Archives of Toxicology

, Volume 82, Issue 4, pp 265–270 | Cite as

Reconstruction of N-acetyltransferase 2 haplotypes using PHASE

  • Klaus Golka
  • Meinolf Blaszkewicz
  • Mirabutaleb Samimi
  • Hermann M. Bolt
  • Silvia Selinski
Short Communication

Abstract

The genotyping of N-acetyltransferase 2 (NAT2) by PCR/RFLP methods yields in a considerable percentage ambiguous results. To resolve this methodical problem a statistical approach was applied. PHASE v2.1.1, a statistical program for haplotype reconstruction was used to estimate haplotype pairs from NAT2 genotyping data, obtained by the analysis of seven single nucleotide polymorphisms relevant for Caucasians. In 1,011 out of 2,921 (35%) subjects the haplotype pairs were clearcut by the PCR/RFLP data only. For the majority of the data the applied method resulted in a multiplicity (2–4) of possible haplotype pairs. Haplotype reconstruction using PHASE v2.1.1 cleared this ambiguity in all cases but one, where an alternative haplotype pair was considered with a probability of 0.029. The estimation of the NAT2 haplotype is important because the assignment of the NAT2 alleles *12A, *12B, *12C or *13 to the rapid or slow NAT2 genotype has been discussed controversially. A clear assignment is indispensable in surveys of human bladder cancer caused by aromatic amine exposures. In conclusion, PHASE v2.1.1 software allowed an unambiguous haplotype reconstruction in 2,920 of 2,921 cases (>99.9%).

Keywords

PHASE v2.1.1 NAT2 genotyping Single nucleotide polymorphism Haplotype reconstruction 

Notes

Acknowledgments

The financial support of the Deutsche Forschungsgemeinschaft (SFB 475, “Reduction of complexity in multivariate data structures”) is gratefully acknowledged. Many thanks are due to Doris Dannappel for her excellent technical assistance and to Heinz Dieter Giller for his introduction into the DOS editor.

