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Tagging SNPs in the kallikrein genes 3 and 2 on 19q13 and their associations with prostate cancer in men of European origin


Two of the classical kallikrein genes KLK3 and KLK2 on 19q13.4 are plausible candidates in prostate cancer susceptibility. They are expressed almost exclusively in prostate tissue. We have performed a comprehensive analysis of association of variants in these two genes with prostate cancer among men of European descent using a tagging SNP approach. Thirteen SNPs selected from the HapMap database were analyzed in a sample of 596 histologically verified prostate cancer cases and 567 ethnically matched controls. Five SNPs showed significant association at single marker level. Linkage disequilibrium (LD) analysis revealed four LD blocks. We performed a haplotype analysis within each LD block. A major haplotype in block 1 that contains the first two significantly associated SNPs was significantly underrepresented in the prostate cancer cases; a second haplotype in block 3 also showed significant frequency differences between cases and controls. Four of the studied SNPs show positive associations with serum PSA levels. A structure analysis revealed no population stratification in our samples that could have confounded the association results. These findings suggest a plausible role of kallikrein gene variants in the etiology of prostate cancer among men of European ancestry.

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  1. Amundadottir LT, Sulem P, Gudmundsson J, Helgason A, Baker A, Agnarsson BA, Sigurdsson A, Benediktsdottir KR, Cazier JB, Sainz J, Jakobsdottir M, Kostic J, Magnusdottir DN, Ghosh S, Agnarsson K, Birgisdottir B, Le Roux L, Olafsdottir A, Blondal T, Andresdottir M, Gretarsdottir OS, Bergthorsson JT, Gudbjartsson D, Gylfason A, Thorleifsson G, Manolescu A, Kristjansson K, Geirsson G, Isaksson H, Douglas J, Johansson JE, Bälter K, Wiklund F, Montie JE, Yu X, Suarez BK, Ober C, Cooney KA, Gronberg H, Catalona WJ, Einarsson GV, Barkardottir RB, Gulcher JR, Kong A, Thorsteinsdottir U, Stefansson K (2006) A common variant associated with prostate cancer in African and European populations. Nat Genet 38:652–658

  2. Albertsen PC, Hanley JA, Fine J (2005) 20-year outcomes following conservative management of clinically localized prostate cancer. JAMA 293:2095–2101

  3. Beebe-Dimmer JL, Lange LA, Cain JE, Lewis RC, Ray AM, Sarma AV, Lange EM, Cooney KA (2006) Polymorphisms in the prostate-specific antigen gene promoter do not predict serum prostate-specific antigen levels in African–Amerian men. Prostate Cancer Prostatic Dis 9:50–55

  4. Boehnke M (1991) Allele frequency estimation from data on relatives. Am J Hum Genet 48:22–25

  5. Borgono CA, Michael IP, Diamandis EP (2004) Human tissue kallikreins: physiologic roles and applications in cancer. Mol Cancer Res 2:257–280

  6. Broman KW (2005) Estimation of allele frequencies with data on sibships. Genet Epidemiol 20:307–315

  7. Browning SR, Briley JD, Briley LP, Chandra G, Charnecki JH, Ehm MG, Johansson KA, Jones BJ, Karter AJ, Yarnall DP, Wagner MJ (2005) Case-control single-marker and haplotypic association analysis of pedigree data. Genet Epidemiol 28:110–122

  8. Burmester JK, Suarez BK, Lin JH, Jin CH, Miller RD, Zhang KQ, Salzman SA, Reding DJ, Catalona WJ (2004) Analysis of candidate genes for prostate cancer. Hum Hered 57:172–178

  9. Carlson CS, Eberle MA, Rieder MJ, Yi Q, Kruglyak L, Nickerson DA (2004) Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am J Hum Genet 74:106–120

  10. Catalona WJ, Smith DS, Ratliff TL, Basler JW (1993) Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA 270:948–954

