Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

0

Share

Download to read offline

ACE_Vitiligo

Download to read offline

Related Audiobooks

Free with a 30 day trial from Scribd

See all
  • Be the first to like this

ACE_Vitiligo

  1. 1. L’essentiel de l’information scientifique et m´edicale www.jle.com Le sommaire de ce num´ero http://www.john-libbey-eurotext.fr/fr/ revues/medecine/ejd/sommaire.md?type= text.html Montrouge, le 05/20/2011 Parveen JAHAN Vous trouverez ci-apr`es le tir´e `a part de votre article au format ´electronique (pdf) : Angiotensin converting enzyme (ACE) gene polymorphism in vitiligo: protective and predispo- sing effects of genotypes in disease susceptibility and progression paru dans European Journal of Dermatology, 2011, Volume 21, Num´ero 2 John Libbey Eurotext Ce tir´e `a part num´erique vous est d´elivr´e pour votre propre usage et ne peut ˆetre transmis `a des tiers qu’`a des fins de recherches personnelles ou scientifiques. En aucun cas, il ne doit faire l’objet d’une distribution ou d’une utilisation promotionnelle, commerciale ou publicitaire. Tous droits de reproduction, d’adaptation, de traduction et de diffusion r´eserv´es pour tous pays. © John Libbey Eurotext, 2011
  2. 2. © John Libbey Eurotext, 2011 doi:10.1684/ejd.2011.1279 EJD, vol. 21, n◦ 2, March-April 2011 173 To cite this article: Tippisetty S, Ishaq M, Komaravalli PL, Jahan P. Angiotensin converting enzyme (ACE) gene polymorphism in vitiligo: protective and predisposing effects of genotypes in disease susceptibility and progression. Eur J Dermatol 2011; 21(2): 173-7 doi:10.1684/ejd.2011.1279 Genes and skin Eur J Dermatol 2011; 21(2): 173-7 Surekha TIPPISETTY1 Mohammed ISHAQ1 Prasanna Latha KOMARAVALLI2 Parveen JAHAN1 1 Osmania University, Dept. of Genetics, Hyderabad, Andhra Pradesh, Hyd -12, India 2 Shadan Institute for PG studies, Dept. of Genetics, Hyd -04, India Reprints: P. Jahan <parveenjahan_dr@yahoo.in> Article accepted on 12/20/2010 Angiotensin converting enzyme (ACE) gene polymorphism in vitiligo: protective and predisposing effects of genotypes in disease susceptibility and progression Vitiligo is a depigmenting skin disorder with profound heterogenity in its aetio-pathophysiology, and is associated with inter-individual variation in progression of disease. Angiotensin converting enzyme (ACE) is a regulator of renin angiotensin system (RAS) that plays an important role in the physiology of the vasculature, blood pressure, inflammation, adipocyte distribution of various diseases. The present study was carried out in 243 vitiligo patients (132 males and 111 females), aged between 3-62 years with a mean age at onset of 21.6 ± 13.6 yrs, and in 205 healthy controls of south Indian origin. The main objectives of the present study were to evaluate the ACE I/D (insertion/deletion) polymorphism in the patientandcontrolgroups.Further,I/Dgenotypeswerecomparedamong the patients with and without the family history of vitiligo as well as the progression of the disease, through polymerase chain reaction (PCR) methods. The results revealed a highly significant association of DD genotype with disease susceptibility (p < 0.01) in patients with a family history of vitiligo (p < 0.05) in terms of early age at onset. Further, the pre-dominance of ID genotype among patients revealed its association with a slow progression of the disease (p < 0.05). The present study is the first report to highlight the protective role of II genotype and the significant association of ID genotype with slow progression of the disease. Key words: angiotensin converting enzyme, progression, protection, susceptibility, vitiligo V itiligo (leucoderma) is a common skin disorder in which depigmented macules appear on the skin, due to destruction of melanocytes. It is usually bilateral, rarely unilateral, developing anywhere on the body and may gradually enlarge. Irrespective of sex, race and age, ∼1-2% of the world population suffer from this disorder. It is reported that 18-20% of vitiligo probands exhibit familial incidence of the disease [1, 2]. The aetiol- ogy of vitiligo is multifactorial, involving both genetic and the environmental triggers; however, it remains ambiguous whether oxidative stress and autoimmunity