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Molecular Biology and Genetics |
Departments of Experimental Radiation Oncology [C. K. H., X. Z., L. G-R., R. I., R. D., M. W., E. L. T.] and Epidemiology [X. G., C. I. A.], University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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38% of the measured phenotypic variation could be attributed to effects from a few genetic factors. In addition, we identified one genetic factor on chromosome 17 in the MHC region. To identify any additional genetic loci that might influence interstrain variability, we conducted a genome-wide linkage scan using 214 markers and the phenotypically extreme 94 (of 268) F2 mice. In regions exceeding suggestive linkage (LOD = 2.8), we followed up with additional markers. This scan revealed evidence for quantitative trait locus (QTL) on chromosomes 17 (LOD = 4.2), 1 (LOD = 4.5), and 18 (LOD = 3.9), which influence susceptibility to radiation-induced pulmonary fibrosis. An additional region containing a QTL on chromosome 6, LOD = 4.6, showed linkage in female mice only. The evidence for linkage to chromosome 18 weakened when it was analyzed jointly with other markers. These four loci are estimated to account for 70% of the genetic contribution to this trait with chromosome 17 and 1 accounting for 28 and 24%, respectively. To confirm and better define the influence of the chromosome 17-linked QTL on radiation sensitivity, we conducted studies on congenic mice in which the linked region on chromosome 17 had been transferred onto a B6.AKR or a C3.SW background. The chromosome 17-linked QTL was confirmed to influence the phenotype as the fibrotic radiation response of B6.AKR-H2k mice was significantly less than that of B6 mice (P = 0.0001). The QTL on chromosome 17 for radiation-induced lung fibrosis is within the same region as QTLs identified for lung damage after other insults, including bleomycin, ozone, and particle exposure, as well as for asthma, suggesting that this region of chromosome 17 may harbor a "universal" lung injury gene. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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20% to resistant patients without exceeding an acceptable incidence of normal tissue complications. Although the proportion of sensitive individuals in a patient population is most likely small, this group of patients defines dose limitations to the whole population. Thus, the ability to prospectively screen patients for normal tissue complication susceptibility could allow more patient-individualized treatments to be given, which could enhance the therapeutic benefit. There are currently no assays, either genetic based or otherwise, available to determine individual susceptibility to radiation-induced lung damage. The finding that inbred strains of mice differ in their propensity to develop lung fibrosis after exposure to radiation (5, 6, 7, 8, 9)
provides a useful model to identify genetic factors influencing this trait. Studies by Sharplin and Franko (8
, 9) and by our lab (5)
showed that after whole thorax irradiation, various substrains of C3H mice develop a diffuse alveolitis, which resolves with no fibrosis, or is lethal, depending on the dose. C57BL/6J mice, in contrast, respond to lung irradiation with a less severe alveolitis and atelectatic regions of fibrosis, which increase with radiation dose. We completed previously an inheritance study in F1 and F2 mice derived from an intercross of C3Hf/Kam (C3H) and C57BL/6J (B6) mice and reported that susceptibility to radiation-induced pulmonary fibrosis has a heritability of 40% and is influenced by a few genetic factors (5)
. Our segregation results were consistent with the inheritance model proposed by Franko et al. (7)
, suggesting that susceptibility to radiation-induced lung fibrosis is controlled by two autosomal genes. In the prior inheritance study (5) , we reported an association of the fibrotic phenotype with a marker on chromosome 17. Mapping in this prior study was limited to investigating loci demonstrated to predict for pulmonary response to bleomycin,4 motivated by the consistent strain difference of B6 mice as susceptible to fibrosis in response to radiation or bleomycin, and C3H mice as resistant. We estimated that the chromosome 17 association accounted for 17% of the phenotypic variability of this trait in the radiation study. In the present study, a genome-wide scan was undertaken to identify additional loci influencing susceptibility to radiation-induced pulmonary fibrosis and to define the linkage region on chromosome 17. Furthermore, the influence of the chromosome 17-linked QTL5 on this trait was assessed by phenotyping congenic mice after radiation treatment.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Genotype.
DNA from F2 animals was prepared, using a DNA extraction kit from liver samples collected at necropsy. We genotyped the F2 intercross progeny by PCRs based on simple sequence repeats using mouse markers defined by Dietrich et al. (12)
. PCR was performed with one radiolabeled primer (P32) and one unlabelled primer, and we visualized the products by autoradiography of 6% polyacrylamide gels.
QTL Mapping.
