Genetic screening: programs, principles, and research--thirty years later. Reviewing the recommendations of the Committee for the Study of Inborn Errors of Metabolism (SIEM).

Screening programs for genetic diseases and characteristics have multiplied in the last 50 years. 'Genetic Screening: Programs, Principles, and Research' is the report of the Committee for the Study of Inborn Errors of Metabolism (SIEM Committee) commissioned by the Division of Medical Sciences of the National Research Council at the National Academy of Sciences in Washington, DC, published in 1975. The report is considered a classic in the field worldwide, therefore it was thought appropriate 30 years later to present the Committee's modus operandi and bring the Committee's recommendations to the attention of those involved in genetics, including organizational, educational, legal, and research aspects of genetic screening. The Committee's report anticipated many of the legal, ethical, economic, social, medical, and policy aspects of genetic screening. The recommendations are current, and future committees should be familiar with them. In 1975 the Committee stated: 'As new screening tests are devised, they should be carefully reviewed. If the experimental rate of discovery of new genetic characteristics means an accelerating rate of appearance of new screening tests, now is the time to develop the medical and social apparatus to accommodate what later on may otherwise turn out to be unmanageable growth.' What a prophetic statement that was. If the Committee's recommendations had been implemented on time, there would be today a federal agency in existence, responsive and responsible to carry out the programs and support research on various aspects of genetic screening, including implementation of a federal law that protects consumers from discrimination by their employers and the insurance industry on the basis of genetic information.

Evolutionary aspects of diet, the omega-6/omega-3 ratio and genetic variation: nutritional implications for chronic diseases.

Anthropological and epidemiological studies and studies at the molecular level indicate that human beings evolved on a diet with a ratio of omega-6 to omega-3 essential fatty acids (EFA) of approximately 1 whereas in Western diets the ratio is 15/1 to 16.7/1. A high omega-6/omega-3 ratio, as is found in today's Western diets, promotes the pathogenesis of many diseases, including cardiovascular disease, cancer, osteoporosis, and inflammatory and autoimmune diseases, whereas increased levels of omega-3 polyunsaturated fatty acids (PUFA) (a lower omega-6/omega-3 ratio), exert suppressive effects. Increased dietary intake of linoleic acid (LA) leads to oxidation of low-density lipoprotein (LDL), platelet aggregation, and interferes with the incorporation of EFA in cell membrane phospholipids. Both omega-6 and omega-3 fatty acids influence gene expression. Omega-3 fatty acids have anti-inflammatory effects, suppress interleukin 1beta (IL-1beta), tumor necrosis factor-alpha (TNFalpha) and interleukin-6 (IL-6), whereas omega-6 fatty acids do not. Because inflammation is at the base of many chronic diseases, dietary intake of omega-3 fatty acids plays an important role in the manifestation of disease, particularly in persons with genetic variation, as for example in individuals with genetic variants at the 5-lipoxygenase (5-LO). Carotid intima media thickness (IMT) taken as a marker of the atherosclerotic burden is significantly increased, by 80%, in the variant group compared to carriers with the common allele, suggesting increased 5-LO promoter activity associated with the (variant) allele. Dietary arachidonic acid (AA) and LA increase the risk for cardiovascular disease in those with the variants, whereas dietary intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) decrease the risk. A lower ratio of omega-6/omega-3 fatty acids is needed for the prevention and management of chronic diseases. Because of genetic variation, the optimal omega-6/omega-3 fatty acid ratio would vary with the disease under consideration.

The traditional diet of Greece and cancer.

The term 'Mediterranean diet', implying that all Mediterranean people have the same diet, is a misnomer. The countries around the Mediterranean basin have different diets, religions and cultures. Their diets differ in the amount of total fat, olive oil, type of meat, wine, milk, cheese, fruits and vegetables; and the rates of coronary heart disease and cancer, with the lower death rates and longer life expectancy occurring in Greece. The diet of Crete represents the traditional diet of Greece prior to 1960. Analyses of the dietary pattern of the diet of Crete shows a number of protective substances, such as selenium, glutathione, a balanced ratio of n-6/n-3 essential fatty acids (EFA), high amounts of fibre, antioxidants (especially resveratrol from wine and polyphenols from olive oil), vitamins E and C, some of which have been shown to be associated with lower risk of cancer, including cancer of the breast. Epidemiological studies and animal experiments indicate that n-3 fatty acids exert protective effects against some common cancers, especially cancers of the breast, colon and prostate. Many mechanisms are involved, including suppression of neoplastic transformation, cell growth inhibition, and enhanced apoptosis and anti-angiogenicity, through the inhibition of eicosanoid production from n-6 fatty acids; and suppression of cyclooxygenase 2 (COX-2), interleukin 1 (IL-1) and IL-6 gene expression by n-3 fatty acids. Recent intervention studies in breast cancer patients indicate that n-3 fatty acids, and docosahexaenoic acid (DHA) in particular, increase the response to chemopreventive agents. In patients with colorectal cancer, eicosapentaenoic acid (EPA) and DHA decrease cell proliferation, and modulate favourably the balance between colonic cell proliferation and apoptosis. These findings should serve as a strong incentive for the initiation of intervention trials that will test the effect of specific dietary patterns in the prevention and management of patients with cancer.

