This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Haiman, C. A. Articles by Henderson, B. E. Search for Related Content PubMed PubMed Citation Articles by Haiman, C. A. Articles by Henderson, B. E.

Genetic Variation in Angiotensin I-Converting Enzyme (ACE) and Breast Cancer Risk

The Multiethnic Cohort¹

Departments of Preventive Medicine [C. A. H., S. O. H., P. B., B. E. H.] and Emergency Medicine [S. O. H.], University of Southern California, Keck School of Medicine, Norris Comprehensive Cancer Center, Los Angeles, California 90089, and Cancer Etiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii 96813 [L. N. K.]

	ABSTRACT

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
The A-240T and I/D polymorphisms in the angiotensin I-converting enzyme (ACE) gene are markers of circulating ACE levels and have been associated with numerous cardiovascular disease outcomes. More recently, the low-activity A and I alleles at these polymorphic sites have been inversely related with breast cancer risk. We assessed the relationship between the A-240T and I/D ACE variants and breast cancer risk in a case-control analysis (n = 1263 cases with invasive breast cancer and 2269 controls) among African-American, Japanese, Latina, and white women in the Multiethnic Cohort Study. Odds ratios and 95% confidence intervals are presented adjusted for established breast cancer risk factors. Among all women combined, we observed no significant association between the A-240T polymorphism and breast cancer risk. For the I/D polymorphism, contrary to expectation, women with the I/I genotype had a marginally significant increase in breast cancer risk (versus DD genotype: odds ratio, 1.30; 95% confidence interval, 1.05–1.61), although associations were not entirely consistent across ethnic groups. These data do not support the hypothesis that women with lower ACE levels, as predicted by the low-activity A and I ACE alleles, are at reduced risk of breast cancer. Overall, these results suggest that the A-240T and I/D ACE polymorphisms are not likely to be strong predictors of breast cancer risk.

	INTRODUCTION

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Angiotension II is a key regulator of blood pressure homeostasis in humans and is produced from angiotensin I by ACE.³ Plasma ACE concentrations vary between individuals, and a substantial proportion of the interindividual difference in ACE levels is governed by genetic variation at the ACE locus (1) . Two polymorphisms in the ACE gene, a 287-bp Alu insertion/deletion (I/D) polymorphism in intron 16 and the A-240T polymorphism in the 5'-flanking region, have been associated with circulating ACE levels (1 , 2) . Studies subsequently evaluating the I/D polymorphism as a marker of blood pressure and risk of myocardial infarction, however, have provided inconsistent results (3, 4, 5, 6, 7) .

An etiologic relationship between hypertension and hormone-related cancer incidence has been suggested. Hypertension during pregnancy and after menopause has been positively associated with breast cancer risk in a small number of studies (8 , 9) . Women using ACE inhibitors and other antihypertensive medications have been reported to have lower risks of breast cancer, although study findings have not been entirely consistent (10, 11, 12) . There are new data to support the direct involvement of angiotensin II in breast cell proliferation (13) , angiogenesis, and tumor metastasis (14) , key processes implicated in breast cancer development and progression. Based on the prior evidence linking ACE activity and angiotensin II with breast cancer, Koh et al. (15) hypothesized that women carrying the low-activity (A and I) alleles of the ACE A-240T and I/D polymorphisms would have lower ACE levels and decreased synthesis of angiotensin II and, consequently, would be less susceptible to developing breast cancer. In a breast cancer case-control study among Chinese women from Singapore (n = 189 cases), the authors reported that women with the low-activity genotypes were at decreased risk of breast cancer (ID + II genotypes versus DD: OR, 0.63; 95% CI, 0.37–1.07; AT + AA genotypes versus TT: OR, 0.55; 95% CI, 0.34–0.90; Ref. 15 ).

In the present study we have evaluated the A-240T and I/D polymorphisms in the ACE gene in relation to breast cancer risk among African-American, Japanese, Latina, and white women in a large nested case-control in the MEC. We also characterized the degree of LD between the two polymorphisms in each ethnic group.