We completed a scan of the genome by genotyping 94 phenotypically extreme mice from a total population of 268. The genotyped animals were mice with no fibrosis (n = 54) or >3% fibrosis (n = 40). Male and female mice were equally represented in both extremes. We completed the initial scan using 154 markers and produced genetic maps with a mean inter-marker distance of 10 cM. The data were analyzed using maximum likelihood methods in MapManager QTL software (13)
to identify loci that influence susceptibility to radiation-induced pulmonary fibrosis. To evaluate the data, MapManager fits a regression model in which the genetic marker information forms a design matrix that is used to predict the phenotype data. Once the regression coefficients are obtained, they are used to obtain the likelihood of the data, assuming approximate normality. A LRS is provided, which is the ratio of the likelihood of the data including versus not including the marker data in the regression model. The LRS of MapManager was converted to a comparable LOD score by dividing the LRS by 4.6 (= 2 ln; Ref. 10
). With the computed LOD scores, we assessed linkage using the conservative standards proposed by Lander and Kruglyak (14)
for an intercross for which a suggestive result is indicated by a LOD score of 
2.8, and a significant result is indicated by a LOD score of 4.3. The program was run initially to localize putative QTLs using an interval mapping approach (15)
and successively rerun conditioning on identified QTL regions (on chromosomes 17 and 1), which yielded significant results, to identify all remaining suggestive regions by using a composite interval mapping approach (16)
. Regions suggestive of linkage after conditioning were then followed up with higher density mapping by genotyping the 94 F2 mice with 60 additional markers. The mean inter-marker distance for the maps of these regions ranges from a minimum of 2.1 cM on chromosome 17 to a maximum of 4.3 cM on chromosome 1.
The support interval for the position of each QTL was defined by the region where the LOD score decreased by a value of one on either side of the peak (17)
. To identify linkage standards for our non-normal distribution phenotype, we further investigated the existence of the support for our localization of the QTLs by using the permutation test of Churchill and Doerge (18)
with 10,000 replicates. We performed this simulation study using the phenotypic and marker data (154 markers) from the 94 F2 mice. In the absence of any genetic linkage, a LOD score of 3.87 was found in 5% of replicate genome scans.
All 268 mice were genotyped for markers in the peak region defining each QTL identified in the linkage analysis. We assessed the percentage of variability that could be attributed to each locus and to the joint effects of the loci by using ANOVA (19) . ANOVA was also used to test for interactions among putative loci. The model of inheritance of each of the identified QTLs, as additive, dominant, or recessive, was assessed using t tests (20) . To construct hypothesis tests for mode of inheritance, we compared the general model, in which the phenotypic means are estimated for the three genotypes at each locus (B6/B6, C3H/C3H, and B6/C3H) to the other models. In this analysis, for the additive model, the heterozygote mean is the average of the homozygote means. For the dominant model, the heterozygotes are assumed to have the same mean as the C3H/C3H homozygotes. For the recessive model, the heterozygotes are assumed to have the same mean as the B6/B6 homozygotes.
Chromosome 17 Congenic Study.
The previous study (5)
identified an association of marker D17Mit13, in the region of the MHC, with radiation-induced pulmonary fibrosis. The two inbred strains used in our studies differ in MHC haplotype; the fibrosis-prone C57BL/6J strain is H2b, whereas the fibrosis-resistant C3Hf/Kam strain is H2k. We tested the effect of these two haplotypes on radiation-induced lung fibrosis by irradiating and phenotyping mice of the MHC congenic strains, C3.SW-H2b/SnJ and B6.AKR-H2k, using our standard protocol. The C3.SW-H2b/SnJ mouse was derived from an initial cross of a C3H/HcSnJ parent with a SW mouse, followed by subsequent back-cross matings to a C3Hf/Kam parent and selection only for the H2b region from the SW progenitor. The B6.AKR-H2k is similarly constructed to consist of a C57BL/6J mouse with a small interval near the MHC that is H2k (rather than H2b). Thirty-three male mice of each of the B6 and B6.AKR-H2k strains, and 24 male mice of each of the C3H and C3.SW-H2b/SnJ strains, were irradiated in this study. In addition, 13 female B6 and 16 female B6.AKR-H2k mice were treated. The congenic mice were genotyped using the chromosome 17 markers. The donor (AKR-H2k) region of the B6.AKR-H2k congenic mouse was determined to extend from D17Mit175 to D17Mit142 (a distance of 29.7 cM), whereas that of the C3.SW-H2b/SnJ congenic mouse was determined to extend from D17Mit198 to D17Mit177 (a distance of 8 cM; Table 1
, columns 4–6).
