Department of Clinical Pharmacology, University Medical Center Göttingen, Göttingen, Germany.
Int J Radiat Oncol Biol Phys. 2011 Mar 1;79(3):866-74. doi: 10.1016/j.ijrobp.2010.08.040. Epub 2010 Dec 22.
To determine whether genetic variability in TGFB1 is related to circulating transforming growth factor-β1 (TGF-β1) plasma concentrations after radiotherapy and to radiosensitivity of lymphoid cells.
Transforming growth factor-β1 plasma concentrations (n=79) were measured in patients 1 year after radiotherapy and chromosomal aberrations (n=71) ex vivo before therapy start. Furthermore, TGF-β1 secretion and apoptosis were measured in isolated peripheral blood mononuclear cells of 55 healthy volunteers. These phenotypes were analyzed in relation to five germline polymorphisms in the 5' region of the TGFB1 gene. Because of high linkage disequilibrium, these five polymorphisms reflect frequent genetic variation in this region. A presumed impact of TGF-β1 on DNA damage or repair was measured as micronucleus formation in 30 lymphoblastoid cell lines.
We identified a hypofunctional genetic haplotype termed H3 tagging the 5' region of the TGFB1 gene encoding TGF-β1. H3 was associated with lower TGF-β1 plasma concentrations in patients (p=0.01) and reduced TGF-β1 secretion in irradiated peripheral blood mononuclear cells (p=0.003). Furthermore, cells with H3 were less prone to induction of chromosomal aberrations (p=0.001) and apoptosis (p=0.003) by irradiation. The hypothesis that high TGF-β1 could sensitize cells to DNA damage was further supported by increased micronuclei formation in 30 lymphoblastoid cell lines when preincubated with TGF-β1 before irradiation (p=0.04).
On the basis of TGF-β1 plasma levels and radiation sensitivity of lymphoid cells, this study revealed a putatively hypofunctional TGFB1 haplotype. The significance of this haplotype and the suggested link between TGF-β1 function and DNA integrity should be further explored in other cell types, as well as other experimental and clinical conditions.
确定转化生长因子-β1（TGF-β1）基因的遗传多态性是否与放射治疗后循环 TGF-β1 血浆浓度以及淋巴细胞的放射敏感性有关。
在放射治疗后 1 年测量 79 例患者的 TGF-β1 血浆浓度，并在治疗前开始时测量 71 例患者的染色体畸变。此外，还测量了 55 名健康志愿者分离的外周血单个核细胞中的 TGF-β1 分泌和细胞凋亡。这些表型与 TGFB1 基因 5' 区的 5 个种系多态性相关分析。由于高度连锁不平衡，这 5 个多态性反映了该区域的常见遗传变异。TGF-β1 对 DNA 损伤或修复的潜在影响通过 30 个淋巴母细胞系中的微核形成来测量。
我们确定了一种低功能遗传单倍型，称为 H3，它标记了 TGFB1 基因的 5' 区域，该区域编码 TGF-β1。H3 与患者 TGF-β1 血浆浓度降低相关（p=0.01），并与照射后外周血单个核细胞中 TGF-β1 分泌减少相关（p=0.003）。此外，携带 H3 的细胞对辐射引起的染色体畸变（p=0.001）和细胞凋亡（p=0.003）的诱导作用较弱。当在照射前用 TGF-β1 孵育时，30 个淋巴母细胞系中的微核形成增加，进一步支持了高 TGF-β1 可使细胞对 DNA 损伤敏感的假设（p=0.04）。
基于 TGF-β1 血浆水平和淋巴细胞的放射敏感性，本研究揭示了一种潜在的低功能 TGFB1 单倍型。该单倍型的意义以及 TGF-β1 功能与 DNA 完整性之间的建议联系应在其他细胞类型以及其他实验和临床条件下进一步探索。
