Haplotype analysis

Similar to the difference between the Ukelihood-based haplotype inference methods and coalescent model-based methods, the above approach does not take similarity among haplot5q)es into account. It seems reasonable to assume that if a gene is associated with disease, similar haplotypes may have similar effects on disease 

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Haplotype analysis may be necessary if the candidate genes do not have known functional polymorphisms. Prior knowledge of haplotype tag single-nucleotide polymorphisms (SNPs) for each gene is essential to limit the number of assays required to avoid wasting finite patient samples. 

Sai K, Kaniwa N, Itoda M et al. Haplotype analysis of ABCBl/MDRl blocks in a Japanese population reveals genotype-dependent renal clearance of irinotecan. Pharmacogenetics 2003 13 741-757. 

Haplotype analysis performed for the polymorphisms in exons 12, 21, and 26. dNo correlation of 3 months post transplantation. eThe genotype affect CYP3A4 mRNA level (TT < CT < CC). fVerapamil, digoxin, vinblastine, cyclosporine. 

Our knowledge about how haplotype analysis may be applied to pharmacogenomics, as well as our understanding of human haplotype structure in general, is in its infancy. In fact, only recently has it been discovered... 

Zill P, Baghai TC, Zwanzger P, et al. SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression. Mol Psychiatry 2004 9( 11) 1030-1036. 

Ikeda Y, Dalton JC, Moseley ML, Gardner KL, Bird TD, Ashizawa T, Seltzer WK, Pandolfo M, Milunsky A, Potter NT, Shoji M, Vincent JB, Day JW, Ranum LP (2004) Spinocrebellar ataxia type 8 molecular genetic comparisons and haplotype analysis of 37 families with ataxia. Am J Hum Genet 75 3-16... 

Hyperserotonemia has been a consistent finding in subjects with autism, which may be due to activity of serotonin-associated platelet proteins (Hranilovic et al., 2008, 2009). Interestingly, 99% of blood serotonin is contained in platelets (Anderson et al., 1987) and studies have shown that there is an approximate 50% increase in blood-levels of serotonin in subjects with autism vs. controls (McBride et al., 1998). Hypotheses for increased serotonin include increased synthesis of serotonin by tryptophan hydroxylase (TPHl), increased uptake of serotonin into platelets via serotonin transporters (5-HTT), diminished release of serotonin from platelets via serotonin 2A receptor, and decreased breakdown of serotonin by monoamine oxidase (MAOA) (Hranilovic et al., 2008). A study by Hranilovic et al. (2008) identified polymorphisms of tryptophan hydroxylase and MAOA with increased serum serotonin levels. Similarly, haplotype analysis has shown a significant association between polymorphisms of TPHl and increased serotonin in whole blood (Cross et al., 2008). 

Carlo H, Schwarz K, Jorch N, Kyank U, Petrides PE, Schneider DT, Uhle R, Debatin KM, Kohne E. Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene and VHL-haplotype analysis in patients with presumable congenital erythrocytosis. Haematologica 2005 90 19-24. 

Saito, K. Miyake, S. Moriya, H. Yamazaki, M. Itoh, F. Imai, K. Kurosawa, N. Owada, E. Miyamoto, A. detection of the four sequence variations of MDRl gene using TaqMan MGB probe based real-time PCR and haplotype analysis in healthy Japanese subjects. Clin. Biochem. 2003, 36, 511-518. 

Owen, R.P., Lagpacan, L.L., Taylor, T.R., De LaCruz, M., Huang, C.C., Kawamoto, M., Johns, S.J., Stryke, D., Ferrin, T.E. and Giacomini, KM. (2006) Functional characterization and haplotype analysis of polymorphisms in the human equilibrative nucleoside transporter, ENT2. Drug Metabolism and Disposition The Biological Fate of Chemicals, 34 (1), 12-15. 

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