Genes, Environment, and Cardiovascular Disease

Abstract

Abstract-In this essay, we call to attention what every medical researcher knows about the etiology of cardiovascular disease but most deny, or choose to ignore, when designing, carrying out, and reporting genetic studies. Medical research is entering an era of synthesis that will take advantage of the successes of reductionism over the past decade in defining and describing human genome variations. Meaningful insights into the role of such variation requires a biological model of genome-phenotype relationships that incorporates interactions between subsets of possible genetic and environmental agents as causations in particular contexts indexed by time and space. We make recommendations for what needs to be done to cope with these complexities. The ProblemCommon chronic multifactorial diseases are responsible for the greatest demand on medical services. 1-3 They also make the largest contribution to loss of human life and productivity in westernized societies (eg, see Murray and Lopez 4 and the American Heart Association 5-7 ). Deviations from health attributable to these diseases, which include cardiovascular disease (CVD), cancer, diabetes, and the psychiatric disorders, typically aggregate in families but they do not segregate as Mendelian single-gene disorders. The distribution of disease among individuals, families, and populations is a direct consequence of the distribution of interactions between the effects of many susceptibility genes and many environmental exposures, that, through dynamic, epigenetic, regulatory mechanisms, ultimately become integrated to generate the disease phenotype. 8 -18 The genetic analysis of a multifactorial disease presents the most difficult research challenge facing human geneticists today. We consider CVD in this presentation to illustrate the issues encountered in using genetic information in research to understand the etiology of most common chronic diseases as well as in the identification and treatment of individuals who are at increased risk. We call to attention what every cardiovascular researcher knows about the etiology of CVD but most deny, or choose to ignore, when designing, carrying out, and reporting genetic studies of CVD. We close by suggesting steps that should be taken to cope with this inconsistency. Disease SusceptibilityAll cases of CVD have a complex multifactorial etiology. Neither genetic nor environmental agents acting independently cause disease. Full knowledge about an individual's genetic makeup or exposures to adverse environments cannot predict with certainty the onset, progression, or severity of disease. Disease develops as a consequence of interactions between the "initial" conditions, coded in the genotype, and exposures to environmental agents indexed by time and space 19 -21 that are integrated by dynamic, regulatory networks at levels above the genome. 22 The interaction of an individual's environmental experiences with her/his genotype determines the history of her/his multidimensional phenotype, beginning at conception and continui...

Evidence for Non‐additive Influence of Single Nucleotide Polymorphisms within the Apolipoprotein E Gene

“…On the other hand, pairs of SNPs 1998-4951 and 3937-4951 may be measuring the same non-additive effects, because the r 2 value for the 1998-3937 pair is 0.704. Sing et al (1996Sing et al ( , 2003 and Wright et al (2003) have suggested that the genetic architecture of a complex trait consists of many genes with common alleles (relative allele frequencies greater than 0.01) that have a small effect on a particular phenotype, and a few genes with rare alleles that will have relatively larger effects. An alternative hypothesis assumes that genetic architecture of a complex trait is defined by a few genes with common alleles that have large phenotypic effects (Lander, 1996).…”

“…A major impediment in studying the contribution of genetic variation to interindividual variation in quantitative levels of apolipoproteins, and other risk factors for developing coronary heart disease, is that the available statistical models are not realistic representations of the biological complexity of genotype-phenotype relationships (Page et al 2003;Sing et al 2003). Phe-nomena such as allelic and genotypic heterogeneity, pleiotropy, gene by environment interaction and gene by gene interaction (epistasis) are realities that cannot easily be modelled, or estimated and tested, using population based samples of human data (Clark, 2000).…”

Association of the lymphotoxin-α gene Thr26Asn polymorphism with severity of coronary atherosclerosis

“…In the majority of cases, the disease is a result of the combined effect of multiple genetic and environmental factors, where each of the genetic factors makes a moderate contribution. [2][3][4][5] Recently, a large-scale, genome-wide association study of 65 671 gene-based single nucleotide polymorphisms in relation to myocardial infarction, a severe condition of CAD, was performed in a large group of Japanese cases (n ¼ 1133) and two control groups (n ¼ 1006 and 872, respectively). The study showed a strong association between susceptibility to myocardial infarction and polymorphisms in a 50 kb genomic region on chromosome 6p21 that contains the lymphotoxin-a (LTA) gene.…”

Nutrient selection through nutrigenomic approaches

“…143), in utero effects, diet-gene interactions, and the "environmental history"; that is, the life-long exposure to changing diets may alter expression of genetic information later in life (136). Maternal nutrition during pregnancy also has been linked to altered phenotypes in laboratory and farm animals (e.g., 27,30,69,164), and such epigenetic phenomena will likely affect gene-disease association studies.…”

“…Maternal exposure to different nutrients and an organism's exposure during its lifetime to changing diets is likely to also produce different health outcomes because the exposure to food and xenobiotics may act upon the genome to alter gene expression. An excellent discussion of the complexity of genotype ϫ environmental history is presented by Sing and colleagues (136).…”