are implicated as important factors in the pathogenesis of this disease. Genetic marker analysis has revealed a number of candi- date genes such as AIRE, CTLA4, GCH1, VIT1, MHC, CAT, COMT and SLEV1 in the susceptibility to vitiligo [3-8]. However, heterogeneity is observed with respect to loci in different ethnic groups. Inter-individual variation is commonly observed with respect to rate-of-progression and clinical variants of the disease. Understanding the inter-individual variation in the progression of the disease helps in predicting the vitiligo from the very onset. Progression of the disease may be defined as enlargement of the existing depigmented mac- ules or appearance of new lesions over a period of time. If the area of depigmentation is more than three quarters of the total body surface area (TBSA) within one year of disease onset, it is referred to as fast progression; on the other hand, if the depigmented macules cover less than one quarter of the total body surface area it is termed slow pro- gression. The above classification is defined based on few criteria laid down by some authors with slight modifications [9-11]. Angiotensin converting enzyme (ACE) is a regulator of the renin- angiotensin system that plays an important role in the physiology of the vasculature, blood pressure, inflam- mation and adipocyte distribution of various diseases, of which vitiligo is one of them [12]. An insertion/deletion (I/D)polymorphismofa287bprepetitivesequenceinintron 16 of the ACE gene gives two co-dominant alleles. The gene product is a monomeric, membrane-bound, zinc and chloride dependent peptidyl dipeptidase that catalyzes the conversion of angiotensin I to angiotensin II, by removing a carboxy terminal dipeptide. The gene codes for this enzyme is located on chromosome 17q23. The expression and activ- ity of ACE in blood and tissue depends on insertion and deletionpolymorphism[13,14].TheDD(deletionhomozy- gote) genotype exhibits two fold higher plasma and tissue levels than the II (insertion homozygote) genotype and with Author offprint
  3. 3. © John Libbey Eurotext, 2011 174 EJD, vol. 21, n◦ 2, March-April 2011 ID (insertion/deletion heterozygote) having intermediate levels of the enzyme [14, 15]. It has been reported that these genotypes exhibit variations with respect to oxida- tive stress, angiogenesis, vasoconstriction and distribution of subcutaneous fat [16, 17]. In view of existing literature on ACE insertion/deletion polymorphism, it was felt that ACE was a relevant poly- morphic marker for oxidative stress and angiogenesis as well as body fat distribution. We aimed to investigate the role of ACE insertion/deletion polymorphism not only in susceptibility to vitiligo but also in the progression of the depigmentation process, a novel aspect which has not been dealt in other studies. Materials and method Our study enrolled 243 vitiligo cases from South India, which were examined in the vitiligo unit at the Central Research Institute of Unani Medicine (CRIUM, Hyder- abad, India). These cases were not suffering from any other skin or autoimmune disorder. As a control group, 205 healthy age and sex matched volunteers without any clinical evidence of vitiligo or other skin disorders were recruited. This study was approved by the ethical com- mittee of CRIUM and Department of genetics, Osmania University (Hyderabad). All subjects were included only after informed consent for clinical and demographical data was obtained. Based on the progression of the depigmenta- tion, patients were categorized as fast or slow progressive types. If the patients showed depigmentation of more than three quarters of the total body surface area within one year of the disease manifestation, they were categorized as fast progressive type and if it was less than one quarter of the total body surface area they were categorized as slow pro- gressive type. As there is no standard classification of the rate of progression of disease, our categorization is based on the long term observation of CRIUM dermatologists (unpublished) and from studies on treatment response in vitiligo [9-11]. ACE gene polymorphism Blood samples were collected from patients and controls and were subjected to DNA isolation by standard