  11. Catalona WJ, Richie JP, deKernion JB, Ahmann FR, Ratliff TL, Dalkin BL, Kavoussi LR, MacFarlane MT, Southwick PC (1994) Comparison of prostate specific antigen concentration versus prostate specific antigen density in the early detection of prostate cancer: receiver operating characteristic curves. J Urol 152:2031–2036

  12. Cramer SD, Chang BL, Rao A, Hawkins GA, Zheng SL, Wade WN, Cooke RT, Thomas LN, Bleecker ER, Catalona WJ, Sterling DA, Meyers DA, Ohar J, Xu J (2003) Association between genetic polymorphisms in the prostate-specific antigen gene promoter and serum prostate-specific antigen levels. J Natl Cancer Inst 95:1044–1053

  13. Conover WJ (1999) Practical nonparametric statistics, 3rd edn. Wiley, NewYork

  14. De la Vega FM, Lazaruk KD, Rhodes MD, Wenz MH (2005) Assessment of two flexible and compatible SNP genotyping platforms: TaqMan SNP genotyping assays and the SNPlex genotyping system. Mutat Res 573:111–135

  15. Diamandis EP, Yousef GM, Luo LY, Magklara A, Obiezu CV (2000) The human kallikrein gene family: implications in carcinogenesis. Trends Endocrinol Metab 11:54–60

  16. Falush D, Stephens M, Pritchard JK (2003) Inference of population structure using multilocus genotype data: linked loci and correlated allele frequencies. Genetics 164:1567–1587

  17. Freedman ML, Haiman CA, Patterson N, McDonald GJ, Tandon A, Waliszewska A, Penney K, Steen RG, Ardlie K, John EM, Oakley-Girvan I, Whittemore AS, Cooney KA, Ingles SA, Altshuler D, Henderson BE, Reich D (2006) Admixture mapping identifies 8q24 as a prostate cancer risk locus in African–Americans. Proc Natl Acad Sci USA 103:14068–14073

  18. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229

  19. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ (2007) Cancer statistics 2007. CA Cancer J Clin 57:43–66

  20. Lange K, Weeks D, Boehnke M (1988) Programs for pedigree analysis: MENDEL, FISHER and dGENE. Genet Epidemiol 5:471–472

  21. Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A, Hemminki K (2000) Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 343:78–85

  22. Medeiros R, Morais A, Vasconcelos A, Costa S, Pinto D, Oliveira J, Carvalho R, Lopes C (2002) Linkage between polymorphisms in the prostate specific antigen AREI gene region, prostate cancer risk, and circulating tumor cells. Prostate 53:88–94

  23. Nam RK, Zhang WW, Trachtenberg J, Jewett MA, Emami M, Vesprini D, Chu W, Ho M, Sweet J, Evans A, Toi A, Pollak M, Narod SA (2003a) Comprehensive assessment of candidate genes and serological markers for the detection of prostate cancer. Cancer Epidemiol Biomarkers Prev 12:1429–1437

  24. Nam RK, Zhang WW, Trachtenberg J, Diamandis E, Toi A, Emami M, Ho M, Sweet J, Evans A, Jewett MA, Narod SA (2003b) Single nucleotide polymorphisms of the human kallikrein-2 gene highly correlates with serum human kallikrein-2 levels and in combination enhances prostate cancer detection. J Clin Oncol 21:2312–2319

  25. Nam RK, Zhang WW, Klotz LH, Trachtenberg J, Jewett MA, Sweet J, Toi A, Teahan S, Venkateswaran V, Sugar L, Loblaw A, Siminovitch K, Narod SA (2006) Variants of the hK2 protein gene (KLK2) are associated with serum hK2 levels and predict the presence of prostate cancer at biopsy. Clin Cancer Res 12:6452–6458

