Sun Jielin, Lange Ethan M, Isaacs Sarah D, Liu Wennuan, Wiley Kathleen E, Lange Leslie, Gronberg Henrik, Duggan David, Carpten John D, Walsh Patrick C, Xu Jianfeng, Chang Bao-Li, Isaacs William B, Zheng S Lilly
Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Prostate. 2008 Apr 1;68(5):489-97. doi: 10.1002/pros.20695.
Multiple variants in three regions at 8q24 are consistently found to be associated with prostate cancer (PCa) risk in population-based association studies. The role that these variants may play in familial prostate cancer risk has not been extensively investigated.
We evaluated 12 SNPs at three 8q24 regions using population-based association and family-based linkage and association methods in hereditary PCa (HPC) probands and their families, non-HPC patients, and unaffected screened controls, all recruited at Johns Hopkins Hospital.
For multiple variants in Region 1 (e.g., rs1447295) and Region 2 (e.g., rs16901979), we found statistically significantly higher frequencies of previously identified risk alleles and genotypes in HPC probands than in unaffected controls. Furthermore, in Region 2 the risk alleles were statistically significantly more frequent in HPC probands than in non-HPC patients. Family-based transmission tests found risk alleles of SNPs in Region 2, but not in Regions 1 and 3, were significantly over-transmitted to affected men in these families. We found little evidence supporting PCa linkage at 8q24 in 168 HPC families, in part explained by the observation of multiple, different risk allele-containing haplotypes segregating in the vast majority of these families.
Our study further supports the presence of PCa susceptibility loci at 8q24, particular at Region 2, and also provides evidence that these SNPs play an important role in familial prostate cancer. Large family-based studies are needed to confirm our novel findings.
在基于人群的关联研究中，始终发现8q24三个区域的多个变异与前列腺癌（PCa）风险相关。这些变异在家族性前列腺癌风险中可能发挥的作用尚未得到广泛研究。
我们使用基于人群的关联分析以及基于家系的连锁和关联分析方法，对约翰霍普金斯医院招募的遗传性PCa（HPC）先证者及其家族、非HPC患者和未受影响的筛查对照，评估了8q24三个区域的12个单核苷酸多态性（SNP）。
对于区域1（如rs1447295）和区域2（如rs16901979）中的多个变异，我们发现HPC先证者中先前确定的风险等位基因和基因型的频率在统计学上显著高于未受影响的对照。此外，在区域2中，HPC先证者中的风险等位基因在统计学上比非HPC患者更常见。基于家系的传递检验发现，区域2中SNP的风险等位基因（而非区域1和区域3中的）在这些家族中显著过度传递给患病男性。在168个HPC家族中，我们几乎没有发现支持8q24存在PCa连锁的证据，部分原因是观察到绝大多数这些家族中存在多种不同的含风险等位基因的单倍型在分离。
我们的研究进一步支持8q24存在PCa易感位点，特别是在区域2，并且还提供了证据表明这些SNP在家族性前列腺癌中起重要作用。需要开展大规模的基于家系的研究来证实我们的新发现。