pro- cedure. ACE genotyping was carried out by polymerase chain reaction using oligonucleotide sense primer 5 -CTG GAG ACC ACT CCC ATC CTT TCT-3 , and the antisense primer 5 -GAT GTG GCC ATC ACA TTC GTC AGA T-3 . DNA samples (100 ng) were subjected to 35 cycles of PCR amplification in eppendorf thermocycler under the following conditions; initial denaturation 94 ◦C for 5 min, denaturation 94 ◦C for 45 sec; annealing 58 ◦C for 1 min; extension 72 ◦C for 45 sec and final extension of 72 ◦C for 7 min. PCR products were analyzed with 2% agarose gel electrophoresis and ethidium bromide staining in order to identify three patterns: II (a 490 bp fragment), DD (a 190 bp fragment) and ID (both 490 and190 bp fragments). Statistical analyses Statistical analysis for relative risk was done by Odds ratio with 95% confidence interval. ANOVA was carried out for association of ACE insertion/deletion polymorphism and age at onset in relation to familial history. The statistical package for social sciences (SPSS, 15th version) was used to perform the analysis. Hardy-Weinberg equilibrium was evaluated by ␹2 test for genotypic and allelic frequencies in the patient and control groups. Results and discussion WeanalyzedthepolymorphismofACEgenein243patients and 205 healthy volunteers. Based on CRIUM observation (unpublished) 50 (20.6%) patients were categorized as fast progressive and the remaining 193 (79.4%) as slow pro- gressive types. The age at onset was 1-59 yrs of the patients and it was lower in the fast progressive (1-49yrs) compared to the slow progressive group (1-59yrs). The overall mean age at onset was 21.6 ± 13.6 yrs. However, it was found to be 22.3 ± 14.7 yrs and 21.4 ± 13.3 yrs in the fast progres- sive and slow progressive types, respectively. Of the 243 vitiligo patients, 54 (22.2%) individuals showed a family history of the disease. ACE I/D polymorphism in disease susceptibility The frequencies of ACE I/D genotypes in vitiligo patients and controls are given in table 1 and figure 1. Analysis of genotype frequencies revealed an over-representation of DD and ID among patients, compared to that of the con- trol group (p < 0.05). This observation indicates increased susceptibility of the DD genotype to vitiligo. However, the apparent difference of the ID genotype between patients and controls was not significant. ACE, being a pleiotropic gene, may be involved in sus- ceptibility to vitiligo, due to its multiple effects. The role of the ACE gene is implicated in oxidative stress, angio- genesis and the distribution of body fat. Earlier reports on ACE insertion/deletion polymorphism in disease associa- tion have suggested the role of angiogenesis in vitiligo, while in some other diseases its role is suggested in enhanced reactive oxygen species (ROS) and fat distribu- tion [16, 17]. Of the 3 ACE I/D genotypes, DD is considered to be associated with relatively enhanced ROS generation mediated by angiotensin II, compared to other genotypes [17].Moreover,individualswiththishomozygousgenotype DD have also been reported to have greater accumulated visceral fat, which may be contributing to the disease mani- festations associated with high oxidative stress like diabetes and cardiovascular disease [18-21]. These adverse patho- physiological effects of the DD genotype, along with other susceptible genes, may predispose individuals to a derma- tological condition like vitiligo. The aetiopathogenesis of vitiligo involves not only oxidative stress but also angiogen- esis, which may facilitate the access of cells of the immune system and of auto-antibodies to the site of melanocyte destruction. Analysis of the II genotype frequency revealed an almost 50% reduction in the frequency of this genotype among the patients compared to controls. It suggests a protective role of the II homozygous condition against the develop- ment of vitiligo, as the II genotype is suggested to be less Author offprint
