한국인 여아 성조숙증 코호트를 이용한 case-control 전장유전체분석 (GWAS) 발굴한 단일염기다형성(SNP) 중에서 Bonferroni correction p -value 유의성을 통과하는 rs10900855 SNP 의 500Kbp 내에 위치하는 유전자 EGR1, HSPA9, ETF1 에 대한 마우스 사춘기 시기의 발현 패턴 및 시상하부 세포주 과발현을 통한 Gnrh 와 Kiss1r의 mRNA 발현 및 ERK 활성화 변화를 분석한 결과 ETF1유전자가 성조숙증과 밀접한 관련이 있음을 밝혔다.
또한, 다중회귀분석을 통하여 rs1090855 SNP 을 포함한 23 개의 SNP 을 성조숙증 조기진단 바이오마커로 선정하였으며, 질환 예측 민감도는 66%, 특이도는 88.6%, 정확도는 81.2%로 나타났다. 이들 SNP 는 향후 성조숙증 조기진단 바이오마커로 활용될 수 있을 것으로 기대된다.
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- 53 - - ABSTRACT -
Functional study of susceptibility genes to precocious puberty identified by genome-wide association analysis in Korean girls
Mi Ran Jo
Department of Medical Sciences
The Graduate School, Ajou University
(Supervised by Professor Seon-Yong Jeong)
Central precocious puberty results from the premature activation of the hypothalamic-pituitary-gonadal axis and is clinically defined by the development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys.
Incidence of precocious puberty in Korean girls is estimated to be 3.3 to 50.4 per 100,000 girls during the study period (2004–2010), and recent studies have reported that it is increasing significantly in Korea. Genome-wide association studies (GWASs) are very powerful tools for the identification of susceptibility loci for diseases and traits. Our previous case-control GWAS with 300 controls and 699
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cases identified one SNP (p-value=1.1×10-8), which was below the genome wide significance level (p<5.0×10-8) and had a very high disease odds ratio (OR>2.0).
In this study, I aimed to identify the gene(s) effected by this SNP and elucidate how the SNP affects precocious puberty in vitro. Because, three genes, EGR1,
HSPA9, and ETF1, were located close to this SNP, I firstly investigated whether the
mRNA expression patterns of these genes in mouse hypothalamus altered during puberty. EGR1 and ETF1 gene expression were significantly changed 22 ~30 days after birth (puberty period). Next, I overexpressed these genes in mouse hypothalamus cells GT1-7, gonadotrophin-releasing hormone (GnRH)-producing cells, and then assessed the gene expression levels of the precocious puberty enhancing markers Gnrh and Kiss1r. Only Etf1 over expression significantly reducedGnrh and Kiss1r expression. Notably, the activated form of ERK
(phosphorylated-ERK) which is involved in GnRH production was decreased in an Eff1 dose dependent manner.
These results suggest that ETF1 gene expression levels may be closely engaged in the pathogenesis of precocious puberty in girls.
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