	MATERIALS AND METHODS

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
The MEC consists of 215,251 men and women in Hawaii and Los Angeles and has been described in detail elsewhere (16) . In brief, the cohort is comprised predominantly of Hawaiian, Japanese, and white residents living in Hawaii and African-Americans and Latinos living in Los Angeles. Between 1993 and 1996, participants entered the MEC by completing a 26-page self-administered mail questionnaire that asked detailed information about dietary habits, demographic factors, personal behaviors, history of prior medical conditions (e.g., heart attack, diabetes, and cancer), current medication use, family history of common cancers, and for women, reproductive history and exogenous hormone use (HRT). Potential cohort members were identified primarily through the Department of Motor Vehicles drivers’ license files in Hawaii and California and, additionally for African-Americans, Health Care Financing Administration data files. The participants were between the ages of 45 and 75 years when they entered the cohort.

Eligible cases in this nested breast cancer case-control study consisted of African-American, Japanese, Latina, and white women with incident breast cancer (including second primaries) diagnosed after enrollment in the MEC through May 2002. Incident cancers in the MEC are identified by cohort linkage to population-based Surveillance, Epidemiology and End Results (SEER) cancer registries in Hawaii and Los Angeles and to the California State cancer registry. Information on stage of disease at the time of diagnosis is also collected from the cancer registries. Women with nonlocalized tumors were classified as having advanced disease. Beginning in 1995, blood sample collection was initiated from incident breast cancer cases, including those diagnosed since recruitment into the cohort. At this time, blood collection was also initiated from a random sample of the cohort within each ethnic group to serve as controls for genetic analyses in the cohort. The participation rates for providing a blood sample are 74% and 66% for cases and controls, respectively. Controls in this study were women without breast cancer before entry into the cohort and without a diagnosis up to May 2002. The breast cancer case-control study consists of 1263 breast cancer cases (316 with advanced disease) and 2269 controls. This study was approved by the Institutional Review Boards at the University of Southern California and at the University of Hawaii.

Laboratory Methods.
DNA was extracted from WBC fractions using the Qiagen DNA Blood Kit (Qiagen, Valencia, CA). Genotyping was performed by the 5' nuclease TaqMan allelic discrimination assay (Applied Biosystems, Foster City, CA) using the protocol described by Koh et al. (15) . Laboratory personnel were blinded to case-control status, and quality control samples (5%) were inserted to validate genotyping procedures. The concordance rates for the blinded samples were 99% and 97% for the A-240T and I/D polymorphisms, respectively. Subjects missing genotype information were removed from variant specific analyses [A-240T, n = 294 (8.3%); I/D, n = 408 (11.6%)].

Statistical Analysis.
Because of the initially delayed but thereafter ongoing collection of samples from cases and controls, we have adopted a standard case-control approach to statistical analysis. In this analysis, we adjusted for age by equating the age at diagnosis of the case to the age at blood draw of the control. No adjustment was made for calendar year of blood draw because the cases were collected over a relatively short time period of 7 years. Eighty-eight controls became cases after their blood draw as a control; these women were included in the analysis as cases with age at diagnosis as the age variable (other approaches to deal with these cases did not alter the results because they comprise such a small fraction of the total cases).

LD between the A-240T and I/D alleles was evaluated among controls for each ethnic group using the D' statistic (17) . ORs and 95% CIs were calculated for cases and controls using unconditional logistic regression. In addition to age (<55 years, 55–64 years, 65 years) we also adjusted for the established breast cancer risk factors: age at menarche (12 years, 13–14 years, 15 years), parity (nulliparous, 1 child, 2–3 children, 4+ children), menopausal status/HRT use [five categories: (a) premenopausal women; (b) postmenopausal women (women with a natural menopause or bilateral oophorectomy)/never user of HRT; (c) postmenopausal women/past HRT user; (d) postmenopausal women/current HRT user; and (e) women with an unknown menopausal or unknown HRT user status], history of breast cancer in a first-degree family relative (yes/no), and current alcohol consumption (0 drinks/day, 1–2 drinks/day, 3+ drinks/day). Body mass index was not a confounder in the analysis and was not included in the multivariate models. Controlling for self-reported history of high blood pressure also did not alter the results. For comparison with the data of Koh et al. (15) , polymorphisms were evaluated using the TT (A-240T) and DD (I/D) hypothesized high-risk genotypes as the reference categories. Analyses were stratified by ethnicity, and a summary OR was estimated controlling for age*ethnicity and the established breast cancer risk factors. We also evaluated associations among women not likely to be users of ACE inhibitors. We defined users as women reporting a previous history of high blood pressure or any use of high blood pressure medication (n = 1549). All controls were included in analyses by stage of disease (localized or advanced). One case missing age at diagnosis was removed from all analyses. We used the SAS statistical package version 8.2 for all analyses (SAS Institute, Cary, NC).