  4. 4. © John Libbey Eurotext, 2011 EJD, vol. 21, n◦ 2, March-April 2011 175 Table 1. Distribution of ACE I/D genotypes in vitiligo patients and controls. Allele frequency Groups II (%) ID (%) DD (%) ␹2 (p value) I D ␹2 (p value) Patients 54 (22.3) 115 (47.3) 74 (30.4) 18.2 (0.000) 0.45 0.55 4.51 (0.03) Controls 83 (40.5) 80 (39) 42 (20.5) 0.60 0.40 OR (95% CI) p value II vs DD 0.369 (0.227-0.644) 0.000 ID vs DD 0.816 (0.509-1.309) NS DD vs II 2.708 (1.627-4.506) 0.000 I vs D 0.545 (0.312-0.955) 0.04 Note: NS is not significant. ROS-generating compared to other genotypes. Hence, the suggestive protective role of II in susceptibility to vitiligo. A few reports on vitiligo dealing with ACE I/D geno- types have emphasized the predisposing effects of the DD genotype. Our results go in accordance with a Korean and another Indian study [12, 19, 22] were generalized and localized vitiligo patients were included. However, in con- trast to Akhtar et al and Dwivedi et al restricted their studies to generalized vitiligo [23, 24]. The present study revealed not only the predisposition of DD individuals to vitiligo but also reported a considerable protection conferred by the II genotype against this depigmenting condition. The current study appears to be the first report highlighting the protective role of II genotypes. ACE I/D genotypes in relation to family history of vitiligo and influence on age at onset of the disease Of the total 243 patients, 22.2% (n = 54) show a positive family history of vitiligo, whereas 77.8% (n = 189) were without family history of vitiligo. When the ACE I/D poly- morphism was analyzed, 16.7%, 46.3% and 37% of the familial cases showed II, ID and DD genotypes respec- tively. However, 23.8%, 47.6% and 28.6% of non-familial cases revealed the above genotypes. When genotype vs fam- ily history of vitiligo with age at onset was analyzed by Percentageofindividuals 0 5 10 15 20 25 30 35 40 45 50 ACE genotypes II ID DD Patients Controls Figure 1. Distribution of percentage of ACE II, ID and DD genotypes in patients and control group. ANOVA, it was observed that the individuals with a family history and the DD genotype had an early age at onset of the disease, indicating that the DD genotype may be contribut- ing to early age at onset of vitiligo (Fisher’s value 32.95, p < 0.01). ACE I/D polymorphism in disease progression In addition to disease susceptibility, another important fac- tor to be noted is disease progression, which is defined as enlargement of the existing depigmented lesions and/or appearance of new depigmented areas. Inter-individual variations in disease progression among patients are fre- quently observed, warranting genetic marker association analysis that may help to predict disease progression in patients. In view of this variation, we analyzed ACE I/D polymorphism in two groups of patients, namely fast pro- gression and slow progression types of the disease. Out of 50 cases observed in the fast progressive group, 13 (26%) showed II genotype and 18 (36%) had ID genotypes. The DD genotype was observed in 19 (38%) cases. In the slow progressive group, which comprised of 193 patients, 41(21.2%) individuals were of II genotype, 97(50.2%) indi- viduals with ID genotype and the remaining 55(28.4%) were of DD genotype. Analysis of the proportion of II and DD homozygotes in the fast progressive and slow progressive groups revealed no significant differences. However, there was an about 9.6% increase in the frequency of the DD genotype among the fast progressive group compared to the slow progressive group. Further, it was observed that the percentage of individuals with an ID genotype was significantly reduced in the fast progressive compared to the slow progressive group (36% vs 50.2%) (table 2, figure 2). Basedonourresults,itislikelythatdiseaseprogressionmay be more due to an angiogenic effect as it facilitates access of cells of the immune system, as well as auto-antibodies, to the site of melanocyte destruction. The observations made in the present study, like the substantial increase in the fre- quency of the DD genotype in the fast progressive group (9.6%) compared to the slow progressive group, are sugges- tive of angiogenic effects of the D allele in a homozygous condition. This assumption is supported by reports of a DD homozygote association with diabetic nephropathy, which Author offprint