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Analysis of this data set defined the QTL region on chromosome 17 to have a maximum LOD score of 4.2 at D17Mit198 and a 1 LOD support interval from D17Mit213 to D17Mit16, encompassing 20 cM, as shown in Fig. 1A
. This region includes D17Mit13, the marker demonstrating previously strong evidence of linkage to both radiation (5)
and bleomycin-induced lung fibrosis.4
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. A maximum LOD score of 4.5 was found at marker D1Mit206, and the 1 LOD support interval extends from D1Mit102 to D1Mit406, which is 28 cM. To investigate if additional loci exist on chromosome 1, the analysis was repeated conditioning on the most significant locus, D1Mit206, and no additional loci were detected (LOD scores were <1.1 after conditioning).
The peak LOD scores and support intervals of the remaining QTLs detected are for chromosomes 6 (LOD = 4.6 at D6Mit254, extending from D6Mit366 to D6Mit15, 20 cM) and 18 (LOD = 3.9 at D18Mit52, extending from D18Mit53 to D18Mit207, 18 cM; Fig. 1, C and D
).
We tested for an independent effect of each locus by analyzing the effect of each locus after conditioning on other loci. The LOD score for the chromosome 1-linked QTL increased to 5.8 when the data were conditioned on marker D17Mit198. Likewise, when the data on chromosome 17 were analyzed conditioning on the putative QTL on chromosome 1, the LOD score increased to 5.2. The remaining putative QTLs were assessed after conditioning on chromosomes 1 and 17. By this analysis, the LOD score for the QTL on chromosome 6 was 2.9, and for the QTL on chromosome 18, the LOD score was 1.5. The localization of the significant QTLs remained the same on all four chromosomes after conditioning. Suggestive evidence for linkage also was noted on chromosome 19 between markers D19Mit13 and D19Mit18 with LOD of 2.9. Genotyping all animals at D19Mit13 led to a LOD score of 2.6. After conditioning on chromosome 1, the LOD score in this region dropped to 2.2. Because this LOD score did not meet our significance criteria, this region was not studied further.
We noted previously evidence of linkage of bleomycin-induced pulmonary fibrosis to chromosome 11;4 thus, we genotyped the phenotypically extreme 94-irradiated mice with 15 markers spanning this chromosome. No suggestive evidence of linkage was found on chromosome 11 for radiation-induced lung fibrosis (data not shown).
Table 2
shows the effect of genotype on the fibrotic phenotype (%PF) for all male and female F2 mice, separately, for the linkage marker on each chromosome. For all of the linkage markers, the presence of the B6 allele in an F2 mouse increases the phenotype, with the exception of chromosome 6. In this case, the presence of the B6 allele decreases the phenotype in females only, and %PF in males is independent of the genotype.
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. The Ps in Table 3
indicate whether the indicated models (additive, dominant, or recessive) fit the data, as well as the general model in which no constraints are placed on the heterozygous means. If the P is small, then the specific model is rejected. The inclusion of all F2 mice in the analysis resulted in an increased LOD score (LOD = 6.8) for the chromosome 17-linked QTL, relative to that based on the analysis of the 94 phenotypically extreme F2 mice only. The LOD score of the chromosome 1 locus did not change, and the LOD scores of the remaining two loci decreased but remain in the suggestive range, when all F2 mice are considered. As shown in Table 3
, the data are consistent with an additive model of inheritance for the putative QTLs on chromosomes 1, 17, and 18. For chromosome 6, the data are consistent with a recessive model. For males and females separately, an additive model fit the data for chromosomes 17, 1, and 18 in both sexes. For chromosome 6, females showed recessive inheritance, and males showed no evidence for linkage.
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Modeling of interactions among loci revealed modest evidence for an interaction between the QTLs localized to chromosomes 1 and 17 (P = 0.0005), but this interaction term has borderline significance after adjusting for the 24 tests for interactions that we did (with Bonferonni adjustment, the P is 0.01). Evaluation of these interaction effects shows that the animals homozygous for the B6 alleles at both D1Mit206 and D17Mit198 had a 1.45 lower fibrosis score than predicted from a model with no interactions (P = 0.03). In addition, mice homozygous for D1Mit206 B6 and homozygous for D17Mit198 C3H alleles had a 1.92 lower fibrosis score than predicted by a model with no interactions (P = 0.02). Although we detected a statistically significant interaction among the loci on chromosomes 1 and 17, additional studies are needed to evaluate the reproducibility and importance of this finding, because we detected the interaction after performing many tests, and the interaction effects are not very strong.
Congenic Mouse Studies.
