Genetic Polymorphism in Corticotropin-releasing Hormone Receptor Type-1 in Preeclamptic Korean Women

Ji Hyae Lim,Shin Young Kim,So Yeon Park,Do Jin Kim,Mi Jin Kim,Hyun Kyong Ahn,Jung Yeol Han,Moon Young Kim,Hyun Young Park,Kwang Soo Lee,Young Ju Kim,Hyun Mee Ryu 대한의학유전학회 2011 대한의학유전학회지 Vol.8 No.2

목적: Corticotropin-releasing hormone receptor type 1은 자간전증과 (CRHR1) 같은 비정상적인 태반의 기능을 가지는 산모에서 감소되어 나타나며, 그것의 발현이나 기능은 유전적으로 영향을 받는다. 이번 연구의 목표는 한국인에서CRHR1 유전자 다형성인 c.33+8199C>T과 자간전증 사이의 연관성을 조사하는 것이었다. 대상 및 방법: CRHR1 유전자 다형성은 SNapShot kit와 ABI Prism 3100 Genetic analyzer를 이용하여 203명의 자간전증 임산부와 211명의 정상 임산부에서 측정되었고, 유전자 다형성과 자간전증 위험도 사이의 연관성을 분석하였다. 결과: CRHR1 유전자 다형성의 유전자형과 대립유전자 빈도는 자간전증 임산부와 정상 임산부 사이에 다르지 않았다. 자간전증 발생 위험도는 분석된 유전자 다형성의 드문 대립 형질(C)을 지닌 이종접합 유전자형(TC)이나 동형접합 유전자형(CC)을 수반하는 그룹에서 증가되지 않았다. CRHR1 유전자의 동형접합 유전자형(CC)을 수반하는 그룹에서 중증 자간전증과 조기 자간전증과 같은 자간전증의 합병증 발병 위험에도 차이가 없었다. 결론: 이 연구는 CRHR1 유전자 다형성인 c.33+8199C>T가 한국인 임신부의 자간전증 발생과 연관이 없음을 나타낸다. Purpose: Placental corticotropin-releasing hormone receptor type 1 (CRHR1) expression is reduced in pregnancies with abnormal placental function such as preeclampsia (PE), and the levels and/or function of CRHR1 are genetically influenced. The aim of this study was to investigate the association between the c.33+8199C>T polymorphism in the CRHR1 gene and PE in a Korean population. Materials and Methods: Using a case-control design, the association between the CRHR1 polymorphism and the risk of PE was investigated in 203 individuals with PE and 211 normotensive controls. Genotypes were determined using a SNapShot kit and an ABI Prism 3100 Genetic analyzer. Results: Genotypes and allele frequencies for the CRHR1 polymorphism did not differ between PE and normotensive pregnancies. The variant T allele was more frequent than the ancestral C allele in both of the groups and was more frequent in the controls than in the cases. In risk analysis for PE, there was not an increased risk of preeclampsia in subjects who were concomitant homozygous rare allele genotypes (CC) (OR, 0.3; P=0.15) or heterozygous rare allele genotypes (TC) (OR, 0.8; P=0.29). There were no differences in the complications of PE such as severity or preterm delivery in patients with the CRHR1 polymorphism. Conclusion: Our findings indicate that the CRHR1 polymorphism was not associated with PE in the present Korean study group.

Genetic Polymorphism in Corticotropin-releasing Hormone Receptor Type-1 in Preeclamptic Korean Women

Lim, Ji-Hyae,Kim, Shin-Young,Park, So-Yeon,Kim, Do-Jin,Kim, Mi-Jin,Ahn, Hyun-Kyong,Han, Jung-Yeol,Kim, Moon-Young,Park, Hyun-Young,Lee, Kwang-Soo,Kim, Young-Ju,Ryu, Hyun-Mee Korean Society of Medical Genetics and Genomics 2011 대한의학유전학회지 Vol.8 No.2

