Daewha Benjamin Hong, MD
Faculty Peer Reviewed
According to the New York Times, a genetic sequencing company called Knome is holding a charity auction on E-Bay with the winner to receive complete sequencing of their personal genome. The opening bid is $68,000, which is a bargain compared to the suggested retail price of $99,500.
But before I pull out my credit card and start bidding,, the April 23rd issue of the New England Journal of Medicine offers an interesting debate between geneticists on the utility of genomewide association studies. This current approach involves sequencing the genomes of large numbers of patients with a given disease and identifying the genetic variants that are shared in common. Unfortunately, for most major diseases, sequencing often reveals several dozen common variants, that even when combined still only explain a fraction of the hereditary risk. For example, Dr. Goldstein brings ups the TCF7L2 genetic variant, which is most strongly associated with type 2 diabetes, yet only confers a relative risk of 1.02 compared to a relative risk of 2-3 among siblings.
Drs. Kraft and Hunter calculate that there may yet be hundreds of undiscovered genetic variants required to explain this discrepancy. Dr. Goldberg suggests that perhaps to explain this unexplained hereditary factor, we should be looking for large numbers of rare variations instead of a small number of common variations. Nevertheless, Dr. Hirschhorn argues that genome wide studies are proving their worth by implicating novel biologic pathways of disease, one example of which is the elucidation of the role of autophagy in Crohn’s disease.
Unfortunately, diseases with single gene variants like BCR-ABL in CML or HER2-Neu in breast cancer, which can be elegantly targeted with highly specific antagonists, are the exception rather than the rule. Given the current high cost of genetic testing and the weak genetic associations of most diseases, decoding my genome (and that of my patients) for susceptibility seems premature pending further research.
In other news, a few studies following large cohorts of older adults were recently published. An April 27 article in the Archives of Internal Medicine from the recent Cardiovascular Health Study studied late new-onset diabetes in 4883 men and women over the age of 65. In this large prospective cohort study, there were 9.8 new cases of drug treated diabetes per 1000 person-years, and 9/10 new cases were found to be attributable to an association with 5 lifestyle factors: low physical activity, diet, smoking, alcohol, and BMI. A March 23 article in the same journal studying a prospective cohort of a half million elderly people aged 50-71 found an association between eating red and processsed meat and modest increases in total, cancer, and cardiovascular mortality. If decoding our genome is not the answer, then, in the meantime it seems that, even later in life, we can still rely on the old standby of lifestyle modification, which costs nothing and requires no fancy tests.
Dr. Hong is a first year resident at NYU Medical Center.
References
Goldstein DB. Common genetic variation and human traits. N Engl J Med. 2009 Apr 23;360(17):1696-8. Epub 2009 Apr 15. No abstract available.
http://content.nejm.org/cgi/content/extract/360/17/1696
Hirschhorn JN. Genomewide association studies–illuminating biologic pathways. N Engl J Med. 2009 Apr 23;360(17):1699-701. http://content.nejm.org/cgi/content/extract/360/17/1699
Kraft P, Hunter DJ. Genetic risk prediction–are we there yet? N Engl J Med. 2009 Apr 23;360(17):1701-3.
http://content.nejm.org/cgi/content/extract/360/17/1701
Mozaffarian D, Kamineni A, Carnethon M, Djoussé L, Mukamal KJ, Siscovick D. Lifestyle risk factors and new-onset diabetes mellitus in older adults: the cardiovascular health study. Arch Intern Med. 2009 Apr 27;169(8):798-807.
http://archinte.ama-assn.org/cgi/content/short/169/8/798
Pollack, A. Mapping a human genome, via an ebay auction. New York Times [Internet]. 2009 April 23 [cited May 3, 2009]; Business. Available from http://www.nytimes.com/2009/04/23/business/23genome.html
Sinha R, Cross AJ, Graubard BI, Leitzmann MF, Schatzkin A. Meat intake an mortality: a prospective study of over half a million people. Arch Intern Med. 2009 Mar 23;169(6):562-71.
http://archinte.ama-assn.org/cgi/content/extract/169/6/543
Wade, N. Genes show limited value in predicting diseases. The New York Times.
One comment on “PrimeCuts-This Week in the Journals”
This is a well thought out, very well written analysis. However, I almost totally disagree. Dr. Hong is in good company with the pessimists but the data derived from GWAS trials do not lose value with their publication. They remain a valuable resource as new information on genetic identity, modulation and copy number variation is derived. A well phenotyped cohort that is associated with genomic DNA will provide information for years to come. We are just seeing the tip of the iceberg.
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