Why are some populations more susceptible than others to particular diseases? Prostate cancer is an example that demonstrates inter-group variation in the risk of developing this disease. While prostate cancer is the most common malignancy in men, it reveals striking differences in incidence and mortality rates by ethnicity. African American men, in particular, suffer from the highest rate in the world of developing prostate cancer. Two important observations suggest genetic links to prostate cancer. First, prostate cancer tends to cluster in families. Second, twin studies demonstrate that identical male twins (who have the exact duplicate set of genes) have a higher concordance rate of prostate cancer than fraternal twins (who share, on average, 50' of their genes). These studies support the notion that genes can influence the risk of developing prostate cancer.

Most human traits that have been studied genetically are monogenic, or single gene disorders. These disorders illustrate the situation in which a mutation in one gene is necessary and sufficient to cause disease. However, diseases responsible for the vast majority of morbidity and mortality in the population are believed to stem from the interactions of more than one gene, often referred to as polygenic, or complex traits. Thus, it follows that for complex diseases, each individual gene contributes a modest effect to disease expression. An apt analogy is that of a light switch and a dimmer. A light switch only allows the light to be on or off just as a monogenic disease is determined by whether or not the mutated gene is inherited. Alternatively, a dimmer can modulate the intensity of light from dim to bright just as the predisposition of developing a polygenic disease is determined by how genes modify the spectrum of risk. This added layer of complexity demands new methods of investigation. Recent advancements provide us with the opportunity to explore how multiple genes may affect the risk of developing a disease.

The human genome project serves as a crucial starting point to study complex traits. This remarkable achievement has largely deciphered the entire sequence and order of the 3 billion letters (A, T, C, and G), referred to as bases, that comprise all of our nuclear DNA. With this blueprint in hand, a natural curiosity is to query how we vary at the level of our DNA. When DNA sequences are randomly chosen from the population and compared, it is apparent that human beings are 99.9' similar. The 0.1' differences are largely in the form of single base changes referred to as single nucleotide polymorphisms (SNPs). Given this relatively low (0.1') degree of variation in our species, it is possible to collect and catalogue these differences. In fact, a human map containing 1.4 million SNPs has been constructed in the past year and is publicly available. Furthermore, technological advances make it possible to ascertain these differences in an efficient, high-throughput manner. With these accomplishments, we are now poised to tackle how and if variation in our DNA impacts disease risk.

I aim to apply these new tools to interrogate if genetic differences can help explain the increased prostate cancer incidence in African American men. As proof of concept, we tested genetic variation in the androgen receptor, a gene extensively studied in prostate cancer. We demonstrated that tremendous racial variation exists in this gene among different ethnic populations. African American men demonstrated the greatest degree of genetic diversity. Differences such as these may aid our understanding of the disproportionate risk of prostate cancer in African American men.

A number of lines of investigation have implicated various molecules that potentially modify prostate cancer risk. Some of the strongest evidence comes from the growth hormone pathway. This pathway is integral to the development and proliferation of many tissues including the prostate gland. For example, a number of reports demonstrate that serum levels of insulin like growth factor-1, a hormone in this pathway, is predictive of developing prostate cancer. Thus, I will comprehensively evaluate genetic variation in the entire growth hormonal pathway and then statistically determine if this variation impacts disease risk.

If genetic variation in this pathway is found to be associated with prostate cancer risk, many possibilities exist for future research. Recognition of persons predisposed to prostate cancer will lead to early screening and prevention strategies, resulting in improved quality and quantity of life. Once genes involved in prostate cancer are identified, targeted drug therapies could be developed to help treat or even prevent the disease from occurring. By exploring our universe of genetic variation and its impact on disease, we can generate results that potentially will have a direct impact on clinical medicine by leading to more effective screening, prevention, and treatment strategies for patients with prostate cancer.