목적: Corticotropin-releasing hormone receptor type 1(CRHR1)은 자간전증과 같은 비정상적인 태반의 기능을 가지는 산모에서 감소되어 나타나며, 그것의 발현이나 기능은 유전적으로 영향을 받는다. 이번 연구의 목표는 한국인에서 CRHR1 유전자 다형성인 c.33+8199C>T과 자간전증 사이의 연관성을 조사하는 것이었다. 대상 및 방법: CRHR1 유전자 다형성은 SNapShot kit와 ABI Prism3100 Genetic analyzer를 이용하여 203명의 자간전증 임산부와 211명의 정상 임산부에서 측정되었고, 유전자 다형성과 자간전증 위험도 사이의 연관성을 분석하였다. 결과: CRHR1 유전자 다형성의 유전자형과 대립유전자 빈도는 자간전증 임산부와 정상 임산부 사이에 다르지 않았다. 자간전증 발생 위험도는 분석된 유전자 다형성의 드문 대립 형질(C)을 지닌 이종접합 유전자형(TC)이나 동형접합 유전자형(CC)을 수반하는 그룹에서 증가되지 않았다. CRHR1 유전자의 동형접합 유전자형(CC)을 수반하는 그룹에서 중증 자간전증과 조기 자간전증과 같은 자간전증의 합병증 발병 위험에도 차이가 없었다. 결론: 이 연구는CRHR1 유전자 다형성인 c.33+8199C>T가 한국인 임신부의 자간전증 발생과 연관이 없음을 나타낸다. Purpose: Placental corticotropin-releasing hormone receptor type 1 (CRHR1) expression is reduced in pregnancies with abnormal placental function such as preeclampsia (PE), and the levels and/or function of CRHR1 are genetically influenced. The aim of this study was to investigate the association between the c.33+8199C>T polymorphism in the CRHR1 gene and PE in a Korean population. Materials and Methods: Using a case-control design, the association between the CRHR1 polymorphism and the risk of PE was investigated in 203 individuals with PE and 211 normotensive controls. Genotypes were determined using a SNapShot kit and an ABI Prism 3100 Genetic analyzer. Results: Genotypes and allele frequencies for the CRHR1 polymorphism did not differ between PE and normotensive pregnancies. The variant T allele was more frequent than the ancestral C allele in both of the groups and was more frequent in the controls than in the cases. In risk analysis for PE, there was not an increased risk of preeclampsia in subjects who were concomitant homozygous rare allele genotypes (CC) (OR, 0.3; P=0.15) or heterozygous rare allele genotypes (TC) (OR, 0.8; P=0.29). There were no differences in the complications of PE such as severity or preterm delivery in patients with the CRHR1 polymorphism. Conclusion: Our findings indicate that the CRHR1 polymorphism was not associated with PE in the present Korean study group.

한국인 알코올의존환자에서의 제1형 부신피질자극 호르몬 분비 촉진 호르몬수용체의 유전자 다형성에 관한 연구

김철민,김성곤,김지훈,김현경,김미경,유정현,민은정 대한생물치료정신의학회 2011 생물치료정신의학 Vol.17 No.2

스트레스 반응에 중요한 역할을 하고 있는 CRHR1 유전자 SNP와 알코올 의존과의 연관성에 관한 선행 연구들이 있다. 이에 본 연구는 백인을 대상으로 조사했던 기존연구와는 달리 한국인 남녀를 대상으로 하여 알코올 의존군과 정상 대조군의 CRHR1 유전자형 빈도 및 대립유전자형 빈도를 비교하였다. 본 연구의 연구대상자들은 알코올 의존군 268명(남자 218명, 여자 50명)과 정상 대조군 137명(남자 78명, 여자 59명)이었다. CRHR1 유전자 SNP를 SNP database와 선행연구를 근거로 선정한 후, 연구 대상자들의 이러한 SNP 유전자형을 PCRRFLP방법으로 조사하였다. 그 결과, 한국인의 CRHR1 유전자 SNPs로 7개(rs242938, rs404623, rs28364027, rs16940686, rs937, rs878886, rs878887)가 분석되었다. 이중 rs28364027의 A 대립 유전자의 빈도는 남녀 각각에서 알코올 의존군이 대조군보다 유의하게 높았다. 그리고 rs28364027의 AA 유전자형 및 A 대립 유전자와 rs878886의 CC유전자형 및 C 대립유전자의 빈도는 알코올 의존군내에서 여성이 남성보다 유의하게 높았다. 이러한 결과를 종합해 보면 CRHR1 유전자 SNP가 알코올 의존의 유전적 원인의 중요한 요인일 가능성을 제시하고 있다. 또 이러한 CRHR1 유전자 SNP가 알코올 의존의 유전적 원인에서 남녀간 차이를 설명할 수 있을 가능성도 시사하고 있다. Objectives:There were several preceding studies investigating the association between alcohol dependence and corticotropine releasing hormone receptor1(CRHR1) gene SNPs that play an important role in response to stress. The frequencies of CRHR1 genotypes and alleles were compared between alcohol-dependent patients and normal control subjects. Methods:The subjects were 268 alcohol-dependent patients(218 males, 50 females) and 137 normal controls(78 male, 59 female). CRHR1 gene SNPs were investigated according to the SNP database and the results from previous studies, and their genotypes were analyzed by polymerase chain reaction(PCR) and restriction fragment length polymorphism(RFLP). Results:Seven CRHR1 gene SNPs(rs242938, rs404623, rs28364027, rs16940686, rs937, rs878886, rs878887) were found in Korean subjects. The frequency of rs28364027 A allele was significantly higher in alcohol-dependent patients than normal controls in both genders. In alcohol-dependent patients, the frequencies of AA genotype and A allele of rs28364027, and of CC genotype and C allele of rs878886 were higher in female than male. Conclusion:These results suggest that CRHR1 gene SNP is one of the important genetic factors in the etiology of alcohol dependence. And also it is supposed that the different frequency of SNP genotype could explain stress-related gender difference in the genetic etiology of alcohol dependence.

