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a single base pair mismatch can be identifi ed by the conductance of the molecule
and can cause a change in the conductance of dsDNA by as much as an order of
magnitude, depending on the specifi c details of the double helix and the SNP.
Impact of SNPs on Personalized Medicine
Pharmacogenetic capabilities have markedly increased since the fi rst SNP map
from the SNP Consortium became available in 2001. SNP-mapping technologies
now enable us to create a genetic profi le of each individual that can be used to iden-
tify patterns of susceptibility genes for common diseases as well as genetic risk/
effi cacy factors that are related to the effects of drugs. Inter-individual variability in
drug response, ranging from lack of effi cacy to life-threatening adverse reactions is
infl uenced by variation in genes that control the absorption, distribution, metabo-
lism and excretion of drugs.
An example of how SNP genotyping may be applied in medicine is the evidence
of association between an SNP in the TNFR (tumor necrosis factor receptor) II gene
and rheumatoid arthritis. TNF is a powerful mediator of infl ammation in rheumatoid
arthritis. In vivo, its acute effects are limited by binding to TNFR, suggesting that
TNFR genes could be important candidate risk factors, the strongest association
being observed in patients with a family history of this disease. The TNFR2 poly-
morphism or other genetic variations in the TNF or related genes may be useful
biomarkers for susceptibility to familial rheumatoid arthritis and response to treat-
ment with TNF inhibitors.
Detection of Copy Number Variations
Although the importance of CNVs in genome wide association studies (GWAS) is
widely accepted, the optimal methods for identifying these variants are still under
evaluation. Extensions of GWAS to CNV have already resulted in discoveries of
both de novo and inherited CNVs associated with risk of common disease. CNVs in
the human genome are detected with high-throughput scanning technologies, such
as CGH and high-density SNP microarrays, or even relatively low-throughput tech-
niques, such as quantitative PCR. A comprehensive view of CNVs in the HapMap
DNA collection using high density 500 K Early Access SNP genotyping arrays has
revealed >1,000 CNVs ranging in size from 1 kb to over 3 Mb. Although the arrays
used most commonly for GWAS predominantly interrogate SNPs, CNV identifi ca-
tion does not necessarily require the use of DNA probes centered on polymorphic
nucleotides and may even be hindered by the dependence on a successful SNP
genotyping assay. Non-polymorphic probes provide a robust approach for CNV
identifi cation, and the increasing precision of CNV boundary delineation should
allow a more complete analysis of their genomic organization. Development of
sequencing technologies has opened the door to novel methods for detecting CNVs
2 Molecular Diagnostics in Personalized Medicine