The importance of the ratio of omega-6/omega-3 essential fatty acids.

Several sources of information suggest that human beings evolved on a diet with a ratio of omega-6 to omega-3 essential fatty acids (EFA) of approximately 1 whereas in Western diets the ratio is 15/1-16.7/1. Western diets are deficient in omega-3 fatty acids, and have excessive amounts of omega-6 fatty acids compared with the diet on which human beings evolved and their genetic patterns were established. Excessive amounts of omega-6 polyunsaturated fatty acids (PUFA) and a very high omega-6/omega-3 ratio, as is found in today's Western diets, promote the pathogenesis of many diseases, including cardiovascular disease, cancer, and inflammatory and autoimmune diseases, whereas increased levels of omega-3 PUFA (a low omega-6/omega-3 ratio) exert suppressive effects. In the secondary prevention of cardiovascular disease, a ratio of 4/1 was associated with a 70% decrease in total mortality. A ratio of 2.5/1 reduced rectal cell proliferation in patients with colorectal cancer, whereas a ratio of 4/1 with the same amount of omega-3 PUFA had no effect. The lower omega-6/omega-3 ratio in women with breast cancer was associated with decreased risk. A ratio of 2-3/1 suppressed inflammation in patients with rheumatoid arthritis, and a ratio of 5/1 had a beneficial effect on patients with asthma, whereas a ratio of 10/1 had adverse consequences. These studies indicate that the optimal ratio may vary with the disease under consideration. This is consistent with the fact that chronic diseases are multigenic and multifactorial. Therefore, it is quite possible that the therapeutic dose of omega-3 fatty acids will depend on the degree of severity of disease resulting from the genetic predisposition. A lower ratio of omega-6/omega-3 fatty acids is more desirable in reducing the risk of many of the chronic diseases of high prevalence in Western societies, as well as in the developing countries, that are being exported to the rest of the world.

The Mediterranean diets: What is so special about the diet of Greece? The scientific evidence.

The term "Mediterranean diet," implying that all Mediterranean people have the same diet, is a misnomer. The countries around the Mediterranean basin have different diets, religions and cultures. Their diets differ in the amount of total fat, olive oil, type of meat and wine intake; milk vs. cheese; fruits and vegetables; and the rates of coronary heart disease and cancer, with the lower death rates and longer life expectancy occurring in Greece. Extensive studies on the traditional diet of Greece (the diet before 1960) indicate that the dietary pattern of Greeks consists of a high intake of fruits, vegetables (particularly wild plants), nuts and cereals mostly in the form of sourdough bread rather than pasta; more olive oil and olives; less milk but more cheese; more fish; less meat; and moderate amounts of wine, more so than other Mediterranean countries. Analyses of the dietary pattern of the diet of Crete shows a number of protective substances, such as selenium, glutathione, a balanced ratio of (n-6):(n-3) essential fatty acids (EFA), high amounts of fiber, antioxidants (especially resveratrol from wine and polyphenols from olive oil), vitamins E and C, some of which have been shown to be associated with lower risk of cancer, including cancer of the breast. These findings should serve as a strong incentive for the initiation of intervention trials that will test the effect of specific dietary patterns in the prevention and management of patients with cancer.

n-3 fatty acids and human health: defining strategies for public policy.

The last quarter of the 20th century was characterized by an increase in the consumer's interest in the nutritional aspects of health. As a result, governments began to develop dietary guidelines in addition to the traditional recommended dietary allowances, which have been superseded now by dietary reference intakes. In addition to governments, various scientific societies and nongovernmental organizations have issued their dietary advice to combat chronic diseases and obesity. Human beings evolved on a diet that was balanced in n-6 and n-3 essential fatty acid intake, whereas Western diets have a ratio of n-6/n-3 of 16.74. The scientific evidence is strong for decreasing the n-6 and increasing the n-3 intake to improve health throughout the life cycle. This paper discusses the reasons for this change and recommends the establishment of a Nutrition and Food Policy, instead of a Food and Nutrition Policy, because the latter subordinates the nutritional aspects to the food policy aspects. Nutrition and food planning comprise a tool of nutrition and food policy, whose objectives are the achievement of the adequate nutrition of the population as defined by nutritional science. The scientific basis for the development of a public policy to develop dietary recommendations for essential fatty acids, including a balanced n-6/n-3 ratio is robust. What is needed is a scientific consensus, education of professionals and the public, the establishment of an agency on nutrition and food policy at the national level, and willingness of governments to institute changes. Education of the public is essential to demand changes in the food supply.