	RESULTS

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Among all women, the mean age of the cases and controls was 64.3 and 63.4 years, respectively. The mean age was similar for cases and controls within each ethnic group (Table 1) . The distributions of established breast cancer risk factors were generally consistent with expectation and were consistent with what we observed in the overall cohort (18) . Compared with controls, cases were more likely to be a current or past user of HRT and to have a first-degree family history of breast cancer. Cases were also more likely to be nulliparous and to have had children at a later age. These associations were generally consistent across all ethnic groups (Table 1) .

Among all women combined, we observed no significant association between A-240T genotype and risk of breast cancer (Table 2) ; compared with the TT genotype, the adjusted OR for A/A homozygotes was 1.05 (95% CI, 0.83–1.33). Associations were not consistent across ethnic groups. Compared with women with the TT genotype, African-American women homozygous for the A allele were at lower risk (OR, 0.59; 95% CI, 0.37–0.94; P for trend, 0.02), whereas a significant positive association was observed for Latinas (OR, 1.91; 95% CI, 1.07–3.41; Table 2 ). We observed a modest positive association between the I allele and breast cancer risk (ID versus DD genotype: OR, 1.16; 95% CI, 0.96–1.41; II versus DD genotype: OR, 1.30; 95% CI, 1.05–1.61; P for trend, 0.02; Table 2 ). Evidence of this association was strongest among the African Americans (II versus DD genotype: OR, 1.76; 95% CI, 1.15–2.68) and noted in all groups except for the Japanese (II versus DD genotype: OR, 1.04; 95% CI, 0.62–1.75). Results were similar when restricting the analysis to women with advanced disease and when limiting the analysis to women classified as not using ACE inhibitors (data not shown).

	DISCUSSION

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

In our study, the prevalence of these two polymorphisms in the different ethnic groups was similar to those reported in other studies (2 , 15 , 19) . Among the Japanese controls, the frequencies of the A allele (63%) and I allele (66%) were nearly identical to those observed among the Chinese women in the study by Koh et al. (Ref. 15 ; A allele, 66%; I allele, 68%). We observed considerable variability in LD between these two markers across ethnic groups; the A and I alleles were more tightly linked among the Japanese, Latinas, and whites and in almost complete linkage equilibrium among the African Americans. These data are consistent with known differences in the extent of LD across the ACE locus between African and non-African populations as reported by other studies (20 , 21) .

Segregation and linkage studies have provided strong support for an ACE-linked quantitative trait locus (2 , 22 , 23) , although the underlying functional variants involved in predicting differences in ACE levels have not been defined. In an initial study in a white European population, individuals with the A allele of the A-240T polymorphism were observed to have lower ACE levels (2) . Subsequent studies have not confirmed this finding (24 , 25) . A more recent study among an African population reported the A allele to be associated with increased ACE concentration (25) . Associations have been more consistently observed with the I/D Alu polymorphism in intron 16, with the I allele demonstrated to be a marker of lower circulating ACE (1 , 2 , 22) . In a white European population, the majority of variation in ACE levels has been localized to an 18-kb region located between two ancestral recombination sites in the ACE gene (26) . The high degree of LD observed between the I/D polymorphism and dozens of other variants in this region has hampered efforts to undercover the functional variant underlying interindividual variation in circulating ACE levels in white populations. Cladistic haplotype analyses of the ACE gene have provided evidence that the I/D variant is not likely to be the underlying functional polymorphism (19 , 27) . In a study among Nigerians, Cox et al. (19) observed significant differences in ACE levels between individuals with haplotypes harboring the I allele, suggesting that this allele may be a marker of low ACE levels in some populations, but not all populations. Differences in LD between populations may also explain the inconsistent associations that we observed with the A-240T polymorphism between African Americans and the other groups.

Genetic associations initially reported in small studies are rarely replicated in subsequent studies (28) . A strength of the present study is the large sample size (>270 cases) among each of four ethnic populations. This study design enables the reproducibility of an association to be evaluated across multiple ethnic groups, providing more convincing support for an underlying relationship between a genetic marker and breast cancer risk. Our sample size within each ethnic group, however, is not large enough to definitively evaluate ethnic-specific risks. These data provide little support for the hypothesis that the A A-240T ACE allele is an independent risk factor for breast cancer. We observed a suggestive positive association between the I/I ACE genotype and breast cancer risk; however, the association was not observed among all ethnic groups. Additional studies exploring the LD block structure and haplotype patterns among these four populations are needed to clarify the contribution of genetic variation in ACE to disease risk.