References

  1. Adkins RM (2004) Comparison of the accuracy of methods of computational haplotype inference using a large empirical dataset. BMC Genet 5:22. http://www.biomedcentral.com/1471-2156/5/22
  2. Arylamine N-acetyltransferase Nomenclature Committee (2007) Latest update 2007 http://www.louisville.edu/medschool/pharmacology/NAT.html
  3. Blaszkewicz M, Dannappel D, Thier R, Lewalter J (2004) N-acetyltransferase 2 (genotyping). In: Angerer J, Müller M, Weiss T et al. (eds) Analyses of hazardous substances in biological materials, vol 9. Special issue: Markers of susceptibility, pp 135–163. Wiley-VCH, WeinheimGoogle Scholar
  4. Bolt HM, Selinski S, Dannappel D, Blaszkewicz M, Golka K (2005) Re-investigation of the concordance of human NAT2 phenotypes and genotypes. Arch Toxicol 79:196–200PubMedCrossRefGoogle Scholar
  5. Clark AG (1990) Inference of haplotypes from PCR-amplified samples of diploid populations. Mol Biol Evol 7:111–122PubMedGoogle Scholar
  6. Coulonges C, Delaneau O, Girard M, Do H, Adkins R, Spadoni J-L, Zagury J-F (2006) Computation of haplotypes on SNPs subsets: advantage of the “global method”. BMC Genet 7:50. http://www.biomedcentral.com/1471-2156/7/50 Google Scholar
  7. Crawford DA, Nickerson DA (2005) Definition and clinical importance of haplotypes. Annu Rev Med 56:303–320PubMedCrossRefGoogle Scholar
  8. Eronen L, Geerts F, Toivonen H (2006) HaploRec: efficient and accurate large-scale reconstruction of haplotypes. BMC Bioinformatics 7:542. http://www.biomedcentral.com/1471-2105/7/542 Google Scholar
  9. Gilks WR, Richardson S, Spiegelhalter DJ (eds) (1996) Markov-Chain Monte Carlo in practice. Chapman & Hall, LondonGoogle Scholar
  10. Golka K, Prior V, Blaszkewicz M, Bolt HM (2002) The enhanced bladder cancer susceptibility of NAT2 slow acetylators towards aromatic amines: a review considering ethnic differences. Toxicol Lett 128:229–241PubMedCrossRefGoogle Scholar
  11. Hein DW (2006) N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk. Oncogene 25:1649–1658PubMedCrossRefGoogle Scholar
  12. Hein DW, Rustan TD, Ferguson RJ, Doll MA, Gray K (1994) Metabolic activation of aromatic and heterocyclic N-hydroxyarylamines by wild-type and mutant recombinant human NAT1 and NAT2 acetyltransferases. Arch Toxicol 68:129–133PubMedCrossRefGoogle Scholar
  13. Hein DW, Ferguson RJ, Doll MA, Deitz AC (1997) Recombinant expression and catalytic analysis of rapid and slow acetylator Syrian hamster chimeric NAT2 alleles. Arch Toxicol 71:306–313PubMedCrossRefGoogle Scholar
  14. Holley SL, Fryer AA, Haycock JW, Grubb SE, Strange RC, Hoban PR (2007) Differential effects of glutathione S-transferase pi (GSTP1) haplotypes on cell proliferation and apoptosis. Carcinogenesis, 8 June 2007 (Epub ahead of print)Google Scholar
  15. Ito T, Chiku S, Inoue E, Tomita M, Morisaki T, Morisaki H, Kamatani N (2003) Estimation of haplotype frequencies, linkage-disequilibrium measures, and combination of haplotype copies in each pool by use of pooled DNA data. Am J Hum Genet 72:384–398PubMedCrossRefGoogle Scholar
  16. Ito T, Inoue E, Kamatani N (2004) Association test algorithm between a qualitative phenotype and a haplotype or haplotype set using simultaneous estimation of haplotype frequencies, diplotype configurations and diplotype-based penetrances. Genetics 168:2339–2348PubMedCrossRefGoogle Scholar
  17. Jain M, Kumar S, Lal P, Tiwari A, Ghoshal UC, Mittal B (2007) Association of genetic polymorphisms of N-acetyltransferase 2 and susceptibility to esophageal cancer in north Indian population. Cancer Invest 25:340–346PubMedCrossRefGoogle Scholar
  18. Jorge-Nebert LF, Eichelbaum M, Griese EU, Inaba T, Arias TD (2002) Analysis of six SNPs of NAT2 in Ngawbe and Embera Amerindians of Panama and determination of the Embera acetylation phenotype using caffeine. Pharmacogenetics 12:39–48PubMedCrossRefGoogle Scholar
  19. Kong SY, Park JW, Lee JA, Park JE, Park KW, Hong EK, Kim CM (2007) Association between vascular endothelial growth factor gene polymorphisms and survival in hepatocellular carcinoma patients. Hepatology 46:446–455PubMedCrossRefGoogle Scholar
  20. Li N, Stephens M (2003) Modeling linkage disequilibrium and identifying recombination hotspot using single-nucleotide polymorphism data. Genetics 165:2213–2233 [Erratum in: Genetics (2004) 167:1039]PubMedGoogle Scholar
