한국인 조현병 환자에서CNR1 유전자의 (AAT)n 삼핵산 반복 다형성과 안구추적운동 이상에 대한 연합 연구

김민재,김채리,박진완,백두현,신형두,최인근,한상우,황재욱,이연정,우성일,Kim, Min Jae,Kim, Chae-Ri,Park, Jin Wan,Pak, Doo Hyun,Shin, Hyoung Doo,Choi, Ihn-Geun,Hahn, Sang Woo,Hwang, Jaeuk,Lee, Yeon Jung,Woo, Sung-Il 대한생물정신의학회 2016 생물정신의학 Vol.23 No.4

Objectives According to previous studies, the cannabinoid receptor 1 (CNR1) gene could be an important candidate gene for schizophrenia. Some studies have linked the (AAT)n trinucleotide repeat polymorphism in CNR1 gene with the risk of schizophrenia. Meanwhile, smooth pursuit eye movement (SPEM) has been regarded as one of the most consistent endophenotypes of schizophrenia. In this study, we investigated the association between the (AAT)n trinucleotide repeats in CNR1 gene and SPEM abnormality in Korean patients with schizophrenia. Methods We measured SPEM function in 167 Korean patients with schizophrenia (84 male, 83 female) and they were divided according to SPEM function into two groups, good and poor SPEM function groups. We also investigated allele frequencies of (AAT)n repeat polymorphisms on CNR1 gene in each group. A logistic regression analysis was performed to find the association between SPEM abnormality and the number of (AAT)n trinucleotide repeats. Results The natural logarithm value of signal/noise ratio (Ln S/N ratio) of the good SPEM function group was $4.34{\pm}0.29$ and that of the poor SPEM function group was $3.21{\pm}0.70$. In total, 7 types of trinucleotide repeats were identified, each containing 7, 10, 11, 12, 13, 14, and 15 repeats, respectively. In the patients with $(AAT)7$ allele, the distributions of the good and poor SPEM function groups were 18 (11.1%) and 19 (11.0%) respectively. In the patients with $(AAT)_{10}$ allele, $(AAT)_{11}$ allele, $(AAT)_{12}$ allele, $(AAT)_{13}$ allele, $(AAT)_{14}$ allele and $(AAT)_{15}$ allele, the distributions of good and poor SPEM function groups were 13 (8.0%) and 12 (7.0%), 4 (2.5%) and 6 (3.5%), 31 (19.8%) and 35 (20.3%), 51 (31.5%) and 51 (29.7%), 36 (22.2%) and 45 (26.2%), 9 (5.6%) and 4 (2.3%) respectively. As the number of (AAT) n repeat increased, there was no aggravation of abnormality of SPEM function. Conclusions There was no significant aggravation of SPEM abnormality along with the increase of number of (AAT)n trinucleotide repeats in the CNR1 gene in Korean patients with schizophrenia.

한국인 조현병 환자에서 Chromogranin B 유전자와 안구운동 이상의 연합에 대한 연구

박진완,백두현,황민규,이민지,신형두,신태민,한상우,황재욱,이연정,우성일,Park, Jin Wan,Pak, Doo Hyun,Hwang, Min Gyu,Lee, Min Ji,Shin, Hyoung Doo,Shin, Tae-Min,Hahn, Sang Woo,Hwang, Jaeuk,Lee, Yeon Jung,Woo, Sung-Il 대한생물정신의학회 2018 생물정신의학 Vol.25 No.4

