A New Tool to Trace Genetic Susceptibility - eg, acetaminophen Tylenol subgroup

[Guest guest]

Notice the reference herein to the subgroup with increased susceptibility

for liver damage via Tylenol. That subgroup *may* also be more

susceptible to other toxins, including thimerosal - thus making thimerosal

+ Tylenol a horrifically poisonous combination - and that combo

exacerbated if the infant or toddler has a prolonged gastro pathology

whereby nutrient ingestion is suboptimal.

- - -

EHP commentary:

A New Tool to Trace Genetic Susceptibility

http://www.ehponline.org/docs/2007/115-1/niehsnews.html#anew

Just like individual people, various mouse strains come in different sizes

and colors, and with different predispositions to disease. Since more than

99% of human genes can be matched to analogous mouse genes that have

similar functions, scientists often study mouse models to better

understand human disease. It's already well known which strains of mice

are genetically at greater risk for certain diseases. But what isn't so

clear is which small genetic variations, or single-nucleotide

polymorphisms (SNPs), lead to these differences.

SNPs aren't large mutations but normal variations of one letter of the

genetic code. For example, a sequence that reads AATTCCG in one strain of

mouse may show up as AATACCG in another. Now Scientists who study mice as

models for human disease have a new tool to help them more quickly home in

on the SNPs that matter when it comes to disease susceptibility. With the

completion of the NIEHS-funded Resequencing and SNP Discovery Project,

announced in October 2006, researchers now have free access to a data set

of 8.3. million SNPs housed on the National Center for Biotechnology

Information website at http://www.ncbi.nlm.nih.gov/SNP/.

Researchers at Perlegen Sciences,under contract to the National Toxicology

Program, resequenced the genomic DNA of 15 genetically diverse research

mouse strains by comparing the sequences to a reference mouse strain (the

first mouse strain to have its DNA completely sequenced to very high

accuracy). Frazer, principal investigator of the project and vice

president of genomics at Perlegen Sciences, says, " We take these pieces of

DNA and align them to that reference sequence, and we look for

differences. " To do that, the scientists used the same high-density

oligonucleotide array technology that was used to discover common DNA

variations in the human genome.

The completion of the project provides a powerful tool; many discoveries

should come when scientists use it. " We're looking forward to researchers

using these . . . SNPs in comparative studies of the different mice

strains that are physiologically and physically well characterized, "

Frazer says.

Threadgill, an associate professor of genetics at the University of

North Carolina at Chapel Hill, says the data set was critical in recent

studies that revealed genes that may contribute to human susceptibility to

liver damage from acetaminophen. His work, currently under review for

publication, was inspired by a paper published 5 July 2006 in JAMA showing

that a subset of the study participants showed greater susceptibility to

liver damage from taking recommended doses of acetaminophen. " However,

clearly it's unethical to go in and treat thousands of individuals to try

to find the underlying genetic causes of that, " Threadgill says.

Instead, Threadgill and colleagues used the SNP maps of the 15 mouse

strains to identify genetic variance between strains of mice that differed

in liver toxicity due to acetaminophen. They then tested two candidate

genes in a small human study.They found that variance in the two candidate

genes correctly predicted the patients who showed high levels of serum

markers of liver toxicity after taking the maximum recommended dose of

acetaminophen for several days. " Without these detailed SNP maps, we would

not have been able to have very quickly done that translational test,

which we were able to do just in a matter of months, " Threadgill says.

NIEHS director Schwartz says the conclusion of the Resequencing and

SNP Discovery Project represents a milestone that builds on fundamental

accomplishments such as the 2003 completion of the human genome sequence.

" This accomplishment provides the tools to discover genes in mice that

play critical roles in the response to environmental toxicants and the

development of disease, " Schwartz says. " The environmentally responsive

genes and the disease-related genes in mice are very likely to be

important in human disease. This development can be used to identify those

at risk, prevent the development of disease, and also identify promising

new forms of treatment. "

Spivey

*

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