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Guilt by association?

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Gene polymorphisms of inflammatory molecules in ischaemic heart disease (IHD) tell a complex story, as a review in Heart testifies. Andreotti et al summarise the findings of population association studies—showing whether the frequency of one allele differs between patients and controls—for case-control studies of 100 subjects or more over almost the past 10 years. They separated, when possible, studies of atherosclerosis or generic IHD from acute coronary syndromes.

Currently, carrying the P selectin Pro allele at position 715 seems to protect against myocardial infarction and having transforming growth factor (TGF) β1 and CD14 variants may increase the risk. In atherosclerosis the interleukin 1 receptor antagonist (IL 1ra) intron 2 variable number of tandem repeat alleles may affect disease extent; some polymorphisms of E selectin and platelet endothelial cell adhesion molecule (PECAM 1) may increase risk.

To the sheer complexity of the interactions of the molecules within the inflammatory process must be added that of interpreting the results. Even if the frequency of an allele apparently differs between patients and controls in a multifactorial disease like IHD, linkage disequilibrium or population stratification are plausible alternatives to a true relation. A single polymorphism affecting a protein directly involved in the inflammatory process is, by itself, unlikely to account for the whole heritable variance. Then there are obscuring effects by coexistent dominant classic risk factors and—not least—publication bias in favour of positive results.

So the stage is set for further work—with DNA chips capable of assessing multiple gene variants simultaneously—and to clarify the influence of single polymorphisms.

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