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- 저자 : Glubb, Dylan (검색결과 2 건)
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The GENICA Network,kConFab Investigators,Norwegian Breast Cancer Study,Glubb, Dylan M.,Maranian, Mel J.,Michailidou, K.,Pooley, Karen A.,Meyer, Kerstin B.,Kar, S.,Carlebur, S.,O'Reilly, M.,Betts, Josh University of Chicago Press [etc.] 2015 American journal of human genetics Vol.96 No.1
Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER<SUP>+</SUP>: odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, p<SUB>trend</SUB> = 5.7 x 10<SUP>-44</SUP>) and estrogen-receptor-negative (ER<SUP>-</SUP>: OR = 1.10, 95% CI = 1.05-1.15, p<SUB>trend</SUB> = 3.0 x 10<SUP>-4</SUP>) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [p<SUB>cond</SUB> = 1.61 x 10<SUP>-5</SUP>]) and five variants composing iCHAV3 (lead rs11949391; ER<SUP>+</SUP>: OR = 0.90, 95% CI = 0.87-0.93, p<SUB>cond</SUB> = 1.4 x 10<SUP>-4</SUP>). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival.
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Association analysis identifies 65 new breast cancer risk loci
Michailidou, Kyriaki,Lindströ,m, Sara,Dennis, Joe,Beesley, Jonathan,Hui, Shirley,Kar, Siddhartha,Lemaç,on, Audrey,Soucy, Penny,Glubb, Dylan,Rostamianfar, Asha,Bolla, Manjeet K.,Wang, Qin,Tyr Macmillan Publishers Limited, part of Springer Nat 2017 Nature Vol.551 No.7678
<P>Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry(1). We identified 65 new loci that are associated with overall breast cancer risk at P < 5 x 10(-8). The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.</P>
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