The influence on radiation-induced lung fibrosis of the putative QTL on chromosome 17 identified in the prior study (5)
, as within the MHC, was further investigated using two strains of mice congenic for this region, the B6.AKR-H2k and C3.SW-H2b. After irradiation, both the survival time and percentage of survival of the two C3H strains, the C3H congenic strain, C3.SW-H2b, and the inbred partner strain, C3Hf/Kam, were not different, as all mice died by 120 days post-treatment (Fig. 2)
. In contrast, both the survival time and percentage of survival were increased in the congenic B6 background strain compared with mice of the B6 inbred partner strain. Phenotypically, the lungs of both C3H strains exhibited a florid diffuse alveolitis with no evidence of fibrosis (mean %PF = 0 for both; Fig. 3
). Although the predominant phenotype in both B6 strains was fibrosis, the mean fibrosis score (0.5% ± 0.3, SE) of the congenic B6 mice was lower than that of mice of the inbred partner strain (C57BL/6J; 4.3% ± 0.9, P = 0.0001), which is consistent with the survival data. These data were confirmed in two independent experiments. This difference in phenotype was also evident in female mice as the mean fibrosis of congenic female mice (0.3% ± 0.7) was lower than that of parental B6 female mice (3.3% ± 1.4, P = 0.02).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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26.5% of the F2 phenotypic variability to radiation-induced pulmonary fibrosis in C57BL/6J mice relative to C3Hf/Kam mice. Because 38% of the variance was heritable, we have thus explained 70% (26.5/38%) of the genetic contribution to this trait. Two of these loci, on chromosomes 17 and 1, are significantly linked in both male and female mice and are named Radpf-1 and Radpf-2, respectively, for radiation-induced pulmonary fibrosis. These two loci account for 24 and 28% of the genetic contribution to this trait, respectively. Previously, we demonstrated that a marker on chromosome 17, D17Mit13, was involved in radiation-induced lung fibrosis, accounting for 6.6% of the F2 phenotypic variance (5) . In the current study, the use of additional markers further defined the linkage region to be between the markers D17Mit164 and D17Mit64, a distance of 24 cM, and explained 10.5% of the F2 phenotypic variance or 28% of the heritable component. Radpf-1 is now more clearly defined, and the region includes the marker studied in our previous study. Furthermore, these data are in agreement with that for bleomycin-induced pulmonary fibrosis, where we have clear evidence of a QTL for the fibrotic phenotype in this same region of chromosome 17, between markers D17Mit198 and D17Mit16.4
The QTL region for both radiation- and bleomycin-induced fibrosis on chromosome 17 encompasses the mouse MHC, which extends from the gene KNSL2 (member of kinesin superfamily) at 15.15 cM to phosphoglycerate kinase 2 at 20.8 cM. The mouse MHC is a dense collection of genes that is involved in immunological responses and pathogen defense. Genes within the H2 complex and the human equivalent, the HLA, have been shown to be linked to inflammation and fibrosis in the lung after a variety of insults, including bleomycin (10 , 21 , 22) , ozone (23, 24, 25) , and particle exposure (26) , as well as in the disease asthma (27) . In a survey of 12 inbred strains of mice treated with different cytotoxic insults, including bleomycin but not radiation, Rossi (21) showed that lung fibrosis was associated with the H2 complex and that, in general, mice with the H2b haplotype were prone to pulmonary fibrosis, whereas strains with the H2k haplotype were not.
Table 1
shows the donor strain region for all three congenic strains (black shading) and the 1 LOD support interval showing linkage (gray shading). The most significant marker for radiation-induced pulmonary fibrosis, D17Mit198, is proximal to the congenic region, although the distal end of the 1 LOD support interval encompasses the congenic region in all three strains. The linkage mapping data do not exclude the possibility that the QTL on chromosome 17 is within the congenic region.
The fibrosis data in the irradiated lung of the congenic mice support the location of the chromosome 17 QTL within the congenic regions that we studied, which include the MHC. Specifically, it was shown that mice of the C3H congenic strain, C3.SW-H2b/SnJ, as well as the C3H.SW-Blmf2, when irradiated, did not develop fibrosis but died instead from alveolitis. This indicates that the C3H-derived genetic factor for alveolitis is outside the H2k region and that the H2b haplotype alone does not confer mild alveolitis and fibrosis (Table 1)
. After irradiation, mice of the second congenic strain, B6.AKR-H2k, were protected from both alveolitis and lung fibrosis, i.e., fewer died, and those that did, did so at later times after irradiation. This result indicates the existence of a fibrosis susceptibility locus within a 26.96 megabase region delineated here by the markers D17Mit16 and D17Mit20. The result also supports the C3H alveolitis factor to be separate from H2k and indicates that other B6-derived genetic loci contribute to fibrosis. Collectively, the congenic data confirm the Radpf-1 influence on lung radiation response and indicate that this QTL is not the sole genetic determinant of pulmonary fibrosis or alveolitis, which is consistent with the linkage data.
