Cytokine Genes I IL10, IL6, IL4, and the IL1 Family

Abstract

Abstract There is growing recognition that cytokine production is under tight genetic control and that variations in cytokine genes play a direct role in regulating cytokine production, disease pathogenesis, and host resistance to infectious diseases, particularly those due to intracellular pathogens. This hypothesis has led to epidemiological and functional studies of variant alleles at different polymorphic sites in many human populations. Promoter polymorphism studies, especially of single nucleotide polymorphisms (SNPs), have been conducted in association studies (mostly case–control) in many diseases, including autoimmune=inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, and asthma, and infectious diseases such as malaria, hepatitis B (HBV), hepatitis C (HCV), HIV infection, tuberculosis (TB), leprosy, and sepsis=septic shock. Polymorphisms in TNF, IL12, and IFNG genes are reviewed in other chapters. Here we focus on IL10, IL6, IL4, and the IL1 gene cluster, including available evidence on the functional role of some promoter polymorphisms. Case–control studies have produced variable results, with little consensus on whether any polymorphisms are actually associated with disease, although results have been more consistent in the case of certain infectious diseases. Functional studies have also sometimes produced discrepant results. More recently, instead of focusing on single promoter polymorphisms in isolation, investigators have appropriately begun to examine extended haplotypes, which can better capture the true genetic functional variation. This has led to notable success in the identification of new functional loci and set a new standard, replacing smaller case–control studies using single markers with integrative large-scale studies focusing on haplotype analyses.