  26. Neville PJ, Conti DV, Krumroy LM, Catalona WJ, Suarez BK, Witte JS, Casey G (2003) Prostate cancer aggressiveness locus on chromosome segment 19q12–q13.1 identified by linkage and allelic imbalance studies. Genes Chromosomes Cancer 36:332–339

  27. Pal P, Xi H, Kaushal R, Sun G, Jin CH, Suarez BK, Catalona WJ, Deka R (2006) Variants in the HEPSIN gene are associated with prostate cancer in men of European origin. Hum Genet 12:187–192

  28. Partin AW, Catalona WJ, Finlay JA, Darte C, Tindall DJ, Young CY, Klee GG, Chan DW, Rittenhouse HG, Wolfert RL, Woodrum DL (1999) Use of human glandular kallikrein 2 for the detection of prostate cancer: preliminary analysis. Urology 54:839–845

  29. Pritchard JK, Stephens M, Donnelly P (2000) Inference of population structure using multilocus genotype data. Genetics 155:945–959

  30. Rao A, Chang BL, Hawkins G, Hu JJ, Rosser CJ, Hall MC, Meyers DA, Xu J, Cramer SD (2003) Analysis of G/A polymorphism in the androgen response element I of the PSA gene and its interactions with the androgen receptor polymorphisms. Urology 61:864–869

  31. Riegman PH, Vlietstra RJ, van der Korput JA, Romijn JC, Trapman J (1989) Characterization of the prostate-specific antigen gene: a novel human kallikrein-like gene. Biochem Biophys Res Comm 159:95–102

  32. Roff DA, Bentzen P (1989) The statistical analysis of mitochondrial DNA polymorphisms: chi-square and the problem of small samples. Mol Biol Evol 6:539–545

  33. Schuur ER, Henderson GA, Kmetec LA, Miller JD, Lamparski HG, Henderson DR (1996) Prostate-specific antigen expression is regulated by an upstream enhancer. J Biol Chem 271:7043–7051

  34. Severi G, Hayes VM, Neufing P, Padilla EJ, Tilley WD, Eggleton SA, Morris HA, English DR, Southey MC, Hopper JL, Sutherland RL, Boyle P, Giles GG (2006) Variants in the prostate specific antigen (PSA) gene and prostate cancer risk, survival and circulating PSA. Cancer Epidemiol Biomarkers Prev 15:1142–1147

  35. Simard J, Dumont M, Soucy P, Labrie F (2002) Perspective: prostate cancer susceptibility genes. Endocrinology 143:2029–2040

  36. Slager SL, Schaid DJ, Cunningham JM, McDonnell SK, Marks AF, Peterson BJ, Hebbring SJ, Anderson S, French AJ, Thibodeau SN (2003) Confirmation of linkage of prostate cancer aggressiveness with chromosome 19q. Am J Hum Genet 72:759–762

  37. Smith DS, Humphrey PA, Catalona WJ (1997) The early detection of prostate carcinoma with prostate specific antigen: the Washington University experience. Cancer 80:1852–1856

  38. Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–989

  39. Suarez BK, Lin J, Burmester JK, Broman KW, Weber JL, Banerjee TK, Goddard KA, Witte JS, Elston RC, Catalona WJ (2000a) A genome screen of multiplex sibships with prostate cancer. Am J Hum Genet 66:933–944

  40. Suarez BK, Lin J, Witte JS, Conti DV, Resnick MI, Klein EA, Burmester JK, Vaske DA, Banerjee TK, Catalona WJ (2000b) Replication linkage study for prostate cancer susceptibility genes. Prostate 45:106–114

  41. Suarez BK, Pal P, Jin CH, Kaushal R, Sun G, Jin L, Pasche B, Deka R, Catalona WJ (2005) TGFBR1*6A is not associated with prostate cancer in men of European ancestry. Prostate Cancer Prostatic Dis 8:50–53

  42. Tremblay RR, Deperthes D, Tetu B, Dube JY (1997) Immunohistochemical study suggesting a complementary role of kallikreins hK2 and hK3 (prostate-specific antigen) in the functional analysis of human prostate tumors. Am J Pathol 150:455–459