  5. 5. © John Libbey Eurotext, 2011 176 EJD, vol. 21, n◦ 2, March-April 2011 Table 2. Distribution of ACE I/D genotypes in vitiligo patients with fast progressive and slow progressive type. Allele frequency Groups II (%) ID (%) DD (%) I D Fast progressive 13 (26) 18 (36) 19 (38) 0.44 0.56 Slow progressive 41 (21.2) 97 (50.2) 55 (28.4) 0.46 0.54 OR (95% CI) p value DD vs other 1.538 (0.807-2.933) NS ID vs DD 0.537 (0.281-1.100) 0.05 ID vs others 0.558 (0.317-0.981) 0.05 I vs D 0.92 (0.11-1.60) NS Note: NS is not significant. is explained on the basis of enhanced neovascularization in the kidney [25, 26], progression of sarcoidosis [27] and severity of systemic lupus erythematosus [28]. Moreover, metastasis is observed in cancers more frequently in DD individuals, which is mainly attributed to angiogenic effects [29-31]. The patterns of genotype association with vitiligo suscepti- bility and progression are different. The DD genotype is observed to be associated with a significantly increased susceptibility (p - 0.000). Contrary to this, in disease pro- gression we observed a 14% decrease in the frequency of ID in fast progression, indicating that a heterozygous condition slows down the disease progression. As vitiligo pathogen- esis involves both oxidative stress and autoimmunity, it appears that autoimmune mechanism(s) have a decisive role in progression, while in disease susceptibility oxidative stress mechanisms play a relatively more important role. Converse to our expectation, the ID genotype was associ- ated with a reduced risk of disease progression compared to the other two genotypes (p < 0.05). It appears that an as yet not understood mechanism of allelic interaction is associated with this pleiotropic gene; the oxidative stress- inducing role of D allele predominates in the susceptibility and the angiogenic role in disease progression. However, ACE genotypes Percentageofindividuals II 60 50 40 30 20 10 0 ID p - 0.05 DD Progressive Non-progressive Figure 2. Distribution of percentage of ACE II, ID and DD genotypes with fast progressive and slow progressive vitiligo. II in the homozygous condition is more prominent in a protective role. Though these two alleles are co-dominant in their expression, their product interaction seems to be complex. It is suggested that, in order to understand the role of ACE (a pleiotropic marker on susceptibility and progression of disease), certain markers of angiogenicity and adipocyte distribution could be studied with respect to vitiligo in different populations. Disclosure. Acknowledgements: We thank all the vitiligo subjects for their co-operation in giving consent for blood samples and the clinical information. And we would also like to thank Dr. M.A. Waheed, Deputy Director of Central Research Institute for Unani Medicine, Hyderabad, for his extendedhelpinunderstandingthediseaseofvitiligoandits progression. Financial support: none. Conflict of interest: none. References 1. Surekha T, Ishaq M, Latha KP, Rao PH, Jahan P. Do clinical variants of vitiligo involve X-chromosomal gene(s) too?. J Med Sci 2008; 8: 728- 33. 2. Nordlund JJ, Ortonne JP. Vitiligo vulgaris. In: Nordlund JJ, editor. The Pigmentary System. Physiology and Pathophysiology. New York: Oxford University Press, 1998, p. 513-51. 3. Pamela RF, Katherine G, Gregory SL, et al. A genomewide screen for generalised vitiligo: Conformation of AIS1 on chromosome 1p31 and evidence for additional susceptibility loci. Am J Hum Genet 2003; 72: 1560-4. 4. Richard AS, Katherine G, Dorothy CB, Pamela RF. Novel vitiligo susceptibility loci on chromosome 7(AIS2) and 8 (AIS3), conformation of SLEV1 on chromosome 17 and their roles in autoimmune diathesis. Am J Hum Genet 2004; 74: 188-91. 5. Jian JC, Wei H, Jin PG, et al. A novel linkage to generalised vitiligo on 4q13-q21 identified in genomewide linkage analysis of Chinese families. Am J Hum Genet 2005; 76: 1057-65. 6. Pehlivan S, Ozkinay F, Alper S, et al. Association Between Il4 (-590), Ace (I)/(D), Ccr5 (Delta32), Ctla4 (+49) And Il1-Rn (Vntr In Intron 2) Gene Polymorphisms And Vitiligo. Eur J Dermatol 2009; 19: 126-8. Author offprint
