Polymorphism In The Human Genome

Even at birth the whole individual is destined to die, and perhaps his organic disposition may already contain the indication of what he is to die from.

—Sigmund Freud, The Dissolution of the Oedipus Complex (1924)

Most polymorphisms are expected to be neutral with respect to fitness. However, those polymorphisms that occur either within gene coding or promoter regions may affect either the structure/function of the gene product (2) or the expression of the gene (3) and may therefore have the potential to be of phenotypic or even of pathological significance. It should be noted that although most polymorphisms are of the single nucleotide (SNP) variety, there are some gene-associated polymorphisms in the human genome of other types, for example, triplet repeat copy number, gene deletion, gene duplication, intragenic duplication, microinsertion, inversion, gene fusion, and gene copy number (4).

The mechanisms by which polymorphisms are maintained in human populations are likely to be varied. The neutralist theory assumes no selection on the alleles of a polymorphic locus, and the frequency of an allele may therefore increase simply by genetic drift (the change of allele frequency due to random sampling). Such "transient polymorphisms" often remain at a low frequency in the population before being lost or may instead increase in frequency under the influence of either genetic drift or positive selection until one allele reaches fixation. Most known polymorphisms are probably of this type. However, if the alternative alleles are not neutral with respect to fitness, the DNA polymorphisms may be maintained by selection pressure, possibly overdominant selection (also known as "heterozygote advantage" or "balanced polymorphisms").

In practice, the relationship between a polymorphism and a disease susceptibility should usually be interpreted in terms of linkage disequilibrium. Linkage disequilibrium is said to be present when certain alleles at one locus occur with certain alleles of another locus on the same chromosome at frequencies greater than can be attributed to chance alone. For our purposes, it can be considered to be due to a mutation occurring in a gene a number of generations ago. This mutant gene has then increased in frequency within the population, affected individuals of succeeding generations inheriting not only the mutant gene but also the particular alleles of neighboring polymorphisms. Gradually, the relationship between the marker alleles and the mutant gene will decay due to recombination. As a consequence, marker/disease associations from different populations can be extremely difficult to interpret, although both polymorphic allele frequency and linkage phase can be established in any one population. Also either or both can differ dramatically between populations.

Association studies employing polymorphisms located within or in close proximity to potential candidate genes can be a powerful approach to the epidemiological analysis of complex disorders (5). However, the results of such studies are notoriously difficult to replicate (6). One of the problems we face both in interpreting and comparing the results of disease association studies is that these studies will often vary with respect to the polymorphism(s) used, the population examined, the exact definition of disease phe-notype employed, and the statistical methodology adopted. The possibility of confounding factors (e.g., population stratification, life style, nutritional status) is omnipresent, as is the use of poorly selected and inappropriate controls. Another caveat is reporting bias; there will be a tendency to only report significant associations whereas negative findings will either not be published or published only in more obscure lower-impact journals.

In some cardiovascular conditions, disease associations are evident in polymorphic haplotypes rather than with individual SNPs (7). Haplotypes are specific combinations of alleles of closely linked polymorphisms. Disease-haplotype associations are also explicable in terms of linkage disequilibrium and probably reflect the nonadditive effects of individual SNPs on gene function/expression. Interactions between polymorphic alleles at different loci are also possible. Studies that seek combinatorial effects of polymorphisms at multiple loci may however be at risk of failing to allow for multiple testing in their significance assessment. Indeed, some disease associations may be found only in a given age or ethnic group or in one sex but not the other. Such findings may simply allow one to conclude that if one looks hard enough for an association, one will find another sooner or later. It should therefore be no surprise that significant associations are sometimes found with alternative alleles in different studies focusing on different clinical phenotypes or on different ethnic groups. Also, unsurprising is the fact that "disconfirmation" of previously published positive findings is a common occurrence in this research area (5).

As discussed below, less common types of gene-associated polymorphisms relevant to cardiovascular medicine include an indel (combined micro-insertion/micro-deletion) polymorphism in the apolipoprotein E (APOE) gene (8), a gross insertion polymorphism involving an Alu sequence introduced into the angiotensin I-converting enzyme (ACE) gene (9), and a microinsertion/deletion polymorphism in the plasminogen activator inhibitor-1 (PAI1) gene (10). This PAI1 polymorphism is due to the insertion or deletion of a single G residue within the promoter sequence (10); the ins allele contains an inter-leukin 1-responsive element, which is absent in the del allele, suggesting that individuals homozygous for the del allele could exhibit an altered PAI1 response during the acute phase reaction (10).

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