	ACKNOWLEDGMENTS

 
We thank David van den Berg for assistance with the genotyping and the members of the MEC for their participation and cooperation.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by National Cancer Institute Grants CA 63464 and CA 54281.

² To whom requests for reprints should be addressed, at University of Southern California/Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90089.

³ The abbreviations used are: ACE, angiotensin I-converting enzyme; MEC, Multiethnic Cohort Study; OR, odds ratio; CI, confidence interval; HRT, hormone replacement therapy; LD, linkage disequilibrium.

Received 3/28/03. Revised 6/ 3/03. Accepted 7/23/03.

	REFERENCES

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 

1. Rigat B., Hubert C., Alhenc-Gelas F., Cambien F., Corvol P., Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J. Clin. Investig., 86: 1343-1346, 1990.
2. Villard E., Tiret L., Visvikis S., Rakotovao R., Cambien F., Soubrier F. Identification of new polymorphisms of the angiotensin I-converting enzyme (ACE) gene, and study of their relationship to plasma ACE levels by two-QTL segregation-linkage analysis. Am. J. Hum. Genet., 58: 1268-1278, 1996.[Medline]
3. Cambien F., Poirier O., Lecerf L., Evans A., Cambou J. P., Arveiler D., Luc G., Bard J. M., Bara L., Ricard S., et al Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature (Lond.), 359: 641-644, 1992.[Medline]
4. Schmidt S., van Hooft I. M., Grobbee D. E., Ganten D., Ritz E. Polymorphism of the angiotensin I converting enzyme gene is apparently not related to high blood pressure: Dutch Hypertension and Offspring Study. J. Hypertens., 11: 345-348, 1993.[Medline]
5. Lindpaintner K., Pfeffer M. A., Kreutz R., Stampfer M. J., Grodstein F., LaMotte F., Buring J., Hennekens C. H. A prospective evaluation of an angiotensin-converting-enzyme gene polymorphism and the risk of ischemic heart disease. N. Engl. J. Med., 332: 706-711, 1995.[Abstract/Free Full Text]
6. O’Donnell C. J., Lindpaintner K., Larson M. G., Rao V. S., Ordovas J. M., Schaefer E. J., Myers R. H., Levy D. Evidence for association and genetic linkage of the angiotensin-converting enzyme locus with hypertension and blood pressure in men but not women in the Framingham Heart Study. Circulation, 97: 1766-1772, 1998.[Abstract/Free Full Text]
7. Keavney B., McKenzie C., Parish S., Palmer A., Clark S., Youngman L., Delepine M., Lathrop M., Peto R., Collins R. Large-scale test of hypothesised associations between the angiotensin- converting-enzyme insertion/deletion polymorphism and myocardial infarction in about 5000 cases and 6000 controls. International Studies of Infarct Survival (ISIS) Collaborators. Lancet, 355: 434-442, 2000.[Medline]
8. Talamini R., Franceschi S., Favero A., Negri E., Parazzini F., La Vecchia C. Selected medical conditions and risk of breast cancer. Br. J. Cancer, 75: 1699-1703, 1997.[Medline]
9. Peeters P. H., van Noord P. A., Hoes A. W., Fracheboud J., Gimbrere C. H., Grobbee D. E. Hypertension and breast cancer risk in a 19-year follow-up study (the DOM cohort). Diagnostic investigation into mammarian cancer. J. Hypertens., 18: 249-254, 2000.[Medline]
10. Mack T. M., Henderson B. E., Gerkins V. R., Arthur M., Baptista J., Pike M. C. Reserpine and breast cancer in a retirement community. N. Engl. J. Med., 292: 1366-1371, 1975.[Abstract]
11. Lever A. F., Hole D. J., Gillis C. R., McCallum I. R., McInnes G. T., MacKinnon P. L., Meredith P. A., Murray L. S., Reid J. L., Robertson J. W. Do inhibitors of angiotensin-I-converting enzyme protect against risk of cancer?. Lancet, 352: 179-184, 1998.[Medline]
12. Meier C. R., Derby L. E., Jick S. S., Jick H. Angiotensin-converting enzyme inhibitors, calcium channel blockers, and breast cancer. Arch. Intern. Med., 160: 349-353, 2000.[Abstract/Free Full Text]
13. Muscella A., Greco S., Elia M. G., Storelli C., Marsigliante S. Angiotensin II stimulation of Na⁺/K⁺ATPase activity and cell growth by calcium-independent pathway in MCF-7 breast cancer cells. J. Endocrinol., 173: 315-323, 2002.[Abstract]
