) in male hyperthyroid subjects in order to identify genetic loci conferring susceptibility to TTPP. We genotyped 78 Thai male TTPP cases and 74 Thai male hyperthyroid patients without hypokalemia as controls with Illumina Human-Hap610 Genotyping BeadChip. Among the SNPs analyzed in the GWAS, rs312729 at chromosome 17q revealed the lowest P-value for association (P=2.09 × 10(-7)). After fine mapping for linkage disequilibrium blocks surrounding the landmark SNP, we found a significant association of rs623011; located at 75 kb downstream of KCNJ2 on chromosome 17q, reached the GWAS significance after Bonferroni's adjustment (P=3.23 × 10(-8), odds ratio (OR)=6.72; 95% confidence interval (CI)=3.11-14.5). The result was confirmed in an independent cohort of samples consisting of 28 TTPP patients and 48 controls using the same clinical criteria diagnosis (replication analysis P=3.44 × 10(-5), OR=5.13; 95% CI=1.87-14.1; combined-analysis P=3.71 × 10(-12), OR=5.47; 95% CI=3.04-9.83).
几项研究结果表明，遗传因素在毒性弥漫性甲状腺肿伴低钾周期性瘫痪（TTPP）中起作用。本研究首次对男性甲亢患者进行全基因组关联研究（GWAS），以确定与 TTPP 易感性相关的遗传位点。我们使用 Illumina Human-Hap610 Genotyping BeadChip 对 78 例泰国男性 TTPP 病例和 74 例泰国男性无低钾血症的甲亢患者进行基因分型。在 GWAS 分析的 SNP 中，染色体 17q 上的 rs312729 显示出与关联的最低 P 值（P=2.09×10(-7)）。在对 landmark SNP 周围的连锁不平衡块进行精细映射后，我们发现 rs623011 存在显著关联；位于染色体 17q 上 KCNJ2 下游 75kb 处，在经过 Bonferroni 调整后达到 GWAS 显著性（P=3.23×10(-8)，优势比（OR）=6.72；95%置信区间（CI）=3.11-14.5）。使用相同的临床标准诊断，在由 28 例 TTPP 患者和 48 例对照组成的独立样本队列中对该结果进行了验证（复制分析 P=3.44×10(-5)，OR=5.13；95% CI=1.87-14.1；联合分析 P=3.71×10(-12)，OR=5.47；95% CI=3.04-9.83）。
