Gene-nutrient interactions and genetic susceptibility

 Gene-nutrient interactions and genetic susceptibility

There is good evidence that nutrients and physical activity influence gene expression and have shaped the genome over several million years of human evolution. Genes define opportunities for health and susceptibility to disease, while environmental factors determine which susceptible individuals will develop illness. In view of changing socioeconomic conditions in developing countries, such added stress may result in exposure of underlying genetic predisposition to chronic diseases. Gene-nutrient interactions also involve the environment. The dynamics of the relationships are becoming better understood but there is still a long way to go in this area, and also in other aspects, such as disease prevention and control. Studies continue on the role of nutrients in gene expression; for example, researchers are currently trying to understand why omega-3 fatty acids suppress or decrease the mRNA of interleukin, which is elevated in atherosclerosis, arthritis and other autoimmune diseases, whereas the omega-6 fatty acids do not . Studies on genetic variability to dietary response indicate that specific genotypes raise cholesterol levels more than others. The need for targeted diets for individuals and subgroups to prevent chronic diseases was acknowledged as being part of an overall approach to prevention at the population level. However, the practical implications of this issue for public health policy have only begun to be addressed. For example, a recent study of the relationship between folate and cardiovascular disease revealed that a common single gene mutation that reduces the activity of an enzyme involved in folate metabolism (MTHFR) is associated with a moderate (20%) increase in serum homocysteine and higher risk of both ischaemic heart disease and deep vein thrombosis.

Although humans have evolved being able to feed on a variety of foods and to adapt to them, certain genetic adaptations and limitations have occurred in relation to diet. Understanding the evolutionary aspects of diet and its composition might suggest a diet that would be consistent with the diet to which our genes were programmed to respond. However, the early diet was presumably one which gave evolutionary advantage to reproduction in the early part of life, and so may be less indicative of guidance for healthy eating, in terms of lifelong health and prevention of chronic disease after reproduction has been achieved. Because there are genetic variations among individuals, changes in dietary patterns have a differential impact on a genetically heterogeneous population, although populations with a similar evolutionary background have more similar genotypes. While targeted dietary advice for susceptible populations, subgroups or individuals is desirable, it is not feasible at present for the important chronic diseases considered in this report. Most are polygenic in nature and rapidly escalating rates suggest the importance of environmental change rather than change in genetic susceptibility.

Diet, nutrition and the prevention of chronic diseases through the life course

The rapidly increasing burden of chronic diseases is a key determinant of global public health. Already 79% of deaths attributable to chronic diseases are occurring in developing countries, predominantly in middleaged men. There is increasing evidence that chronic disease risks begin in fetal life and continue into old age. Adult chronic disease, therefore, reflects cumulative differential lifetime exposures to damaging physical and social environments.

For these reasons a life-course approach that captures both the cumulative risk and the many opportunities to intervene that this affords, was adopted by the Expert Consultation. While accepting the imperceptible progression from one life stage to the next, five stages were identified for convenience. These are: fetal development and the maternal environment; infancy; childhood and adolescence; adulthood; and ageing and older people.

4.2.1 Fetal development and the maternal environment

The four relevant factors in fetal life are: 
(i) intrauterine growth retardation (IUGR); 
(ii) premature delivery of a normal growth for gestational age fetus; 
(iii) overnutrition in utero; and 
(iv) intergenerational factors. 

There is considerable evidence, mostly from developed countries, that IUGR is associated with an increased risk of coronary heart disease, stroke, diabetes and raised blood pressure. It may rather be the pattern of growth, i.e. restricted fetal growth followed by very rapid postnatal catch-up growth, that is important in the underlying disease pathways. On the other hand, large size at birth (macrosomia) is also associated with an increased risk of diabetes and cardiovascular disease. Among the adult population in India, an association was found between impaired glucose tolerance and high ponderal index (i.e. fatness) at birth. 

In Pima Indians, a U-shaped relationship to birth weight was found, whereas no such relationship was found amongst Mexican Americans. Higher birth weight has also been related to an increased risk of breast and other cancers.

In sum, the evidence suggests that optimal birth weight and length distribution should be considered, not only in terms of immediate morbidity and mortality but also in regard to long-term outcomes such as susceptibility to diet-related chronic disease later in life.

Diet, nutrition and chronic diseases in context:

Relative weight in adulthood and weight gain have been found to be associated with increased risk of cancer of the breast, colon, rectum, prostate and other sites. Whether there is an independent effect of childhood weight is difficult to determine, as childhood overweight is usually continued into adulthood. Relative weight in adolescence was significantly associated with colon cancer in one retrospective cohort study. 

Frankel, Gunnel & Peters , in the follow-up to an earlier survey by Boyd Orr in the late 1930s, found that for both sexes, after accounting for the confounding effects of social class, there was a significant positive relationship between childhood energy intake and adult cancer mortality. The recent review by the International Agency for Research on Cancer (IARC) in Lyon, France, concluded that there was clear evidence of a relationship between onset of obesity (both early and later) and cancer risk.

