Download Assessment of space-radiation effects on immune function on the

1. Title
FY2006 Ground - based Research Program for Space Utilization Research Report
2. Research Term
FY2006〜2008
3. Research Fields
Life Science
4. Research Categories
Exploratory Research for Space Utilization
5. Research Theme
Assessment of space-radiation effects on immune function on the basis of genetic polymorphisms
and immunological parameters
6. Investigators
Kengo Yoshida, Tomonori Hayashi, and Kei Nakachi
7. Organization
Radiation Effects Research Foundation
5-2 Hijiyama Park, Minami-ku, Hiroshima City, 732-0815, Japan.
8. Summary of Research
The results of this project are shown below:
(1) Association between genetic polymorphism of inflammatory cytokine IL-10, plasma levels of IL-10,
and radiation exposure
Interleukin-10 (IL-10) is an anti-inflammatory cytokine produced by T-cells, monocytes, and other cells,
and immune-suppression by IL-10 is thought to act on cancer development. In this study targeting a
group of A-bomb survivors, plasma IL-10 levels were measured as an immunological biomarker, and 10
analyzed. Four SNPs among the analyzed ones
were closely linked to each other, suggesting the
presence of a haplotype block to which these 4
SNPs belong.
Thus, association between the
IL-10 haplotypes, plasma IL-10 levels, and
radiation exposure was analyzed.
indicated
that
plasma
IL-10
The analysis
levels
varied
significantly depending on the IL-10 haplotyping
and that radiation exposure greatly enhanced
IL-10 levels for the ATTA / ATTA homozygote
IL-10 levels
(pg/ml, mean ± SE)
SNPs located in the IL-10 gene region were
6.0
ATTA / ATTA
ATTA / GGCG
GGCG / GGCG
(n = 305)
5.0
4.0
3.0
n=32
32
6
Non-exposed
(< 5 mGy)
n=109 107
19
Exposed
(≧5 mGy)
Radiation dose
(Fig.1).
Fig.1. Association between IL-10 haplotypes,
plasma levels of IL-10, and radiation exposure
In terms of plasma levels of inflammatory cytokine IL-10, the findings suggest the possibility that
individuals having certain IL-10 haplotypes are highly susceptible to cosmic radiation.
(2)
Association between EGFR genetic polymorphism and cancer development
Epidermal growth factor receptor (EGFR) is well known for its crucial roles in cell
differentiation/proliferation and development/progression of cancer (especially lung and breast cancers),
and recent studies have suggested that EGFR may be engaged in the regulation of chemokine genes’
expression and inflammatory responses. This study focused on EGFR as an inflammation-related gene and
assessed association between EGFR genetic polymorphism and cancer development among A-bomb
survivors. A copy number variation of CA (cytosine adenine) repeat sequence, which is located at EGFR
intron-1, is known to be inversely associated with expression level of EGFR mRNA. Regression analysis
using Long genotype (37 CA repeats and above) as a reference showed that risk of all sites cancer as well
as that of lung cancer was increased among individuals with Short genotype (data not shown). Specifically
concerning lung cancer, no significant
association was observed between EGFR CA
repeat polymorphism and risk of cancer
Control
Genotypes
Lung cancer
no. (%)
no. (%)
OR (95% CI)*
Long
754 (64.1)
12 (41.4)
1.00 (Ref.)
Short
422 (35.9)
17 (58.6)
2.67 (1.24 - 5.77)
Non-exposed
development in the high-dose range (1,000 mGy
and above), however significant association
between short CA repeats and high risk of
cancer development was observed in the dose
1-999 mGy
Long
1061 (61.2)
27 (50.9)
1.00 (Ref.)
Short
672 (38.8)
26 (49.1)
1.71 (0.97 - 2.99)
Long
486 (63.0)
30 (69.8)
1.00 (Ref.)
Short
286 (37.0)
13 (30.2)
0.78 (0.40 - 1.54)
range under 1 mGy (Table 1). These results
indicate a minor contribution of the EGFR
signaling pathway to lung cancer development
>= 1000 mGy
at a high radiation dose, also provide a clue to
*Odds ratio (OR) adjusted for age, gender, city, and smoking status.
elucidate the mechanisms of
radiation-associated lung carcinogenesis.
Table 1. EGFR CA repeat polymorphism and lung cancer risk
By enlarging the scope of such research in the future to cover immunity-/inflammation-related genes
other than IL-10 and EGFR, as well as DNA repair genes, it should be possible to comprehensively predict
the health effects of cosmic radiation in those living in outer space on the basis of genetic polymorphisms
and immunological biomarkers.
9. Publication List
1) Kengo Yoshida, Tomonori Hayashi, Yukari Morishita, Hiroko Nagamura, Mayumi Maki, Kazue Imai, Yoichiro Kusunoki,
Kei Nakachi. A genome approach to inter-individual variations in cancer susceptibility among atomic-bomb survivors.
12th Congress of the International Association of Biomedical Gerontology, Molecular Mechanisms and Models of Ageing
(2007.5.20-5.24, Spetses Island, Greece)
2) Kengo Yoshida, Tomonori Hayashi, Kazue Imai, Mayumi Maki, Hiroko Nagamura, Yukari Morishita, Yoichiro Kusunoki,
Kei Nakachi. Polymorphic NBN and EGFR genes affect cancer development among atomic-bomb survivors in Hiroshima
and Nagasaki. Cold Spring Harbor Meeting, Molecular Genetics of Aging (2008.9.24-9.28, New York, USA)
3) Kengo Yoshida, Tomonori Hayashi, Yukari Morishita, Hiroko Nagamura, Mayumi Maki, Misae Sora, Kazue Imai,
Yoichiro Kusunoki, Kei Nakachi. Genetic factors underlying individual responses to radiation exposure and cancer risks.
Nagasaki Medical Journal (2008, in press)
10. URL