Interleukin-4 유전자의 Promoter 일배체형에 따른전사능의 차이

최은화,김희섭,이환종,Chanock,Stephen J. 대한소아청소년과학회 2005 Clinical and Experimental Pediatrics (CEP) Vol.48 No.5

Purpose:Interleukin-4(IL-4) is a critical component of the Th2 cytokine pathway and contributes to severity of respiratory syncytial virus(RSV) bronchiolitis. Previous studies observed an association between severe RSV bronchiolitis in Korean children with a common haplotype of the IL4 promoter. This study was performed to investigate functional differences of the variant IL4 promoter haplotypes. Methods:Genomic DNA was obtained from 20 children from 6 to 48 months of age in the Department of Pediatrics, Seoul National University Bundang Hospital. The IL4 promoter spanning an 1.2 kb region was amplified and haplotype was determined by cloning and the PHASE reconstruction. Transcriptional activity of Jurkat T cells which were transfected with each IL4 haplotype were analyzed by use of luciferase assay. Results:Three haplotypes of the IL4 promoter have been identified with the frequency of GCC(7 percent), TCC(17 percent), and TTT(76 percent). The TTT haplotype demonstrated the highest luciferase values in both unstimulated and PMA-stimulated Jurkat T cells. Increases in transcriptional activity compared to GCC have been shown in TTT(5.3 fold higher) followed by TCC(4.2 fold higher) in unstimulated Jurkat T cells. Conclusion:We provided evidence that increased transcriptional activity of the TTT haplotype of the IL4 promoter, which has previously been over-represented in Korean children with severe RSV bronchiolitis. Therefore, IL-4 could play a potential role in the pathogenesis of RSV infection, possibly via an altered transcriptional activity of the different IL4 haplotypes 목 적 : IL-4는 Th2 면역 반응의 중요한 매개체로 IL4 유전자의 promoter 일배체형(haplotype)은 한국인 소아에서 RSV에 의한 심한 모세기관지염과 연관된다고 알려져 있다. 본 연구는 IL4 유전자의 promoter 다형성에 따른 IL-4 단백의 기능적인 변화를 분석하여 심한 RSV 하기도 감염증에 기여하는 IL4 유전자의 발병 기전의 연관성을 연구하고자 시행하였다. 방 법 : 면역 기능이 정상인 소아 20명을 대상으로 전혈을 채취한 후 genomic DNA를 추출하여 IL4 유전자 promoter 약 1.2 kb 부위를 증폭시켰다. 염기서열 분석을 통하여 IL4 유전자 promoter의 유전형을 결정하고, PHASE 분석으로 일배체형을 결정하였다. 각 일배체형별로 5 g의 DNA를 Jurkat T 세포에 핵형질변환 시켜서 정상 Jurkat T 세포와 PMA(50 ng/mL)로 자극한 세포에서의 luciferase 활성도를 분석하여 IL4 유전자 promoter의 전사능을 결정하였다.결 과 : 한국인 소아의 일배체형은 3가지 유형 GCC(7%), TCC(17%), 및 TTT(76%)로 분포하였다. Jurkat T 세포의 절대 luciferase 활성도는 GCC형이 가장 낮았고 TTT형이 가장 높았다. GCC 일배체형을 기준으로 하여 나타낸 Jurkat T 세포의 상대 luciferase 활성도는 TCC형이 4.2배, TTT형이 5.3배로 증가되었다. PMA로 자극한 후에 측정한 각 일배체형의 luciferase 활성도 역시 GCC형에 비하여 TCC형이 3.0배, TTT형이 4.1배로 증가되어 자극하지 않은 세포에서와 유사한 활성도의 차이를 보였다. 결 론:소아의 심한 RSV 하기도 감염증과 연관된 IL4 유전자의 promoter 일배체형 TTT는 IL4 유전자의 promoter의 전사능을 증가시킴으로써 영아 및 소아의 RSV 하기도 감염증의 병인에 중요한 역할을 할 것으로 생각된다.

Polymorphisms in genes involved in innate immunity and susceptibility to benzene-induced hematotoxicity

Min Shen,H. Dean Hosgood,Luoping Zhang,이경무,Roel Vermeulen,Guilan Li,Songnian Yin,Nathaniel Rothman,Stephen Chanock,Martyn T. Smith,Qing Lan 생화학분자생물학회 2011 Experimental and molecular medicine Vol.43 No.6

Benzene, a recognized hematotoxicant and carcinogen,can damage the human immune system. We studied the association between single nucleotide polymorphisms (SNPs) in genes involved in innate immunity and benzene hematotoxicity in a cross-sectional study of workers exposed to benzene (250 workers and 140 controls). A total of 1,236 tag SNPs in 149gene regions of six pathways were included in the analysis. Six gene regions were significant for their association with white blood cell (WBC) counts (MBP,VCAM1, ALOX5, MPO, RAC2, and CRP) based on gene-region (P < 0.05) and SNP analyses (FDR <0.05). VCAM1 rs3176867, ALOX5 rs7099684, and MPO rs2071409 were the three most significant SNPs. They showed similar effects on WBC subtypes, especially granulocytes, lymphocytes, and monocytes. A 3-SNP block in ALOXE3 (rs7215658, rs9892383, and rs3027208) showed a global association (omnibus P =0.0008) with WBCs even though the three SNPs were not significant individually. Our study suggests that polymorphisms in innate immunity genes may play a role in benzene-induced hematotoxicity; however, independent replication is necessary.