These studies support the suggestion that there may be a universal "fibrotic" gene (1 , 28) . Furthermore, QTL regions for lung damage after other cytotoxic insults, such as bleomycin,4 ozone (25) , and particle exposure-induced lung damage (26) , as well as for asthma (29) , have been mapped to mouse chromosome 17 within the same region as Radpf 1, providing further support for the suggested MHC location of this universal "fibrotic" gene.
Each of the putative QTL detected here has been localized to regions extending 15–20 cM in length, which is expected for QTL detection (30) . Thus, causative genes are speculative. The genes in the fibrotic pathway mapped to each putative QTL region may be considered positional and physiological candidates for further study. To identify physiological candidates, it is proposed that fibrosis develops after an inflammatory reaction in which the release of cytokines or apoptotic factors regulates lung fibroblast and type II cell proliferation and collagen production (1 , 31 , 32) .
Candidate genes mapping to Radpf-1 include TNF, MnSOD, plasminogen, and p21. Physiological evidence implicating TNF in lung fibrosis includes overexpression of the gene leading to the development of pulmonary inflammation and fibrosis (33) and the administration of anti-TNF antibodies significantly reducing the severity of inflammation and fibrosis (25 , 34) . MnSOD is a potent protector against oxidant damage in a number of tissues, including the lung, where radiation damage is at least partly mediated by the induction of free oxygen radicals. Epperly et al. (35, 36, 37) showed that MnSOD given to the fibrosis-prone C57BL/6J mice prevented organizing alveolitis after irradiation of the lung. Furthermore, gene therapy using a human MnSOD liposome complex reversed the resistance of MnSOD-deficient mice to radiation-induced lung damage (38, 39, 40) . Radpf-2 physiological candidates include fas ligand, two TNF ligands, and a number of selectin genes. A physiological candidate for the QTL on chromosome 6 is the TNF receptor, R1, or P55. There are no obvious candidates on chromosome 18.
Although the mechanism is unclear, pulmonary inflammation and fibrosis most likely occur via more than one pathway (31
, 41, 42, 43)
. Studies of the time course to develop lung damage in mice support distinct mechanisms. In the radiation model used here, fibrosis developed in mice prone to this injury 4 months after the radiation insult (5)
. In contrast, pulmonary fibrosis appears in B6 mice within 2 months of bleomycin treatment (10)
. In addition to the disparate time course, distinct genetic loci (excluding Radpf-1) have been mapped for each of these traits. Significant linkage to chromosome 11 has been identified for bleomycin-induced lung fibrosis but was not found here for lung fibrosis after irradiation. In addition, the QTL regions identified in the present study on chromosomes 1, 6, and 18 do not overlap with those linked to bleomycin sensitivity.4
Similarly, other QTL regions found to be associated with ozone- (25)
and particle- (26)
induced lung damage and asthma (29)
also do not overlap with those mapped here for radiation-induced lung fibrosis. Further study of the common loci on chromosome 17 and distinct genetic loci mapped for these traits will help elucidate the fibrotic pathway(s) in the lung.
In summary, the congenic mouse data generated here show radiation-induced pulmonary fibrosis, in this model, to be influenced by a QTL region on chromosome 17, Radpf-1, and inbred partner strain background. Furthermore, the effect of the genetic background was identified in the linkage study to be because of the QTLs on chromosomes 1 (Radpf-2), 6, and possibly 18. Further work with this model may uncover a universal (chromosome 17) and radiation-specific (chromosomes 1, 6, and 18) factors influencing susceptibility to pulmonary fibrosis.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by NCI RO1CA 64193 (to E. L. T.) and RO1HG02275 (to C. I. A.). 
2 C. K. H. and X. Z. contributed equally to this manuscript.
3 To whom requests for reprints should be addressed, at the Department of Experimental Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Box 066, 1515 Holcombe Boulevard, Houston, TX 77030.
4 E. L. Travis, unpublished data.
5 The abbreviations used are: QTL, quantitative trait locus, Radpf, radiation pulmonary fibrosis; TNF, tumor necrosis factor; MnSOD, manganese superoxide dismutase; PF, pulmonary fibrosis; LRS, likelihood ratio statistic.
6 R. Dejournett, unpublished data.
Received 1/11/02. Accepted 5/ 2/02.
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and TGF-ß correlates with delay of organizing alveolitis/fibrosis. Biol. Blood Marrow Transplant., 5: 204-214, 1999.[Medline]
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