Human requirement for N-3 polyunsaturated fatty acids.

The diet of our ancestors was less dense in calories, being higher in fiber, rich in fruits, vegetables, lean meat, and fish. As a result, the diet was lower in total fat and saturated fat, but contained equal amounts of n-6 and n-3 essential fatty acids. Linoleic acid (LA) is the major n-6 fatty acid, and alpha-linolenic acid (ALA) is the major n-3 fatty acid. In the body, LA is metabolized to arachidonic acid (AA), and ALA is metabolized to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The ratio of n-6 to n-3 essential fatty acids was 1 to 2:1 with higher levels of the longer-chain polyunsaturated fatty acids (PUFA), such as EPA, DHA, and AA, than today's diet. Today this ratio is about 10 to 1:20 to 25 to 1, indicating that Western diets are deficient in n-3 fatty acids compared with the diet on which humans evolved and their genetic patterns were established. The n-3 and n-6 EPA are not interconvertible in the human body and are important components of practically all cell membranes. The N-6 and n-3 fatty acids influence eicosanoid metabolism, gene expression, and intercellular cell-to-cell communication. The PUFA composition of cell membranes is, to a great extent, dependent on dietary intake. Therefore, appropriate amounts of dietary n-6 and n-3 fatty acids need to be considered in making dietary recommendations. These two classes of PUFA should be distinguished because they are metabolically and functionally distinct and have opposing physiological functions; their balance is important for homeostasis and normal development. Studies with nonhuman primates and human newborns indicate that DHA is essential for the normal functional development of the retina and brain, particularly in premature infants. A balanced n-6/n-3 ratio in the diet is essential for normal growth and development and should lead to decreases in cardiovascular disease and other chronic diseases and improve mental health. Although a recommended dietary allowance for essential fatty acids does not exist, an adequate intake (AI) has been estimated for n-6 and n-3 essential fatty acids by an international scientific working group. For Western societies, it will be necessary to decrease the intake of n-6 fatty acids and increase the intake of n-3 fatty acids. The food industry is already taking steps to return n-3 essential fatty acids to the food supply by enriching various foods with n-3 fatty acids. To obtain the recommended AI, it will be necessary to consider the issues involved in enriching the food supply with n-3 PUFA in terms of dosage, safety, and sources of n-3 fatty acids.

Role of plant-derived omega-3 fatty acids in human nutrition.

An international workshop on the role of plant-derived omega-3 fatty acids in human nutrition took place in Milan on February 9, 2000. The meeting was sponsored by the Nutrition Foundation of Italy and was organized by its Scientific Director, Dr. Andrea Poli. It was attended by experts in polyunsaturated fatty acids and human lipid nutrition. This is the first meeting devoted to the health aspects of alpha-linolenic acid, the omega-3 fatty acid contained in plant-derived edible products, as distinct from the more widely studied long-chain omega-3 products typically present in fish and fish-derived products. This report, which is based on updated scientific evidence presented and discussed at the workshop, was prepared by the international expert panel.

Essential fatty acids in health and chronic disease.

Human beings evolved consuming a diet that contained about equal amounts of n-3 and n-6 essential fatty acids. Over the past 100-150 y there has been an enormous increase in the consumption of n-6 fatty acids due to the increased intake of vegetable oils from corn, sunflower seeds, safflower seeds, cottonseed, and soybeans. Today, in Western diets, the ratio of n-6 to n-3 fatty acids ranges from approximately 20-30:1 instead of the traditional range of 1-2:1. Studies indicate that a high intake of n-6 fatty acids shifts the physiologic state to one that is prothrombotic and proaggregatory, characterized by increases in blood viscosity, vasospasm, and vasoconstriction and decreases in bleeding time. n-3 Fatty acids, however, have antiinflammatory, antithrombotic, antiarrhythmic, hypolipidemic, and vasodilatory properties. These beneficial effects of n-3 fatty acids have been shown in the secondary prevention of coronary heart disease, hypertension, type 2 diabetes, and, in some patients with renal disease, rheumatoid arthritis, ulcerative colitis, Crohn disease, and chronic obstructive pulmonary disease. Most of the studies were carried out with fish oils [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)]. However, alpha-linolenic acid, found in green leafy vegetables, flaxseed, rapeseed, and walnuts, desaturates and elongates in the human body to EPA and DHA and by itself may have beneficial effects in health and in the control of chronic diseases.