Objectives According to previous studies, the Chromogranin B (CHGB) gene could be an important candidate gene for schizophrenia which is located on chromosome 20p12.3. Some studies have linked the polymorphism in CHGB gene with the risk of schizophrenia. Meanwhile, smooth pursuit eye movement (SPEM) abnormality has been regarded as one of the most consistent endophenotype of schizophrenia. In this study, we investigated the association between the polymorphisms in CHGB gene and SPEM abnormality in Korean patients with schizophrenia. Methods We measured SPEM function in 24 Korean patients with schizophrenia (16 male, 8 female) and they were divided according to SPEM function into two groups, good and poor SPEM function groups. We also investigated genotypes of polymorphisms in CHGB gene in each group. A logistic regression analysis was performed to find the association between SPEM abnormality and the number of polymorphism. Results The natural logarithm value of signal/noise ratio (Ln S/N ratio) of good SPEM function group was $4.19{\pm}0.19$ and that of poor SPEM function group was $3.17{\pm}0.65$. In total, 15 single nucleotide polymorphisms of CHGB were identified and the genotypes were divided into C/C, C/R, and R/R. Statistical analysis revealed that two genetic variants (rs16991480, rs76791154) were associated with SPEM abnormality in schizophrenia (p = 0.004). Conclusions Despite the limitations including a small number of samples and lack of functional study, our results suggest that genetic variants of CHGB may be associated with SPEM abnormality and provide useful preliminary information for further study.nwhile, smooth pursuit eye movement (SPEM) abnormality has been regarded as one of the most consistent endophenotype of schizophrenia. In this study, we investigated the association between the polymorphisms in CHGB gene and SPEM abnormality in Korean patients with schizophrenia. MethodsZZWe measured SPEM function in 24 Korean patients with schizophrenia (16 male, 8 female) and they were divided according to SPEM function into two groups, good and poor SPEM function groups. We also investigated genotypes of polymorphisms in CHGB gene in each group. A logistic regression analysis was performed to find the association between SPEM abnormality and the number of polymorphism. ResultsZZThe natural logarithm value of signal/noise ratio (Ln S/N ratio) of good SPEM function group was $4.19{\pm}0.19$ and that of poor SPEM function group was $3.17{\pm}0.65$. In total, 15 single nucleotide polymorphisms of CHGB were identified and the genotypes were divided into C/C, C/R, and R/R. Statistical analysis revealed that two genetic variants (rs16991480, rs76791154) were associated with SPEM abnormality in schizophrenia (p = 0.004). ConclusionsZZDespite the limitations including a small number of samples and lack of functional study, our results suggest that genetic variants of CHGB may be associated with SPEM abnormality and provide useful preliminary information for further study.

한국인에서 조현병과 Cannabinoid Receptor 1 유전자의 삼핵산 반복서열의 연합에 대한 연구

김지원,노양호,김민재,김채리,박병래,배준설,신형두,최인근,한상우,황재욱,우성일,Kim, Ji-Won,Roh, Yang-Ho,Kim, Min-Jea,Kim, Chea-Ri,Park, Byung-Lae,Bae, Joon Seol,Shin, Hyoung Doo,Choi, Ihn-Geun,Han, Sang-Woo,Hwang, Jaeuk,Woo, Sung-Il 대한생물정신의학회 2014 생물정신의학 Vol.21 No.3

Objectives Previous studies suggest that the cannabinoid receptor 1 (CNR1) gene could be an important candidate gene for schizophrenia. According to linkage studies, this gene is located on chromosome 6q14-q15, which is known to harbor the schizophrenia susceptibility locus (locus 5, SCZ5, OMIM 803175). The pharmacological agent delta-9-tetrahydrocannabinol (${\Delta}$-9-THC) seems to elicit the symptoms of schizophrenia. The association between CNR1 polymorphisms and schizophrenia is actively being investigated, and some studies have linked the AAT-trinucleotide repeats in CNR1 to the onset of schizophrenia. In this study, we have investigated the association between the AAT-trinucleotide repeats in CNR1 and schizophrenia by studying schizophrenia patients and healthy individuals from Korea. Methods DNA was extracted from the blood samples of 394 control subjects and 337 patients diagnosed with schizophrenia (as per the Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria). After polymerase chain reaction amplification, a logistic regression analysis, with age and gender as the covariates, was performed to study the variations in the AAT-repeat polymorphisms between the two groups. Results In total, 8 types of trinucleotide repeats were identified, each containing 7, 8, 10, 11, 12, 13, 14, and 15 repeats, respectively. $(AAT)_{13}$ allele was most frequently observed, with a frequency of 33.6% and 31.6% in the patient and control groups, respectively. The frequency of the other repeat alleles in the patient group (in the decreasing order) was as follows : $(AAT)_{13}$ 33.6%, $(AAT)_{14}$ 21.6%, $(AAT)_{12}$ 18.5%, and $(AAT)_{7}$ 11.1%. The frequency of the repeat alleles in the control group (in the decreasing order) was as follows : $(AAT)_{13}$ 31.6%, $(AAT)_{14}$ 24.5%, $(AAT)_{12}$ 17.2%, and $(AAT)_{7}$ 11.6%. However, there were no significant differences in the AAT-repeat polymorphisms of the CNR1 gene between the patient group and the control group. Conclusions Although our study revealed no significant association of the AAT-repeat polymorphism of the CNR1 gene with schizophrenia, it will serve as a good reference for future studies designed to examine the cannabinoid hypothesis of schizophrenia.