14. Fujita M., Hayashi I., Yamashina S., Itoman M., Majima M. Blockade of angiotensin AT1a receptor signaling reduces tumor growth, angiogenesis, and metastasis. Biochem. Biophys. Res. Commun., 294: 441-447, 2002.[Medline]
15. Koh W. P., Yuan J. M., Sun C. L., van den Berg D., Seow A., Lee H. P., Yu M. C. Angiotensin I-converting enzyme (ACE) gene polymorphism and breast cancer risk among Chinese women in Singapore. Cancer Res., 63: 573-578, 2003.[Abstract/Free Full Text]
16. Kolonel L. N., Henderson B. E., Hankin J. H., Nomura A. M., Wilkens L. R., Pike M. C., Stram D. O., Monroe K. R., Earle M. E., Nagamine F. S. A multiethnic cohort in Hawaii and Los Angeles: baseline characteristics. Am. J. Epidemiol., 151: 346-357, 2000.[Abstract/Free Full Text]
17. Lewontin R. C. The interaction of selection and linkage. I. General considerations; heterotic models. Genetics, 49: 49-67, 1964.[Free Full Text]
18. Pike M. C., Kolonel L. N., Henderson B. E., Wilkens L. R., Hankin J. H., Feigelson H. S., Wan P. C., Stram D. O., Nomura A. M. Breast cancer in a multiethnic cohort in Hawaii and Los Angeles: risk factor-adjusted incidence in Japanese equals and in Hawaiians exceeds that in whites. Cancer Epidemiol. Biomark. Prev., 11: 795-800, 2002.[Abstract/Free Full Text]
19. Cox R., Bouzekri N., Martin S., Southam L., Hugill A., Golamaully M., Cooper R., Adeyemo A., Soubrier F., Ward R., Lathrop G. M., Matsuda F., Farrall M. Angiotensin-1-converting enzyme (ACE) plasma concentration is influenced by multiple ACE-linked quantitative trait nucleotides. Hum. Mol. Genet., 11: 2969-2977, 2002.[Abstract/Free Full Text]
20. McKenzie C. A., Abecasis G. R., Keavney B., Forrester T., Ratcliffe P. J., Julier C., Connell J. M., Bennett F., McFarlane-Anderson N., Lathrop G. M., Cardon L. R. Trans-ethnic fine mapping of a quantitative trait locus for circulating angiotensin I-converting enzyme (ACE). Hum. Mol. Genet., 10: 1077-1084, 2001.[Abstract/Free Full Text]
21. Zhu X., Yan D., Cooper R. S., Luke A., Ikeda M. A., Chang Y. P., Weder A., Chakravarti A. Linkage disequilibrium and haplotype diversity in the genes of the renin-angiotensin system: findings from the family blood pressure program. Genome Res., 13: 173-181, 2003.[Abstract/Free Full Text]
22. Tiret L., Rigat B., Visvikis S., Breda C., Corvol P., Cambien F., Soubrier F. Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels. Am. J. Hum. Genet., 51: 197-205, 1992.[Medline]
23. McKenzie C. A., Julier C., Forrester T., McFarlane-Anderson N., Keavney B., Lathrop G. M., Ratcliffe P. J., Farrall M. Segregation and linkage analysis of serum angiotensin I-converting enzyme levels: evidence for two quantitative-trait loci. Am. J. Hum. Genet., 57: 1426-1435, 1995.[Medline]
24. Keavney B., McKenzie C. A., Connell J. M., Julier C., Ratcliffe P. J., Sobel E., Lathrop M., Farrall M. Measured haplotype analysis of the angiotensin-I converting enzyme gene. Hum. Mol. Genet., 7: 1745-1751, 1998.[Abstract/Free Full Text]
25. Zhu X., Bouzekri N., Southam L., Cooper R. S., Adeyemo A., McKenzie C. A., Luke A., Chen G., Elston R. C., Ward R. Linkage and association analysis of angiotensin I-converting enzyme (ACE)-gene polymorphisms with ACE concentration and blood pressure. Am. J. Hum. Genet., 68: 1139-1148, 2001.[Medline]
26. Soubrier F., Martin S., Alonso A., Visvikis S., Tiret L., Matsuda F., Lathrop G. M., Farrall M. High-resolution genetic mapping of the ACE-linked QTL influencing circulating ACE activity. Eur. J. Hum. Genet., 10: 553-561, 2002.[Medline]
27. Zhu X., McKenzie C. A., Forrester T., Nickerson D. A., Broeckel U., Schunkert H., Doering A., Jacob H. J., Cooper R. S., Rieder M. J. Localization of a small genomic region associated with elevated ACE. Am. J. Hum. Genet., 67: 1144-1153, 2000.[Medline]
28. Ioannidis J. P., Trikalinos T. A., Ntzani E. E., Contopoulos-Ioannidis D. G. Genetic associations in large versus small studies: an empirical assessment. Lancet, 361: 567-571, 2003.[Medline]

