Identification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript.
Identification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript.
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DOI：
10.1007/s00439-011-0981-1
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发表时间：
2011-06
期刊：
影响因子：
5.3
通讯作者：
Eeles RA
中科院分区：
文献类型：
--
作者：
Kote-Jarai Z;Amin Al Olama A;Leongamornlert D;Tymrakiewicz M;Saunders E;Guy M;Giles GG;Severi G;Southey M;Hopper JL;Sit KC;Harris JM;Batra J;Spurdle AB;Clements JA;Hamdy F;Neal D;Donovan J;Muir K;Pharoah PD;Chanock SJ;Brown N;Benlloch S;Castro E;Mahmud N;O'Brien L;Hall A;Sawyer E;Wilkinson R;Easton DF;Eeles RA
全基因组关联研究（GWAS）已经确定了30多个前列腺癌（PrCa）易感位点。其中一个位点（rs2735839）位于一个可能的候选易感基因KLK3附近，该基因编码前列腺特异性抗原（PSA）。PSA被广泛用作PrCa检测和疾病监测的生物标志物。为了完善PrCa与该地区变异之间的关系，我们使用了来自英国和澳大利亚的两阶段GWAS样本的基因分型数据，以及癌症易感性遗传标记（CGEMS）研究。分别从HapMap2和1000基因组计划中获得197个和312个单核苷酸多态性（snp）。与PrCa最显著的关联是先前未确定的SNP rs17632542（组合P = 3.9 × 10−22）。通过对英国/澳大利亚GWAS的三个阶段的直接基因分型证实了这种关联，涉及10,405例病例和10,681例对照（合并P = 1.9 × 10−34）。rs17632542也被证明与PSA水平相关，它是KLK3中的非同义编码SNP （Ile179Thr）。利用分子动力学模拟，我们证明了这种变异有可能在蛋白质中引入改变或影响RNA剪接。我们认为rs17632542可能直接影响PrCa风险。本文的在线版本（doi:10.1007/s00439-011-0981-1）包含补充材料，授权用户可以使用。
Genome-wide association studies (GWAS) have identified more than 30 prostate cancer (PrCa) susceptibility loci. One of these (rs2735839) is located close to a plausible candidate susceptibility gene, KLK3, which encodes prostate-specific antigen (PSA). PSA is widely used as a biomarker for PrCa detection and disease monitoring. To refine the association between PrCa and variants in this region, we used genotyping data from a two-stage GWAS using samples from the UK and Australia, and the Cancer Genetic Markers of Susceptibility (CGEMS) study. Genotypes were imputed for 197 and 312 single nucleotide polymorphisms (SNPs) from HapMap2 and the 1000 Genome Project, respectively. The most significant association with PrCa was with a previously unidentified SNP, rs17632542 (combined P = 3.9 × 10−22). This association was confirmed by direct genotyping in three stages of the UK/Australian GWAS, involving 10,405 cases and 10,681 controls (combined P = 1.9 × 10−34). rs17632542 is also shown to be associated with PSA levels and it is a non-synonymous coding SNP (Ile179Thr) in KLK3. Using molecular dynamic simulation, we showed evidence that this variant has the potential to introduce alterations in the protein or affect RNA splicing. We propose that rs17632542 may directly influence PrCa risk. The online version of this article (doi:10.1007/s00439-011-0981-1) contains supplementary material, which is available to authorized users.
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影响因子：
14.9
作者：
Desmet FO;Hamroun D;Lalande M;Collod-Béroud G;Claustres M;Béroud C
通讯作者：
Béroud C
影响因子：
7.3
作者：
GOODFORD, PJ
通讯作者：
GOODFORD, PJ
影响因子：
2.8
作者：
Pampalakis, Georgios;Scorilas, Andreas;Sotiropoulou, Georgia
通讯作者：
Sotiropoulou, Georgia
影响因子：
30.8
作者：
Eeles, Rosalind A.;Kote-Jarai, Zsofia;Easton, Douglas F.
通讯作者：
Easton, Douglas F.
影响因子：
9.3
作者：
Michael, IP;Kurlender, L;Diamandis, EP
通讯作者：
Diamandis, EP