Short stature (including measures of childhood leg length), a reflection of socioeconomic deprivation in childhood, is associated with an increased risk of CHD and stroke, and to some extent diabetes. Given that short stature, and specifically short leg length, are particularly sensitive indicators of early socioeconomic deprivation, their association with later disease very likely reflects an association between early undernutrition and infectious disease load.

Height serves partly as an indicator of socioeconomic and nutritional status in childhood. As has been seen, poor fetal development and poor growth during childhood have been associated with increased cardiovascular disease risk in adulthood, as have indicators of unfavourable social circumstances in childhood. Conversely, a high calorie intake in childhood may be related to an increased risk of cancer in later life. Height is inversely associated with mortality among men and women from all causes, including coronary heart disease, stroke and respiratory disease.

Height has also been used as a proxy for usual childhood energy intake, which is particularly related to body mass and the child’s level of activity. However, it is clearly an imperfect proxy because when protein intake is adequate (energy appears to be important in this regard only in the first 3 months of life), genetics will define adult height. Protein, particularly animal protein, has been shown to have a selective effect in promoting height growth. It has been suggested that childhood obesity is related to excess protein intake and, of course, overweight or obese children tend to be in the upper percentiles for height. Height has been shown to be related to cancer mortality at several sites, including breast, uterus and colon . The risk of stroke is increased by accelerated growth in height during childhood. As accelerated growth has been linked to development of hypertension in adult life, this may be the mechanism (plus an association with low socioeconomic status).

There is a higher prevalence of raised blood pressure not only in adults of low socioeconomic status, but also in children from low socioeconomic backgrounds, although the latter is not always associated with higher blood pressure later in life. Blood pressure has been found to track from childhood to predict hypertension in adulthood, but with stronger tracking seen in older ages of childhood and in adolescence.

Higher blood pressure in childhood (in combination with other risk factors) causes target organ and anatomical changes that are associated with cardiovascular risk, including reduction in artery elasticity, increased ventricular size and mass, haemodynamic increase in cardiac output and peripheral resistance. High blood pressure in children is strongly associated with obesity, in particular central obesity, and clusters and tracks with an adverse serum lipid profile (especially LDL cholesterol) and glucose intolerance. There may be some ethnic differences, although these often seem to be explained by differences in body mass index. A retrospective mortality follow-up of a survey of family diet and health in the United Kingdom (1937-1939) identified significant associations between childhood energy intake and mortality from cancer.

The presence and tracking of high blood pressure in children and adolescents occurs against a background of unhealthy lifestyles, including excessive intakes of total and saturated fats, cholesterol and salt, inadequate intakes of potassium, and reduced physical activity, often accompanied by high levels of television viewing. In adolescents, habitual alcohol and tobacco use contributes to raised blood pressure.

There are three critical aspects of adolescence that have an impact on chronic diseases: 
(i) the development of risk factors during this period; 
(ii) the tracking of risk factors throughout life; and, in terms of prevention, 
(iii) the development of healthy or unhealthy habits that tend to stay throughout life, for example physical inactivity because of television viewing. 

In older children and adolescents, habitual alcohol and tobacco use contribute to raised blood pressure and the development of other risk factors in early life, most of which track into adulthood.

The clustering of risk factor variables occurs as early as childhood and adolescence, and is associated with atherosclerosis in young adulthood and thus risk of later cardiovascular disease. This clustering has been described as the metabolic - or “syndrome X” - clustering of physiological disturbances associated with insulin resistance, including hyperinsulinaemia, impaired glucose tolerance, hypertension, elevated plasma triglyceride and low HDL cholesterol . Raised serum cholesterol both in middle age and in early life are known to be associated with an increased risk of disease later on. The Johns Hopkins Precursor Study showed that serum cholesterol levels in adolescents and young white males were strongly related to subsequent risk of cardiovascular disease mortality and morbidity.

Although the risk of obesity does not apparently increase in adults who were overweight at 1 and 3 years old, the risk rises steadily thereafter, regardless of parental weight. Tracking has also been reported in China, where overweight children were 2.8 times as likely to become overweight adolescents; conversely, underweight children were 3.6 times as likely to remain underweight as adolescents. The study found that parental obesity and underweight, and the child’s initial body mass index, dietary fat intake and family income helped predict tracking and changes. However, in a prospective cohort study conducted in the United Kingdom, little tracking from childhood overweight to adulthood obesity was found when using a measure of fatness (percentage body fat for age) that was independent of build. The authors also found that only children obese at 13 years of age had an increased risk of obesity as adults, and that there was no excess adult health risk from childhood or adolescent overweight. Interestingly, they found that in the thinnest children, the more obese they became as adults, the greater was their subsequent risk of developing chronic diseases.

The real concern about these early manifestations of chronic disease, besides the fact that they are occurring earlier and earlier, is that once they have developed they tend to track in that individual throughout life. On the more positive side, there is evidence that they can be corrected. Overweight and obesity are, however, notoriously difficult to correct after becoming established, and there is an established risk of overweight during childhood persisting into adolescence and adulthood. Recent analyses  have shown that the later the weight gain in childhood and adolescence, the greater the persistence. More than 60% of overweight children have at least one additional risk factor for cardiovascular disease, such as raised blood pressure, hyperlipidaemia or hyperinsulinaemia, and more than 20% have two or more risk factors.