Genetics and Health Health Article

INTERACTION OF GENES AND ENVIRONMENTAL FACTORS

For many decades there were disputes about whether inheritance or environment were more important in determining health status. The debate was framed as genetics versus environment, or nature versus nurture. That kind of thinking is no longer appropriate. It is firmly established that genes act by generating a molecular framework in cells and organisms, including people, that environmental factors act upon. Thus, people are exposed to many kinds of radiation; noise; chemicals and infectious agents in air, water, food, consumer products, cigarettes, alcohol, and drugs; as well as to physical and psychosocial stresses—all of which may interfere with normal cellular functioning. For example, chemicals called polycyclic aromatic hydrocarbons are produced in the combustion of gasoline, oil, cigarettes, and various industrial processes; these chemicals are breathed in through the lungs, enter the circulating blood, are activated in the liver and other organs into very reactive intermediates, and attack the DNA, forming chemical adducts with the DNA. These adducts cause the DNA code letters to be misread, generating mutations in the genetic information of these cells and increasing the risk that these cells will evade normal growth controls and become cancers. Behavioral follow-up studies in Scandinavia of adults who were adopted as infants have provided potent evidence that genetics and biology are crucial to future risks for alcoholism, depression, schizophrenia, and even criminal actions. There is now evidence of relevant inherited variation in dopamine receptors in depression, cigarette-smoking behaviors, and dysfunctional alcoholic intake. Such genetic variation may account for predisposition or resistance to these behavioral disorders.

Many pharmaceutical agents have variable therapeutic effects and variable adverse effects in different patients. In many cases we understand the reason: the drugs are metabolized (changed by enzyme action) into more active, or less active, molecules, depending on the inherited form of the gene coding for that particular metabolizing enzyme. Other chemicals from the external environment may undergo similar variable steps due to the same genes. Interactions of infectious agents with their "hosts," like infected people, may vary with genetic variation in the microbe and genetic variation in the infected person. Responses to high cholesterol foods or to cigarette smoking are subject to marked variation in people with different patterns of relevant genes. The study of these genetic-environmental interactions is called "ecogenetics."

SIGNIFICANCE OF GENETICS IN CLINICAL MEDICINE

There are well-recognized patterns of inheritance involving particular disease genes. If a disorder occurs in a grandparent, parent, and child, such vertical transmission in the pedigree is called dominant (caused by an abnormal gene from just one of the grandparents), and can involve either the X chromosome or any of the twenty-two autosomal chromosomes. Examples are Marfan's syndrome and Huntington's disease. If both parents appear normal, yet carry a recessive mutation, disease may occur when a child receives the mutant gene from each parent; examples include sickle-cell anemia and cystic fibrosis. Finally, the recessive gene may be carried on the X chromosome without manifestation in the female, but with full manifestation in the XY male, who has no normal second X gene; examples are hemophilia and Duchenne muscular dystrophy.

For common diseases like coronary heart disease, diabetes mellitus, breast cancers, depression, cleft lip and palate, and high blood pressure, multiple genes are involved; the heterogeneous causes vary within any group of diagnosed patients. Identical twins are much more likely than nonidentical (fraternal) twins to have the same disease; siblings and other close relatives have higher risks than unrelated individuals. In all cases, environmental factors, maturation factors, and other genes influence the age of onset of disease and the specific manifestations.

It is quite miraculous that such a high proportion of babies appears to be "normal"—within the broad range of normal physical and mental development. Nevertheless, about 3 percent of newborns have major malformations affecting the heart, colon, bones, or other organs. Some 2 to 5 percent have severe or moderate mental retardation or developmental disabilities. Chromosomal abnormalities account for many of the malformations, and various gene mutations contribute to the disabilities. Major chromosomal abnormalities are particularly common in spontaneously aborted fetuses (up to 50%). Variations within the normal range influence height, body habitus, propensity to weight gain, and mental development and temperament.

One of the important concepts in genetic medicine is "inborn errors of metabolism," a phrase introduced by Sir Archibald Garrod in 1908. Specific mutations, usually involving both the maternal and the paternal forms of the gene (autosomal recessive pattern of inheritance, with 25% risk for each offspring), cause deficiency of a key enzyme—as in mental retardation due to a block in the metabolism of the amino acid phenylalanine, which becomes toxic to the developing brain. The effects of this disorder (phenylketonuria, or PKU) can be prevented by diagnosing the condition at birth through newborn screening of a heel-stick blood sample and putting the child on a diet low in phenylalanine for the first five years of life, while the brain is growing rapidly. The special diet can be less stringent (but should, it now seems, be sustained) during childhood and adolescence. For women, it is crucial that they be back on a stringent low-phenylalanine diet during pregnancy; otherwise, the high circulating levels will definitely damage the fetus (100% risk of mental retardation).

Autosomal dominant diseases, like those which affect collagen in bone, cartilage, skin, and teeth, typically distort key proteins that have two or more polypeptides, such that a mutation in one makes the whole protein complex malfunction.

Knowledge from the Human Genome Project should allow identification of susceptibility genes for a broad array of diseases, thereby permitting testing before symptoms become manifest. If a single gene is responsible, testing during pregnancy or at any other appropriate time of life for the particular disease may predict a high risk or eliminate worry about that specific disease. For example, a person found to carry an inherited mutation in one of the colon cancer mutation repair genes could benefit from annual colonoscopy beginning at age thirty, so that any polyps would be detected and removed long before they progress to a potentially invasive cancer. In more complicated inherited conditions, multiple genes will be tested using new microarray and protein expression methods, answers will be couched in terms of increased or decreased risk and the likelihood of favorable responses to treatment. In other situations, the value of testing is limited due to lack of effective treatments, as for Huntington's disease. Of course, it is hoped that research will lead to effective therapies and preventive interventions and patients and families do value having the correct diagnosis, even if therapy is not (yet) available.