  6. 6. © John Libbey Eurotext, 2011 EJD, vol. 21, n◦ 2, March-April 2011 177 7. Aksoy Sn, Erbagci Z, Saygili Ei, Sever T, Erbagci Ab, Pehlivan S. Analysis Of Myeloperoxidase Promotor Polymorphism And Enzyme Activity In Turkish Patients With Vitiligo. Eur J Dermatol 2009; 19: 576-80. 8. Kim Hj, Uhm Yk, Yun Jy, et al. Association Between Polymor- phisms Of Discoidin Domain Receptor Tyrosine Kinase 1 (Ddr1) And Non-Segmental Vitiligo In The Korean Population. Eur J Dermatol 2010; 20: 231-2. 9. Dammak I, Boudaya S, Ben Abdallah F, Turki H, Attia H, Hentati B. Antioxidant enzymes and lipid peroxidation at the tissue level in patients with stable and active vitiligo. Int J Dermatol 2009; 48: 476- 80. 10. Thappa DM. Vitiligo. Indian J Dermatol Venereol Leprol 2002; 68: 227-8. 11. Warwick L. Morison-Laser therapy, Puva therapy. http://www. lightandlaser.com/vitiligo.html. 12. Jin SY, Park HH, Li GZ, et al. Association of Angiotensin Convert- ing Enzyme gene I/D polymorphism of Vitiligo In korean population. Pigment Cell Research 2004; 17: 84-6. 13. Koh WP, Yuan JM, Sun CL, et al. Angiotensin I-converting enzyme (ACE) gene polymorphism and breast cancer risk among Chinese women in Singapore. Cancer Res 2003; 63: 573-8. 14. 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 Invest 1990; 86: 1343-6. 15. Hubert C, Houot AM, Corvol P, Soubrier F. Structure of angiotensin I converting enzyme gene: two alternate promoters cor- responds to evolutionary steps of a duplicated gene. J Biol Chem 1991; 266: 15377-83. 16. The Skinny-Fat Ectomorph - Part I- Kelly Baggett. http://www. mindandmuscle.net/node/226?page=all. 17. Jian MY, Woon PK, Can LS, Hin PL, Mimi CY. Green tea intake. ACE gene polymorphism and breast cancer risk among Chinese women in Singapore. Carcinogenesis 2005; 26: 1389-94. 18. Molnar GA, Wagner Z, Wagner L, et al. Effect of ACE gene polymorphism on carbohydrate metabolism, on oxidative stress and on end-organ damage in type-2 diabetes mellitus. Orv Hetil 2004; 145: 855-9. 19. Nicholls MG, Richards AM, Agarwal M. The importance of the renin-angiotensin system in cardiovascular disease. J Hum Hypertens 1998; 12: 295-9. 20. Mykkanen L, Kuusisto J, Pyorala K, Laakso M. Cardiovascular dis- ease risk factors as predictors of type 2 (noninsulin-dependent) diabetes mellitus in elderly subjects. Diabetologia 1993; 36: 553-9. 21. Haffner SM, Valdez RA, Hazuda HP, Mitchell BD, Morales PA, Stern MP. Prospective analysis of the insulin resistance syndrome (Syn- drome X). Diabetes 1992; 41: 715-22. 22. Deeba F, Jamil k F, Syed R, Waheed MA, Rao PH. Association of angiotensin converting enzyme gene I/D polymorphism with vitiligo in South Indian population. Int J Med Med Sci 2009; 1: 009-12. 23. Akhtar S, Gavalas NG, Gawkrodger DJ, et al. An inser- tion/deletion polymorphism in the gene encoding angiotensin converting enzyme is not associated with generalised vitiligo in an English Population. Arch Dermatol Res 2005; 297: 94-8. 24. Dwivedi M, Naresh CL, Shajil EM, Shah BJ, Begum R. The ACE gene I/D polymorphism is not associated with generalized vitiligo sus- ceptibility in Gujarat population. Pigment Cell & Melanoma Research 2008; 21: 407-8. 25. Groop L. Genetics of the metabolic syndrome. Br J Nutri 2000; 83 (Suppl. 1): S39-84. 26. Matsusaka T, Hymes J, Ichikawa I. Angiotensin in progressive renal disease: theory and practice. J Am Soc Nephrol 1996; 7: 2025- 43. 27. Pietinalho A, Furuya K, Yamaguchi E, Kawakami K, Selroos O. The angiotensin - converting enzyme DD gene is associated with poor prognosis in Finnish Sarcoidosis patients. Eur Respir J 1999; 13: 723- 6. 28. Malik AR, Saeed MM, Sabeen FM, Philippe MF. Association of Angiotensin-Converting enzyme gene dimorphisms with sever- ity of Lupus disease. Saudi J Kidney Dis Transplant 2008; 19: 761-6. 29. Rocken C, Lendeckel U, Dierkes J, et al. The number of lymph node metastases in gastric cancer correlates with the angiotensin I-converting enzyme gene insertion/deletion polymorphism. Clin Can- cer Res 2005; 11: 2526-30. 30. Medeiros R, Vasconcelos A, Costa S, et al. Linkage of angiotensin I-converting enzyme gene insertion/deletion polymorphism to the progression of human prostate cancer. J Pathol 2004; 202: 330-5. 31. Haiman CA, Henderson SO, Bretsky P, Kolonel LN, Hender- son BE. Genetic variation in angiotensin I-converting enzyme (ACE) and breast cancer risk: the multiethnic cohort. Cancer Res 2003; 63: 6984-7. Author offprint

Views

Total views

202

On Slideshare

0

From embeds

0

Number of embeds

3

Actions

Downloads

2

Shares

0

Comments

0

Likes

0

×