Inflammation, genetics, and ischemic heart disease: focus on the major histocompatibility complex (MHC) genes.
BACKGROUND
Increasing data suggest that ischemic heart disease (IHD) shares several characteristics with common inflammatory diseases (such as rheumatoid arthritis), in which the pathogenetic role of inflammatory gene polymorphisms is well established. Variants in the genes for the major histocompatibility complex (MHC) molecules on the short arm of chromosome 6 show profound "linkage disequilibrium", leading to the formation of "haplotypes", i.e., frozen blocks of alleles travelling together through generations.


METHODS
We performed a review of published studies linking IHD with gene polymorphisms of the MHC molecules tumor necrosis factor (TNF)-alpha and -beta, the class II DR human leukocyte antigens, heat shock protein 70-1, hemochromatosis related gene, and complement C4.


RESULTS
The emerging data are quite conflicting and do not provide definitive evidence for a role of these gene variants in the pathogenesis of IHD; a possible exception is the G252A and polymorphism in the TNF-beta gene (also known as lymphotoxin-alpha) which, in a comprehensive genome-scan linkage analysis of unrelated Japanese, but not in a smaller German population, was linked to myocardial infarction. However, some important biases appear, e.g. different study design and variable linkage disequilibrium among different populations.


CONCLUSIONS
Preliminary positive results should encourage future studies to focus on clinical models of IHD with well-codified inflammatory components, using novel methods (such as haplotype analysis) to assess gene polymorphisms and their clinical effect.
Porto
Italo
I
Catholic University Medical School, Department of Cardiovascular Medicine, Rome, Italy. i.porto@eudoramail.com
Leone
Antonio Maria
AM
Crea
Filippo
F
Andreotti
Felicita
F
D000483:Alleles; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D003181:Complement C4 / Q000235:genetics / Q000276:immunology; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008285:Major Histocompatibility Complex / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics; D017202:Myocardial Ischemia / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D011110:Polymorphism, Genetic / Q000235:genetics; D048069:Tumor Necrosis Factors / Q000235:genetics
D003181:Complement C4; C103673:HFE protein, human; D018840:HSP70 Heat-Shock Proteins; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D008565:Membrane Proteins; D048069:Tumor Necrosis Factors