Immune-related gene polymorphisms in pulmonary diseases

Abstract

Between the DNA sequences of two randomly-selected human genomes, which consist of over 3 billion base pairs and twenty five thousand genes, there exists only 0.1% variation and 99.9% sequence identity. During the last couple of decades, extensive genome-wide studies have investigated the association between single-nucleotide polymorphisms (SNPs), the most common DNA variations, and susceptibility to various diseases. Because the immune system's primary function is to defend against myriad infectious agents and diseases, the large number of people who escape serious infectious diseases underscores the tremendous success of this system at this task. In fact, out of the third of the global human population infected with Mycobacterium tuberculosis during their lifetime, only a few people develop active disease, and a heavy chain smoker may inexplicably escape all symptoms of chronic obstructive pulmonary disease (COPD), lung cancer, and other smoke-associated lung diseases. This may be attributable to the genetic makeup of the individual(s), including their SNPs, which provide some resistance to the disease. Pattern recognition receptors (PRRs), transcription factors, cytokines and chemokines all play critical roles in orchestrating immune responses and their expression/activation is directly linked to human disease tolerance. Moreover, genetic variations present in the immune-response genes of various ethnicities may explain the huge differences in individual outcomes to various diseases and following exposure to infectious agents. The current review focuses on recent advances in our understanding of pulmonary diseases and the relationship of genetic variations in immune response genes to these conditions.

Keywords: Chemokines; Cytokines; NLRs; TLRs; Transcription factors.

Figure 1. Schematic diagram representing a general mechanism of SNP mediated regulation of gene function

The expression of a gene is tightly regulated from the promoter region. Sequence of promoter regionrecognized by transcription factor, enhancer or suppressor molecules for optimalactivation. Any variation in the promoter region sequence may lead to defective binding of transcription factor/enhancer/suppressor which may lead to no-, hypo-, or hyper- transcription. A. Normal (wild type) regulatory region of the gene and their transcription factor/suppressor and enhancers. B. SNP in the promoter region. C. Mutated transcription factor/enhancer/suppressor. Mutation in the Exon region may also lead to mutated protein. D. Normal PAMP receptors. E. Mutated receptor with less binding affinity for PAMPs. F. Mutated receptor with no binding ability for PAMPs. Figure also demonstrates the regulation of immune responses which involve recognition of cytokines and chemokines by their receptors. Any change in this interaction may lead to reduced or hyper immune response as demonstrate in: G. WT-Receptor/WT-Cytokines & Chemokines. H. WT-Receptor/Mutated Cytokines & Chemokines and I. Mutated receptor/normal cytokines & Chemokines.