한국인에서 Neuregulin 3(NRG3) 유전자와 조현병의 연합 연구

신수진,최종택,김지원,노양호,박병래,배준설,신형두,최인근,한상우,황재욱,우성일,Shin, Su-Jin,Choi, Jong-Taek,Kim, Ji-Won,Roh, Yang-Ho,Park, Byung-Lae,Bae, Joon-Seol,Shin, Hyoung-Doo,Choi, Ihn-Geun,Han, Sang-Woo,Hwang, Jae-Uk,Woo, Sung-I 대한생물정신의학회 2012 생물정신의학 Vol.19 No.3

Objectives : Located on chromosome 10q22-q23, the human neuregulin 3 (NRG3) is suggested as a strong positional and functional candidate gene involved in the pathogenesis of schizophrenia. Several case-control studies examining the association between polymorphisms on NRG3 gene with schizophrenia and/or its traits (such as delusion) have been reported recently in cohorts of Han Chinese, Ashkenazi Jews, Australians, white Americans of Western European ancestry and Koreans. Thus, this study aimed to investigate the association of one SNP in exon 9 (rs2295933) of NRG3 gene with the risk of schizophrenia in a Korean population. Methods : Using TaqMan assay, rs2295933 in the exon 9 of NRG3 was genotyped in 435 patients with schizophrenia as cases and 393 unrelated healthy individuals as controls. Differences in frequency distributions were analyzed using logistic regression models following various modes of genetic inheritance and controlling for age and sex as covariates. Results : Subsequent analysis revealed that the frequency distribution of rs2295933 of NRG3 was not different between schizophrenia patients and healthy controls of Korean ethnicity. Conclusions : This study does not support the role of NRG3 in schizophrenia in a Korean population.

B형 간염의 만성화 및 간세포암종 발생과 Interleukin-12 유전자 다형성

박진선 ( Jin Sun Park ),정재연 ( Jae Youn Cheong ),강준구 ( Joon Koo Kang ),조진희 ( Jin Hee Cho ),유수경 ( Su Kyong Yu ),신형두 ( Hyoung Doo Shin ),박병래 ( Byung Lae Park ),조성원 ( Sung Won Cho ) 대한소화기학회 2007 대한소화기학회지 Vol.50 No.5

목적: B형 간염바이러스(hepatitis B virus, HBV) 감염은 다양한 임상 경과를 갖는다. HBV 감염의 자연경과의 다양성의 원인으로 유전자 다형성을 포함한 숙주 요인을 들 수 있으며, 사이토카인은 숙주 면역능에 중요한 역할을 한다. 이번 연구는 HBV 감염 후의 자연 경과와 간세포암종 발생에서 interleukin (IL)-12A 유전자 다형성(single neucleotide polymorphisms, SNP)과의 상관성을 알아보고자 하였다. 대상 및 방법: 2002년 3월부터 2004년 12월까지 외래를 내원한 HBV 만성화군 730명과 HBV 감염 후 자연 회복된 HBV 제거군 320명을 포함하여 총 1,050명을 대상으로 하였다. B형 간염의 만성화와 IL-12A의 유전자 다형성과의 관련성을 조사하기 위하여, HBV 만성화군과 HBV 제거군의 IL-12A SNP 및 haplotype에 따른 차이를 비교 분석하였고, 간세포암종 발생과 IL-12A의 유전자 다형성과의 관련성을 조사하기 위하여, HBV 만성화군을 간세포암종군과 비간세포암종군으로 나누어 IL-12A SNP 및 haplotype에 따른 차이를 비교 분석하였다. 결과: IL-12A의 SNP는 IL-12A 유전자 번역 시작 부위로부터 +6400, +6624, +7003 부위에서 조사하였다. 대상 환자를 HBV 만성화군과 HBV 제거군으로 분류하고, IL-12A SNP와 HBV 만성화와의 관련성을 조사한 결과 IL-12A exon 7 +6400 및 +6624 두 부위 및 3` UTR +7003 한 부위의 SNP는 HBV 만성화군과 HBV 제거군 간에 유의한 차이를 보이지 않았다. 또한 +6400/+6624/+7003 haplotype에 따른 HBV 만성화 관련성 조사에서도 양 군 간에 유의한 차이점은 관찰되지 않았다. IL-12A SNP와 간세포암종과의 관련성을 조사한 결과 각각의 SNP 및 +6400/ +6624/+7003 haplotype에 따른 HBV 감염 후 간세포암종 발생과의 연관성도 관찰되지 않았다. 결론: IL-12A SNP 및 haplotype은 HBV 간염 진행 및 간세포암종 진행과는 무관함을 알 수 있었다. HBV 감염의 자연 경과에서 숙주의 유전적인 인자의 중요성을 인지하고, 향후 환자의 유전 소인에 대한 연구가 더 진행되어야 할 것으로 판단한다. Background/Aims: Infection with hepatitis B virus (HBV) may result in various conditions. Natural course of HBV infection is influenced by various host immune factors and cytokines play a crucial role in host immune defense. This study was undertaken to investigate the association between HBV persistence and development of hepatocelluar carcinoma (HCC) and single nucleotide polymorphisms (SNPs) of interleukin (IL)-12A. Methods: Between March 2002 and December 2004, seven hundred thirty Korean patients with HBV infection and 320 healthy individuals who recovered from HBV infection were enrolled. We assessed polymorphisms and haplotype in IL-12A, and the genotype distributions of the HBV clearance and persistence groups were compared in order to investigate the association between HBV persistence and SNPs of IL-12A. Moreover, the genotypic distributions between patients with HCC and without HCC were compared to investigate the association between the development of HCC and SNPs of IL-12A. Results: We asssesed the SNPs of IL-12A at position +6400, +6624 and +7003. On the basis of logistic regression analysis, no statistically significant association with HBV persistence was observed with IL-12A exon 7 +6400, +6624, 3` UTR +7003 SNP and haplotype of IL-12A +6400/+6624/+7003. Furthermore, no statistically significant association of HCC development with IL-12A exon 7 +6400, +6624, 3` UTR +7003 SNP and haplotype of IL-12A +6400/+6624/+7003 was observed. Conclusions: These results suggest that SNPs and haplotype of IL-12A are not associated with HBV persistence and development of HCC. Further studies are needed to identify the host genetic factors in immune defense including cytokine gene polymorphisms of both IL-12A and IL-12B. (Korean J Gastroenterol 2007;50:313-318)