주의력결핍-과잉행동장애와 Corticotropin releasing hormone receptor 1 (CRHR1) 유전자 다형성의 관련성 연구

박주연(Jooyeon Park),김나현(Nahyun Kim),김대광(DaeKwang Kim) 인문사회과학기술융합학회 2018 예술인문사회융합멀티미디어논문지 Vol.8 No.4

주의력결핍-과잉행동장애(Attention deficit-hyperactivity disorder, ADHD)는 충동성, 과잉행동 등의 증상을 보이는 질환으로 유전적 요인의 역할에 대한 중요성이 주목받고 있다. 시상하부-뇌하수체-부신축(hypothalamus–pituitary–adrenal axis, HPA axis)의 활성도는 주의력결핍-과잉행동장애 환아의 스트레스반응에 영향을 미치는 것으로 보고되고 있으며, 이에 본 연구는 Corticotropin releasing hormone receptor 1 (CRHR1) 유전자의 유전자다형성 rs110402와 ADHD의 관련성을 파악해보고자한다. 대상자는 실험군으로 ADHD 환아(107명)를, 정상 대조군으로 정상 신생아(106명)를 대상으로 하였으며, ADHD 환아군과 정상대조군에서 CRHR1 유전자다형성 rs110402의 대립유전자 및 유전자형을 분석하였다. 연구 결과, ADHD 환아군과 정상대조군은 유전자형, 대립유전자의 분포에서 유의한 차이를 나타냈다. 본 연구의 결과는 CRHR1 유전자의 유전자 다형성이 한국인 ADHD의 원인이 될 수 있는 후보유전자로서의 가능성을 제시하였다. Attention deficit hyperactivity disorder (ADHD) is known to be associated with a variety of risk factors, such as personal characteristics, psychosocial, neurologic, and physiological factor. Few studies have examined the genetic factors related to ADHD. In recent studies, ADHD may be associated to hypothalamus–pituitary–adrenal axis (HPA axis) activity. Corticotropin releasing hormone receptor 1 (CRHR1) gene is an important regulator of system of the HPA axis, we selected CRHR1 gene (rs110402) as candidated gene for ADHD. 107 ADHD patients and 106 normal newborns were used as frozen DNA. For analysis, CRHR1 (rs110402) gene was genotyped by Single strand conformation polymorphism analysis (SSCP). The genotype and allele distribution of CRHR1 (rs110402) gene polymorphism in ADHD group and normal control group were analyzed. As a result, ADHD and CRHR1 gene polymorphism showed significant differences in genotype and allele distribution. Plymorphism of CRHR1 may play an importatn role in ADHD in the Korean.

Genetic Polymorphism in Corticotropin-releasing Hormone Receptor Type-1 in Preeclamptic Korean Women

임지혜,김신영,박소연,김도진,김미진,안현경,한정열,김문영,박현영,이광수,김영주,류현미 대한의학유전학회 2011 대한의학유전학회지 Vol.8 No.2

Purpose: Placental corticotropin-releasing hormone receptor type 1 (CRHR1) expression is reduced in pregnancies with abnormal placental function such as preeclampsia (PE), and the levels and/or function of CRHR1 are genetically influenced. The aim of this study was to investigate the association between the c.33+8199C>T polymorphism in the CRHR1 gene and PE in a Korean population. Materials and Methods: Using a case-control design, the association between the CRHR1 polymorphism and the risk of PE was investigated in 203 individuals with PE and 211 normotensive controls. Genotypes were determined using a SNapShot kit and an ABI Prism 3100 Genetic analyzer. Results: Genotypes and allele frequencies for the CRHR1 polymorphism did not differ between PE and normotensive pregnancies. The variant T allele was more frequent than the ancestral C allele in both of the groups and was more frequent in the controls than in the cases. In risk analysis for PE, there was not an increased risk of preeclampsia in subjects who were concomitant homozygous rare allele genotypes (CC) (OR, 0.3; P=0.15) or heterozygous rare allele genotypes (TC) (OR, 0.8; P=0.29). There were no differences in the complications of PE such as severity or preterm delivery in patients with the CRHR1polymorphism. Conclusion: Our findings indicate that the CRHR1 polymorphism was not associated with PE in the present Korean study group.

