Human Genome Project and the Genetics of Psoriasis

One of the biggest science news stories of the new century was the announcement that the Human Genome Project had completed its task of sequencing the human genome. It was an announcement that scientific and clinical medicine welcomed—with cautionary qualifications. While the sequenced human genome is the first complete map of the genetic makeup of humans, it is a rough draft that needs to be "cleaned up" and it should not be expected to immediately lead the way to cures for a host of diseases with a genetic component.

What are the implications of the human genome map for people with psoriasis and other diseases with a genetic component? It may take a while to say with any degree of certainty.

The sequencing of the human genome was completed in early 2001, providing the first complete "map" of the genetic makeup of humans. What does this mean for people who have a disease such as psoriasis that is known to have a genetic component? A widely shared anticipation (and hope) is that the human genome map will allow investigators to identify the specific genes associated with diseases that have a genetic component, in turn providing information to better understand these diseases and develop specifically targeted treatments.

Some Surprising Findings
A surprise for the Human Genome Project investigators and many other scientists was the total number of about 32,000 human genes identified. It was previously believed that humans carry about 100,000 genes. Although the Human Genome Project map is acknowledged to be a "rough draft," the current estimate of most investigators is that the final total of human genes after "dotting all the i’s and crossing all the t’s" will be between 32,000 and 40,000.

Genes and Multifactorial Diseases
Many diseases with a genetic component are already known to involve multiple genes and gene mutations as well as environmental factors. Psoriasis falls into this category.

So-called single-gene diseases are different from multi-factor diseases in very important ways:

• In single-gene diseases, mutation in a single gene is both necessary and sufficient to produce the disease. Whether or not one "gets" the disease depends heavily on inheritance patterns and other factors, but genetic risk for the disease can be assessed.
• In multi-factor (multiple gene plus environment or other factors) diseases such as psoriasis, variations in a gene or number of genes may produce a genetic predisposition for the disease. This physical, biochemical and physiologic makeup may respond to environmental factors in such a way as to produce the disease. Gene mutation(s) or variation(s) are often not necessary or sufficient to explain the clinical response. A tendency for inheritance within families is observed but the inheritance patterns are not in a pattern that can be readily assessed for risk [McKusick VA. Mendelian Inheritance in Man. Baltimore: John Hopkins University Press, 12^th ed.; 1998].

A number of genes involved in psoriasis are already known or suspected. In order to search the human genome map for genes involved in multi-factor diseases such as psoriasis, investigators need a great deal of information that will give them clues as to where to begin.

• Animal models can provide important information if investigators can find an animal in which the disease can be reliably reproduced and/or genes can be "knocked out" to indicate the relative importance of gene function and products in producing the disease.
• Epidemiologic data can help establish genetic patterns in large populations.

Epidemiologic investigations of psoriasis have supported the genetic predisposition concept. A "family tendency" for psoriasis has been identified—i.e., a higher-than-average incidence of psoriasis is found in relatives of psoriasis patients, although some people with psoriasis have no family history of the disease. Psoriasis in one or both parents is known to increase risk for psoriasis in a child. In studies of identical and fraternal twins, psoriasis is much more likely to appear in both identical twins than in both fraternal twins. This provides strong evidence for a hereditary basis for psoriasis.

Candidate genes for involvement in psoriasis have been identified by various approaches. These studies indicate a higher-than-expected frequency of certain white cell antigens (Class 1 human leucocyte antigens or HLAs) on cells of people with psoriasis and their close relatives. The finding supports inheritability for psoriasis and suggests that the gene(s) involved in psoriasis may be on the chromosome that holds genes for HLA. The HLA complex has a critical role in the immune system. It is involved in the timing, onset and severity of many diseases in which immune-system dysfunction or immune system-environmental inter-relationships are suspected.

Of interest, perhaps, is that all of the current candidate genes are associated with the "adaptive immune system" of disease-fighting cells (e.g., T cells) and humoral immunity (e.g., antibodies). The so-called adaptive immune system is a late development in evolution. Its elegantly complex cellular and humoral immune protection against disease is not found in older organisms from which we inherited so much of our genome. The adaptive immune system may have evolved from the more ancient system known as "innate immune response," an inflammatory reaction that helps control infection in its earliest stages. On an evolutionary time scale, the human immune system may be regarded as a work in progress.

In Summary
The map of the human genome produced by the Human Genome Project is a tool of enormous importance in the investigation of human diseases. It will not, of itself, produce "answers" to advance understanding and treatment of complex, multifactorial diseases until investigators are able to ask the right questions. But one can be optimistic. When the Human Genome Project was undertaken in the 1990s it was anticipated that it would not be completed until 2003 or later. But with technological advances and a "can do" spirit, investigators finished the task at least two years earlier than the most optimistic previous predictions.