Polymorphisms in genes involved in innate immunity and susceptibility to benzene-induced hematotoxicity

Shen, Min,Zhang, Luoping,Lee, Kyoung-Mu,Vermeulen, Roel,Hosgood, H. Dean,Li, Guilan,Yin, Songnian,Rothman, Nathaniel,Chanock, Stephen,Smith, Martyn T.,Lan, Qing Korean Society for Biochemistry and Molecular Bion 2011 Experimental and molecular medicine Vol.43 No.6

Benzene, a recognized hematotoxicant and carcinogen, can damage the human immune system. We studied the association between single nucleotide polymorphisms (SNPs) in genes involved in innate immunity and benzene hematotoxicity in a cross-sectional study of workers exposed to benzene (250 workers and 140 controls). A total of 1,236 tag SNPs in 149 gene regions of six pathways were included in the analysis. Six gene regions were significant for their association with white blood cell (WBC) counts ($MBP$, $VCAM1$, $ALOX5$, $MPO$, $RAC2$, and $CRP$) based on gene-region (P < 0.05) and SNP analyses (FDR <0.05). $VCAM1$ rs3176867, $ALOX5$ rs7099684, and $MPO$ rs2071409 were the three most significant SNPs. They showed similar effects on WBC subtypes, especially granulocytes, lymphocytes, and monocytes. A 3-SNP block in $ALOXE3$ (rs7215658, rs9892383, and rs3027208) showed a global association (omnibus P = 0.0008) with WBCs even though the three SNPs were not significant individually. Our study suggests that polymorphisms in innate immunity genes may play a role in benzene-induced hematotoxicity; however, independent replication is necessary.

IL10 and TNF variants and risk of non-Hodgkin lymphoma among three Asian populations

Hosgood III, H. Dean,Au, Wing-Yan,Kim, Hee Nam,Liu, Jie,Hu, Wei,Tse, Jovic,Song, Bao,Wong, Kit-fai,Lee, Je-Jung,Chanock, Stephen J.,Siu, L. P.,Purdue, Mark P.,Shin, Min-ho,Yu, Jinming,Liang, Raymond,K Springer-Verlag 2013 International journal of hematology Vol.97 No.6

<P>Genetic variation in immune-related genes, such as IL10 and TNF, have been associated with the development of non-Hodgkin lymphoma (NHL) in Caucasian populations. To test the hypothesis that IL10 and TNF polymorphisms may be associated with NHL risk in Asian populations, we genotyped 20 single nucleotide polymorphisms (SNPs) within the IL10 and TNF/LTA loci in three independent case-control studies (2635 cases and 4234 controls). IL10 rs1800871, rs1800872, and rs1800896 were genotyped in all three studies, while 5 of the remaining SNPs were genotyped in two studies, and 12 in a single study. IL10 rs1800896 was associated with B cell lymphoma [per-allele odds ratio (OR)?=?1.25, 95?% confidence interval (CI)?1.08-1.45; p trend?=?0.003], specifically diffuse large B cell lymphoma (DLBCL) (per-allele OR?=?1.29, 95?% CI?1.08-1.53; p trend?=?0.004), as well as T cell lymphoma (per-allele OR?=?1.44, 95?% CI?1.13-1.82; p trend?=?0.003). TNF rs1800629, which was genotyped in only two of our studies, was also associated with B cell lymphoma (per-allele OR?=?0.77, 95?% CI?0.64-0.91; p trend?=?0.003), specifically DLBCL (per-allele OR?=?0.69, 95?% CI?0.55-0.86; p trend?=?0.001). Our findings suggest that genetic variation in IL10 and TNF may also play a role in lymphomagenesis in Asian populations.</P>

A common coding variant in CASP8 is associated with breast cancer risk

Cox, Angela,Dunning, Alison M,Garcia-Closas, Montserrat,Balasubramanian, Sabapathy,Reed, Malcolm W R,Pooley, Karen A,Scollen, Serena,Baynes, Caroline,Ponder, Bruce A J,Chanock, Stephen,Lissowska, Jola Nature Pub. Co 2007 Nature genetics Vol.39 No.3

The Breast Cancer Association Consortium (BCAC) has been established to conduct combined case-control analyses with augmented statistical power to try to confirm putative genetic associations with breast cancer. We genotyped nine SNPs for which there was some prior evidence of an association with breast cancer: CASP8 D302H (rs1045485), IGFBP3 −202 C → A (rs2854744), SOD2 V16A (rs1799725), TGFB1 L10P (rs1982073), ATM S49C (rs1800054), ADH1B 3′ UTR A → G (rs1042026), CDKN1A S31R (rs1801270), ICAM5 V301I (rs1056538) and NUMA1 A794G (rs3750913). We included data from 9–15 studies, comprising 11,391–18,290 cases and 14,753–22,670 controls. We found evidence of an association with breast cancer for CASP8 D302H (with odds ratios (OR) of 0.89 (95% confidence interval (c.i.): 0.85–0.94) and 0.74 (95% c.i.: 0.62–0.87) for heterozygotes and rare homozygotes, respectively, compared with common homozygotes; P<SUB>trend</SUB> = 1.1 × 10<SUP>−7</SUP>) and weaker evidence for TGFB1 L10P (OR = 1.07 (95% c.i.: 1.02–1.13) and 1.16 (95% c.i.: 1.08–1.25), respectively; P<SUB>trend</SUB> = 2.8 × 10<SUP>−5</SUP>). These results demonstrate that common breast cancer susceptibility alleles with small effects on risk can be identified, given sufficiently powerful studies.