  21. Mahid SS, Colliver DW, Crawford NP, Martini BD, Doll MA, Hein DW, Cobbs GA, Petras RE, Galandiuk S (2007) Characterization of N-acetyltransferase 1 and 2 polymorphisms and haplotype analysis for inflammatory bowel disease and sporadic colorectal carcinoma. BMC Med Genet 8:28. http://www.biomedcentral.com/1471-2350/8/28 Google Scholar
  22. Marchini J, Cutler D, Patterson N, Stephens M, Eskin E, Halperin E et al (2006) A comparison of phasing algorithms for trios and unrelated individuals. Am J Hum Genet 78:437–450PubMedCrossRefGoogle Scholar
  23. Meisel P, Timm R, Sawaf H, Fanghanel J, Siegmund W, Kocher T (2000) Polymorphism of the N-acetyltransferase (NAT2), smoking and the potential risk of periodontal disease. Arch Toxicol 74:343–348PubMedCrossRefGoogle Scholar
  24. Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215–1216PubMedCrossRefGoogle Scholar
  25. Niu T (2004) Algorithms for inferring haplotypes. Genet Epidemiol 27:334–347PubMedCrossRefGoogle Scholar
  26. Niu T, Qin ZS, Xu X, Liu JS (2002) Bayesian haplotype inference for multiple linked single-nucleotide polymorphisms. Am J Hum Genet 70:157–169PubMedCrossRefGoogle Scholar
  27. Qin ZS, Nui T, Liu JS (2002) Partition–ligation–expectation–maximization algorithm for haplotype inference with single-nucleotide polymorphisms. Am J Hum Genet 71:1242–1247PubMedCrossRefGoogle Scholar
  28. Rodriguez JW, Kirlin WG, Ferguson RJ, Doll MA, Gray K, Rustan TD, Lee ME, Kemp K, Urso P, Hein DW (1993) Human acetylator genotype: relationship to colorectal cancer incidence and arylamine N-acetyltransferase expression in colon cytosol. Arch Toxicol 67:445–452PubMedCrossRefGoogle Scholar
  29. Sabbagh A, Darlu P (2005) Inferring haplotypes at the NAT2 locus: the computational approach. BMC Genet 6:30. http://www.biomedcentral.com/1471-2156/6/30 Google Scholar
  30. Sak SC, Barrett JH, Paul AB, Bishop DT, Kiltie AE (2007) DNA repair gene XRCC1 polymorphisms and bladder cancer risk. BMC Genet 8:13. http://www.biomedcentral.com/1471-2156/8/13 Google Scholar
  31. Salem RM, Wessel J, Schork NJ (2005) A comprehensive literature review of haplotyping software and methods for use with unrelated individuals. Hum Genomics 2:39–66PubMedGoogle Scholar
  32. Scheet P, Stephens M (2006) A fast and flexible statistical model for large-scale population genotype data: applications to inferring missing genotypes and haplotypic phase. Am J Hum Genet 78:629–644PubMedCrossRefGoogle Scholar
  33. Stephens M, Donnelly P (2003) A comparison of Bayesian methods for haplotype reconstruction. Am J Hum Genet 73:1162–1169PubMedCrossRefGoogle Scholar
  34. Stephens M, Scheet P (2005) Accounting for decay of linkage disequilibrium in haplotype inference and missing-data imputation. Am J Hum Genet 76:449–462PubMedCrossRefGoogle Scholar
  35. Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–989PubMedCrossRefGoogle Scholar
  36. Tanaka E, Taniguchi A, Urano W, Nakajima H, Matsuda Y, Kitamura Y et al (2002) Adverse effects of sulphasalazine in rheumatoid arthritis patients are associated with diploid configuration at N-acetyltransferase 2 gene. J Rheumatol 29:2492–2499PubMedGoogle Scholar
  37. Vineis P, Marinelli D, Autrup H, Brockmoller J, Cascorbi I, Daly AJ et al (2001) Smoking, occupation, N-acetyltransferase-2 and bladder cancer: a pooled analysis of genotyped studies. Cancer Epidemiol Biomarkers Prev 10:1249–1252PubMedGoogle Scholar
  38. Xu CF, Lewis K, Cantone KL, Khan P, Donally C, White N et al (2002) Effectiveness of computational methods in haplotype prediction. Hum Genet 110:148–156PubMedCrossRefGoogle Scholar
  39. Zang Y, Doll MA, Zhao S, States JC, Hein DW (2007) Functional characterization of single-nucleotide polymorphisms and haplotypes of human N-acetyltransferase 2. Carcinogenesis 28:1665–1671 (Epub ahead of print)PubMedCrossRefGoogle Scholar
  40. Zhang J, Vingron M, Hoehe MR (2005) Haplotype reconstruction for diploid populations. Hum Hered 59:144–156PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Klaus Golka
    • 1
  • Meinolf Blaszkewicz
    • 1
  • Mirabutaleb Samimi
    • 1
  • Hermann M. Bolt
    • 1
  • Silvia Selinski
    • 1
    • 2
  1. 1.Institute for Occupational Physiology at the University of Dortmund (IfADo)DortmundGermany
  2. 2.Department of StatisticsUniversity of DortmundDortmundGermany

Personalised recommendations