  43. Wigginton JE, Cutler DJ, Abecasis GR (2005) A note on exact tests of Hardy–Weinberg equilibrium. Am J Hum Genet 76:887–893

  44. Witte JS, Goddard KA, Conti DV, Elston RC, Lin J, Suarez BK, Broman KW, Burmester JK, Weber JL, Catalona WJ (2000) Genomewide scan for prostate cancer-aggressiveness loci. Am J Hum Genet 67:92–99

  45. Witte JS, Suarez BK, Thiel B, Lin J, Yu A, Banerjee TK, Burmester JK, Casey G, Catalona WJ (2003) Genome-wide scan of brothers: replication and fine mapping of prostate cancer susceptibility and aggressiveness loci. Prostate 57:298–308

  46. Xu J, Dimitrov L, Chang BL, Adams TS, Turner AR, Meyers DA, Eeles RA, Easton DF, Foulkes WD, Simard J, Giles GG, Hopper JL, Mahle L, Moller P, Bishop T, Evans C, Edwards S, Meitz J, Bullock S, Hope Q, Hsieh CL, Halpern J, Balise RN, Oakley-Girvan I, Whittemore AS, Ewing CM, Gielzak M, Isaacs SD, Walsh PC, Wiley KE, Isaacs WB, Thibodeau SN, McDonnell SK, Cunningham JM, Zarfas KE, Hebbring S, Schaid DJ, Friedrichsen DM, Deutsch K, Kolb S, Badzioch M, Jarvik GP, Janer M, Hood L, Ostrander EA, Stanford JL, Lange EM, Beebe-Dimmer JL, Mohai CE, Cooney KA, Ikonen T, Baffoe-Bonnie A, Fredriksson H, Matikainen MP, Tammela TLj, Bailey-Wilson J, Schleutker J, Maier C, Herkommer K, Hoegel JJ, Vogel W, Paiss T, Wiklund F, Emanuelsson M, Stenman E, Jonsson BA, Gronberg H, Camp NJ, Farnham J, Cannon-Albright LA, Seminara D (2005) A combined genomewide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics. Am J Hum Genet 77:219–229

  47. Xu J, Meyers DA, Sterling DA, Zheng SL, Catalona WJ, Cramer SD, Bleecker ER, Ohar J (2002) Association studies of serum prostate-specific antigen levels and the genetic polymorphisms at the androgen receptor and prostate-specific antigen genes. Cancer Epidemiol Biomarkers Prev 11:664–669

  48. Xue WM, Coetzee GA, Ross RK, Irvine R, Kolonel L, Henderson BE, Ingles SA (2001) Genetic determinants of serum prostate-specific antigen levels in healthy men from a multiethnic cohort. Cancer Epidemiol Biomarkers Prev 10:575–579

  49. Yousef GM, Luo LY, Diamandis EP (1999) Identification of novel human kallikrein-like genes on chromosome 19q13.3–q13.4. Anticancer Res 19:2843–2852

  50. Zaykin DV, Westfall PH, Young SS Karnoub MA, Wagner MJ, Ehm MG (2002) Testing association of statistically inferred haplotypes with discrete and continuous traits in samples of unrelated individuals. Hum Hered 53:79–91

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This study was supported by a grant from the Urological Research Foundation.

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Correspondence to Ranjan Deka.

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Pal, P., Xi, H., Sun, G. et al. Tagging SNPs in the kallikrein genes 3 and 2 on 19q13 and their associations with prostate cancer in men of European origin. Hum Genet 122, 251–259 (2007). https://doi.org/10.1007/s00439-007-0394-3

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  • Prostate Cancer
  • Linkage Disequilibrium
  • Prostate Cancer Risk
  • Linkage Disequilibrium Block
  • Prostate Cancer Case