Jorgenson Eric, Deitcher Steven R, Cicek Mine, Liu Xin, Plummer Sarah, Casey Graham, Witte John S
Department of Epidemiology and Biostatistics, Center for Human Genetics, University of California, San Francisco, San Francisco, California 94143-0794, USA.
Prostate. 2007 Feb 1;67(2):172-7. doi: 10.1002/pros.20512.
Variation in the expression of plasminogen activator inhibitor type-1 (PAI-1) is associated with many human diseases, including several types of cancer. In particular, tumor cell overexpression of PAI-1 has been found to inhibit prostate cancer tumor growth, angiogenesis, and metastasis in mouse models. Normal host cell expression of PAI-1 is influenced by the 4G/5G insertion/deletion polymorphism in the promoter region of the PAI-1 gene. To evaluate the effect of PAI-1 expression on cancer development, we examined the association of the 4G/5G polymorphism in a sibling-based case-control study of prostate cancer.
One thousand one hundred thirty seven subjects, 655 cases, and 482 sibling controls from 526 families, were recruited from the major medical institutions in the greater Cleveland, OH area and from the Henry Ford Health System, Detroit, MI. A Cox age-of-onset model with robust variance estimation was used to evaluate the association between the PAI-1 4G/5G polymorphism and prostate cancer.
No association was observed between the PAI-1 4G/5G polymorphism and prostate cancer in the entire sample. We did, however, identify a statistically significant association between the PAI-1 4G/5G polymorphism and prostate cancer in subjects with a family history of this disease (OR = 1.28, 95% CI 1.02-1.61, P-value = 0.036). The PAI-1 5G/5G genotype, associated with lower PAI-1 expression, appears to drive this result as it was associated with an increased risk of prostate cancer and an earlier mean age of onset compared to those with the 4G/4G genotype (OR = 1.83, 95% CI 1.12-2.99) while the 4G/5G genotype group did not show a significant difference in prostate cancer risk compared to the 4G/4G genotype group (OR = 0.98, 95% CI 0.75-1.28).
These observations suggest that the 4G/5G polymorphism in PAI-1 may explain some of the increased risk and earlier mean age of onset of prostate cancer due to a positive family history.
纤溶酶原激活物抑制剂-1（PAI-1）表达的变化与许多人类疾病相关，包括几种类型的癌症。特别是，在小鼠模型中发现肿瘤细胞PAI-1的过表达可抑制前列腺癌肿瘤的生长、血管生成和转移。PAI-1在正常宿主细胞中的表达受PAI-1基因启动子区域4G/5G插入/缺失多态性的影响。为了评估PAI-1表达对癌症发展的影响，我们在一项基于同胞的前列腺癌病例对照研究中检测了4G/5G多态性的相关性。
从俄亥俄州克利夫兰市及周边地区的主要医疗机构和密歇根州底特律市的亨利福特健康系统招募了1137名受试者，其中655例为病例，482例为来自526个家庭的同胞对照。使用具有稳健方差估计的Cox发病年龄模型来评估PAI-1 4G/5G多态性与前列腺癌之间的相关性。
在整个样本中未观察到PAI-1 4G/5G多态性与前列腺癌之间的关联。然而，我们确实在有前列腺癌家族史的受试者中发现PAI-1 4G/5G多态性与前列腺癌之间存在统计学上的显著关联（比值比=1.28，95%置信区间1.02-1.61，P值=0.036）。与较低PAI-1表达相关的PAI-1 5G/5G基因型似乎导致了这一结果，因为与4G/4G基因型相比，它与前列腺癌风险增加和更早的平均发病年龄相关（比值比=1.83，95%置信区间1.12-2.99），而4G/5G基因型组与4G/4G基因型组相比，前列腺癌风险没有显著差异（比值比=0.98，95%置信区间0.75-1.28）。
这些观察结果表明，PAI-1中的4G/5G多态性可能解释了由于家族史阳性导致的前列腺癌风险增加和更早平均发病年龄的部分原因。
