Dausset found that certain HLA flavors were often associated with inflammatory and autoimmune diseases, such as juvenile diabetes or rheumatoid arthritis (see chart). For example, one in five people carrying a version of HLA called B27 will develop ankylosing spondylitis, an inflammatory disease of the vertebrae. And subsequent studies on twins and families have revealed strong hereditary components to virtually all common disorders--from diabetes, asthma, hypertension and cancer to many mental disorders, including depression, schizophrenia and autism.
Geneticists distinguish between monogenic disorders--in which a single gene rules as an absolute master--and multifactorial disorders. The latter result from "criminal gangs" of genes--often tens of them--and the influence of environmental variables, such as diet and smoking habits, as well as infections or contact with toxic agents.
Thousands of known monogenic diseases, such as cystic fibrosis, muscular dystrophies and retinitis pigmentosa, are caused by single defective genes and are inherited in a predictable way, according to the classic laws of Mendelian genetics. Testing for monogenic diseases, when available, gives clear-cut results: people with the bad copy of the gene will generally manifest symptoms.
But most common disorders are instead multifactorial. Individual genetic variations may render someone susceptible, but they are neither necessary nor sufficient to cause such a disease. People with a genetic tendency toward diabetes, for example, have an increased statistical chance of being affected one day but are also likely to live in good health to a ripe old age. On the other hand, people without any evident predisposition may become diabetics, against all odds. Therefore, genetic tests for multifactorial disorders give only an estimated risk; they will never indicate whether the disease will actually develop.
Probing the Genomic Minefield
During this past decade, thanks to the advances of the Human Genome Project and improved techniques, scientists have started to extricate from a tangle of genetic and environmental factors the causes of many multifactorial diseases. "Researchers have developed more and more effective ways to pinpoint significant variations in the genome," says Dale R. Pfost, CEO at Orchid, a company based in Princeton, N.J., that specializes in the analysis of genetic diversity.
For years geneticists have been using polymorphic markers--regions of DNA that are extremely variable among individuals--as signposts along the genome. Using a method called linkage, for example, researchers can look for markers that are common among the diseased individuals of one family and not their healthy relatives. Because DNA regions that are close to each other in the chromosome are usually inherited together, disease genes are expected to lie near these markers.
"The density of markers in the genome has increased dramatically in the last years, allowing more and more accurate analysis," Pfost explains. Researchers have identified hundreds of gene variations that predispose their carriers to commons disorders. For instance, a particular form of the gene coding for angiotensinogen--an important blood pressure regulator--is carried by 35 percent of Caucasians and triples the risk of hypertension and heart attack. The good news is that the same variation makes these people more responsive to preventive measures in the form of low-sodium diets and a class of anti-hypertensive drugs called ACE-inhibitors.
But the revolution in genetic research could soon send the old markers in search of pensions. Most genetic differences between individuals are a result of variations in single "letters" of the DNA, variations that scientists call single nucleotide polymorphisms, or SNPs. Using new techniques, researchers can home in on the SNPs that are associated with specific diseases and analyze thousands of variations in minutes (see part II of this story next week for more on this subject). In the not-too-distant future, your doctor will test for your genetic profile as easily as he screens your cholesterol levels today.