Human Pedigrees

Based on these measurements, individuals who are poor metabolizers can be identified. This is a trait that might be of concern for drug metabolism in general. 

---

Pedigree Analysis, an approach widely used where experimental breeding is not practical. Pedigrees show the inheritance of specific Iraits. which can be traced, in all of lhe members of a family line. Human pedigrees have been very useful in terms of tracing the familial aspects of certain diseases. One of the first diseases so traced was hemophilia. Stock... 

Human pedigree studies of families with Lesch-Nyhan syndrome (Seegmiller et al., 1976) showed that the HPRT gene was X-linked, and this was confirmed by analysis of human-mouse cell hybrids which had lost most of their human chromosomes (Ricciuiti and Ruddle, 1973). 

In 1993/1994 a series of publications caused a stir in the AD research community, since for the first time they linked a specific neuropathological process in late-onset AD to a genetic marker. Researchers looking at the composition of plaques found that the protein apolipoprotein E (ApoE) was associated with p-amyloid in the cerebrospinal fluid (CSF) of AD patients (Strittmatter et al., 1993). The gene for ApoE is on the same human chromosome (number 19) which was a risk factor in some AD pedigrees. The gene for ApoE comes in three versions (alleles) Apo s2, Apo s3 and, most importantly, Apo s4 these result in three slightly different variants of the protein. Humans carry two versions of the allele and so can have none, one or two of any of the versions of the Apo... 

The observed CEPH population mean IC50 for both docetaxel and 5-fluorouracil was similar to IC50 values observed across the NCI60 panel of human tumor cell lines (http //dtp.nci.nih.gov) (17). In addition, docetaxel- and 5-fluorouracil-induced cell death is mediated by caspase-3 cleavage, similar to that observed in tumor cells (17). These data are encouraging for the use of CEPH pedigrees as a discovery tool. However, the ultimate proof of the value of the cell-based models will be the human validation of markers derived from this process. These studies he ahead and will help position cell-based models in their correct place in the drug development process. 

M23. Moser, K. L., Neas, B. R., Salmon, J. E., Yu, H., Gray-McGuire, C., etal., Genome scan of human systemic lupus erythematosus Evidence for linkage on chromosome lq in African-American pedigrees. Proc. Natl. Acad. Sci. USA 95, 14869-14874 (1998). 

---