분만 공포와 5-HTT 유전자 다형성과의 연관분석

김민정 ( Min Jeong Kim ),최정수 ( Jeong Soo Choi ),남궁정 ( Jeong Namgung ),박인양 ( In Yang Park ),허수영 ( Soo Young Hur ),신종철 ( Jong Chul Shin ),김대진 ( Dae Jin Kim ),박병래 ( Byung Rae Park ),신형두 ( Hyoung Doo Shin ) 대한산부인과학회 2007 Obstetrics & Gynecology Science Vol.50 No.1

생물학적인 과정으로서 분만과 관련된 공포와 불안은 임상적으로 흔하며 흥미로운 것으로 여겨졌지만, 임신의 결과가 양호한 경우 대부분 중요하게 연구되지 않았다. 본 연구에서는 분만 공포를 이해하기 위해 534명의 한국인 산모를 대상으로 불안, 공포, 통증과 관련되어 있다고 알려진 5-HTT의 단일염기 다형성을 조사하였다. 534명의 한국인 산모에서 단일염기 다형성 빈도는 5-HTT -15375 insdel (44 bp) 0.24, -1002A>C 0.10, -922A>C 0.11, +18784A>C 0.073이었으며, +3746G>C는 한국인 산모에 있어 유전적 다형성이 없었다. 분만 공포와 유전적 다형성의 연관성을 연구하기 위해 534명 중 자연분만을 시행한 293명의 산모들을 대상으로 분만공포지수를 이용하여 분만 공포를 평가하였으며 분만력으로 보정한 다중회귀분석을 사용하여 분석하였다. 본 연구에서 5-HTT유전자의 단일염기 다형성은 분만 공포와 상호연관성이 없었다. 분만 공포는 유전적 요소인 5-HTT 유전자의 다형성 보다 심리적, 사회적, 환경적 요인 등이 더 중요한 역할을 하는 것으로 보이며 다른 유전자들과 유전자간의 상호 작용에 의해 복합적 영향을 받는 것으로 생각된다. 따라서 분만 공포를 이해하기 위해 이후 사회적, 심리적, 환경적 요소와 이와 관련된 유전자의 상호연관성에 대한 연구가 포괄적으로 진행되어야 할 것이다. The fear and anxiety in the biological processes of childbirth have been of clinical interest, but the studies addressing this subject are rare, particularly where the outcome of the pregnancy has been favourable. In this study, single nucleotide polymorphisms were studied for understanding the fear during childbirth in 534 Korean pregnant women. The frequencies of each SNP were 5-HTT -15375 insdel (44 bp) 0.24, -1002A>C 0.10, -922A>C 0.11, +18784A>C 0.073 in Korean pregnant women (n=534). No polymorphisms was found in 5-HTT +3746G>C The relationship between the fear during childbirth and genetic polymorphisms was investigated by multiple regression analysis adjusting for parity in 293 women who gave birth to a child vaginally and made a reply to Delivery Fear Scale (DFS) which was the measuring instrument for the fear during childbirth among 534 Korean pregnant women. There was no genetic association between the 5-HTT gene polymorphism and fear during childbirth. The results of this study show that the psychological, social, environmental factors play the major role in the fear during childbirth whereas this gene (5-HTT) most likely has only a minor effect in its etiology. And other genes and the interactions between them have been thought to make complex effects. In order to identify the fear during childbirth, further studies will have to be focused on the comprehensive research of the social, psychological, environmental factors and the interaction of the connected genes.