This article has been cited by other articles:

				S. A. Alves Correa, S. M. Ribeiro de Noronha, N. C. Nogueira-de-Souza, C. Valleta de Carvalho, A. M. Massad Costa, J. Juvenal Linhares, M. T. Vieira Gomes, and I. D. C. Guerreiro da Silva Association between the angiotensin-converting enzyme (insertion/deletion) and angiotensin II type 1 receptor (A1166C) polymorphisms and breast cancer among Brazilian women Journal of Renin-Angiotensin-Aldosterone System, March 1, 2009; 10(1): 51 - 58. [Abstract] [PDF]

				D. Rosskopf and M. C. Michel Pharmacogenomics of G Protein-Coupled Receptor Ligands in Cardiovascular Medicine Pharmacol. Rev., December 1, 2008; 60(4): 513 - 535. [Abstract] [Full Text] [PDF]

				M. Sugimoto, T. Furuta, N. Shirai, M. Ikuma, H. Sugimura, and A. Hishida Influences of chymase and Angiotensin I-converting enzyme gene polymorphisms on gastric cancer risks in Japan. Cancer Epidemiol. Biomarkers Prev., October 1, 2006; 15(10): 1929 - 1934. [Abstract] [Full Text] [PDF]

				M. P.A. Ebert, U. Lendeckel, S. Westphal, J. Dierkes, J. Glas, C. Folwaczny, A. Roessner, M. Stolte, P. Malfertheiner, and C. Rocken The Angiotensin I-Converting Enzyme Gene Insertion/Deletion Polymorphism Is Linked to Early Gastric Cancer Cancer Epidemiol. Biomarkers Prev., December 1, 2005; 14(12): 2987 - 2989. [Abstract] [Full Text] [PDF]

				A. M. Gonzalez-Zuloeta Ladd, A. Arias Vasquez, F. A. Sayed-Tabatabaei, J.W. Coebergh, A. Hofman, O. Njajou, B. Stricker, and C. van Duijn Angiotensin-Converting Enzyme Gene Insertion/Deletion Polymorphism and Breast Cancer Risk Cancer Epidemiol. Biomarkers Prev., September 1, 2005; 14(9): 2143 - 2146. [Abstract] [Full Text] [PDF]

				C. Rocken, U. Lendeckel, J. Dierkes, S. Westphal, S. Carl-McGrath, B. Peters, S. Kruger, P. Malfertheiner, A. Roessner, and M. P.A. Ebert The Number of Lymph Node Metastases in Gastric Cancer Correlates with the Angiotensin I-Converting Enzyme Gene Insertion/Deletion Polymorphism Clin. Cancer Res., April 1, 2005; 11(7): 2526 - 2530. [Abstract] [Full Text] [PDF]

				W.-P. Koh, J.-M. Yuan, D. Van Den Berg, H.-P. Lee, and M. C. Yu Polymorphisms in angiotensin II type 1 receptor and angiotensin I-converting enzyme genes and breast cancer risk among Chinese women in Singapore Carcinogenesis, February 1, 2005; 26(2): 459 - 464. [Abstract] [Full Text] [PDF]

				H. Katzov, A. M. Bennet, P. Kehoe, B. Wiman, M. Gatz, K. Blennow, B. Lenhard, N. L. Pedersen, U. de Faire, and J. A. Prince A cladistic model of ACE sequence variation with implications for myocardial infarction, Alzheimer disease and obesity Hum. Mol. Genet., November 1, 2004; 13(21): 2647 - 2657. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Haiman, C. A. Articles by Henderson, B. E. Search for Related Content PubMed PubMed Citation Articles by Haiman, C. A. Articles by Henderson, B. E.