Role of corticotropin-releasing hormone receptor 1 in the regulation of nociception in mice

박수현,서홍원,최성수,심윤범,이진구 한국통합생물학회 2014 Animal cells and systems Vol.18 No.5

Corticotropin-releasing hormone (CRH) is known to be involved in both antinociceptive and nociceptiveprocessing. In the present study, we examined the role of the CRH receptor 1 in the regulation of nociceptionin mice. First, we found that CRH mRNA level was elevated in the hypothalamus or hippocampus byintraperitoneal (i.p.) injection with 1% acetic acid, intraplantar injection of 5% formalin, or intrathecal (i.t.)injection of substance P (0.7 μg/5 μl). Nociceptive behavior induced by acetic acid, formalin, or substance Pwere reduced in CRHR1 heterozygous (CRHR1+/−) mice compared to that in C57BL6 (wild type, CRHR1+/+)mice group. Furthermore, administration with CRHR1 antagonists such as CP 154526 (10 mg/kg, i.p.) orα-helical CRF 9-41 (10 μg/5 μl, intracerebroventricular [i.c.v.]) attenuated nociceptive behaviors observedin the substance P and writhing pain models. Our results suggest that CRHR1 might play an importantrole in the regulation of nociception, especially, toward nociceptive activation rather than producing theantinociception.

Protein-Protein Interaction Analysis of Corticotropin - Releasing Hormone Receptor 1 with Corticotropin-Releasing Hormone and Sauvagine

Nagarajan, Santhosh Kumar The Basic Science Institute Chosun University 2018 조선자연과학논문집 Vol.11 No.2

Corticotropin - releasing hormone receptor 1 (CRHR1) forms an integral part of the pathophysiology of disorders like post-traumatic stress disorder, stress, anxiety, addiction, and depression. Hence it is essential to look for new, potent and structure-specific inhibitors of CRHR1. We have analysed the protein-protein interaction complexes of the CRHR1 receptor with its native ligand CRF and full agonist Sauvagine. The structure of Sauvagine was predicted using homology modelling. We have identified that the residues TYR253, ASP254, GLU256, GLY265, ARG1014 and LY1060 are important in the formation of protein-protein complex formation. Future studies on these residues could throw light on the crucial structural features required for the formation of CRHR1-inhibitor complex and in studies that try to solve the structural complexities of CRHR1.

Protein-Protein Interaction Analysis of Corticotropin – Releasing Hormone Receptor 1 with Corticotropin-Releasing Hormone and Sauvagine

Santhosh Kumar Nagarajan 조선대학교 기초과학연구원 2018 조선자연과학논문집 Vol.11 No.2

3D-QSAR Studies of 8-Substituted-2-aryl-5-alkylaminoquinolines as Corticotropin-releasing Factor-1 Receptor Antagonists

Nagarajan, Santhosh Kumar,Madhavan, Thirumurthy The Basic Science Institute Chosun University 2015 조선자연과학논문집 Vol.8 No.3

Corticotropin-releasing actor receptors (CRFRs) activates the hypothalamic pituitary adrenal axis, one of the 2 parts of the fight or flight response to stress. Increased CRH production has is associated with Alzheimer's disease and major depression and hypoglycemia. In this study, we report the important structural and chemical parameters for CRFR inhibitors using the derivatives of 8-substituted-2-aryl-5-alkylaminoquinolines. A 3D QSAR study, Comparative molecular field analysis (CoMFA) was performed. The best predictions were obtained for the best CoMFA model with a $q^2$ of 0.607 with 6 components and $r^2$ of 0.991. The statistical parameters from the generated CoMFA models indicated that the data are well fitted and have high predictive ability. The contour map resulted from the CoMFA models might be helpful in the future designing of novel and more potent CRFR derivatives.

3D-QSAR Studies of 8-Substituted-2-aryl-5-alkylaminoquinolines as Corticotropin-releasing Factor-1 Receptor Antagonists

Santhosh Kumar Nagarajan,Thirumurthy Madhavan 조선대학교 기초과학연구원 2015 조선자연과학논문집 Vol.8 No.3