Immunological Investigations, 38:198–202, 2009Copyright © Informa Healthcare USA, Inc.ISSN: 0882-0139 print / 1532-4311 onlineDOI: 10.1080/08820130902910526

LIMM0882-01391532-4311Immunological Investigations, Vol. 38, No. 3-4, April 2009: pp. 1–7Immunological InvestigationsGenetic Polymorphisms and Immune ResponsesGenetic Polymorphisms and Immune ResponsesE. De Nardin

Ernesto De Nardin, MS, PhD

Schools of Medicine and Dentistry, State University of New York, University at Buffalo,Buffalo, New York, USA

The etiologic basis for many diseases can be in part attributed to gene-geneand/or gene-environment interactions. Utilization of twins, adoption and familystudies have demonstrated various hereditary components in many commondiseases (Roncaglioni et al., 1992; Iacoviello et al., 1998, Maremberg et al.,1994). The genetic basis of a common disease is defined as “the presence of agenetically susceptible individual, an individual who may or may not developthe disease, depending on the interaction of the factors such as other genes,diet, activity, environmental exposures, or even some degree of random biologicalvariation such as occurs in the immune system and may be operative duringdevelopment” (King et al., 1992). “Genetic” diseases fall into several categories.

Congenital chromosomal disorders are caused by an abnormal dose of nor-mal genes due to a deficiency or excess of chromosomal material. The majorityof these abnormalities are sporadic; they may involve an extra chromosomedue to non-disjunction of meiosis during egg or sperm formation. The classicalexample is Down’s Syndrome, caused by an extra chromosome 21. Mendeliandisorders are caused by a mutation in a single gene (also called “single-genedisorders”); they can be autosomal dominant or autosomal recessive and theeffects depend on inheritance of a particular gene from a parent. In an autosomalrecessive disorder, two alleles of an abnormal gene are necessary for diseaseexpression. Non-Mendelian Disorders reflect situations in which the diseasecannot be explained by either a chromosomal abnormality or a major geneeffect. Typically these disorders are multifactorial, and are caused by a combi-nation of genetic factors as well as a host of environmental ones. With the adventof the human genome project and the sequencing of such genome, a greatincrease in interest has been generated on the effects of genetics and, particu-larly, gene polymorphisms on molecular mechanisms in health and disease.

Address correspondence to Ernesto De Nardin, Schools of Medicine and Dentistry,Department of Oral Biology, Department of Microbiology and Immunology, StateUniversity of New York, University at Buffalo, Buffalo, NY 14214; E-mail: denardin@buffalo.edu

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Genetic Polymorphisms and Immune Responses 199

A genetic map is based on the variations in the genetic constitution of apopulation. The coexistence of more than one variant is called genetic poly-morphism. In a population, a genetic polymorphism is present when variantforms of a gene at a given locus exist with a frequency of more than 1 to 2%.Single Nucleotide Polymorphisms (SNPs) are sites in the genome where theDNA sequence of many individuals differs by a single base. About 10 millionSNPs have been estimated in the human population, with an estimated twocommon missense variations per gene.

Polymorphisms in genes encoding for factors related to disease haveallowed direct association between genetic variations and the development ofdisease (Sing and Moll, 1989; Humphries, 1994). Recent advances in molecularbiology have made the search for genetic risk markers for complex diseases morefeasible. However, the ability to apply these SNPs to association studies is limitedby problems in validating a SNP’s identity, characterizing its occurrence in arelevant population, and understanding its function (Rebbeck et al., 2004).

Commonly used in these studies are population-based case-control studieswhich allow the comparison of the prevalence of a particular genetic markerbetween cases and controls, the markers usually being coding sequence varia-tions or polymorphisms in the DNA of a particular molecule. Although epide-miological studies have provided evidence that polymorphisms in “candidate”genes play a role in the risk of diseases, analysis is complicated by differencesin clinical phenotypes and by clinical population admixture. It is now clearthat many genes and many environmental factors contribute to the suscepti-bility to common multifactorial diseases. In addition, the situation is evenmore complex, since these diseases are determined by a network of interre-lated biological traits. Each of these traits is influenced by several genetic andenvironmental factors that interact in a hierarchical fashion.

Nevertheless, the analysis of association of certain genetic polymorphismswith disease has provided valuable information on the potential molecular andcellular mechanisms (and their aberrations) that may be involved in the suscep-tibility to the disease. In some studies and for some polymorphisms the biologi-cal tie to disease is a presumed alteration (quantity, structure, function) of themolecule the gene encodes for. On the other hand, some associations have notyet been connected to biological phenomena, but rather the polymorphisms havebeen simply described as occurring more frequently in a patient populationthan in a control group. In either case, intense interest in such polymorphismshas developed in the last decade with the search for novel diagnostic tools aswell as novel understanding of basic molecular mechanisms of disease.

In this thematic issue, the articles address the influence of genetic poly-morphisms on the immune response. The articles and their topics were chosenbased on recent interest of specific immune and inflammatory componentsand the effect of some of their polymorphisms. Although many components ofthe immune system have been studied, many reports have focused on various

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200 E. De Nardin

inflammatory components such as Interleukin-1 (IL-1) and Tumor NecrosisFactor (TNF). For example, studies have suggested a role of certain IL1- poly-morphisms in regulating both the cellular response to inflammation as well asthe risk of premature cardiovascular disease (either myocardial infarction orstroke). In addition, subjects with certain alleles showed lower release of IL1-bafter endotoxin stimulation (Iacoviello et al. 2005). Two papers in this issuecover this topic (Latella et al., 2009; Rezaii et al., 2009). An association of IL-1polymorphisms with Chaga’s disease is also presented (Cruz-Robles et al., 2009).Likewise, several different polymorphisms for tumor necrosis factor alpha (TNFa)have been under study as playing a potential role in disease susceptibility;some of these are described by Gupta et al., (2009) and by Dittmar et al. (2009).

The influence of HLA in immune responses has been accepted for decadesand many HLA alleles and their distribution have been associated with a varietyof different clinical conditions. In this issue García Borrás et al. (2009) dis-cusses the role of HLA-DRB1 alleles in Chaga’s disease cardiomyopathy whileZepeda-Gomez et al. (2009) discusses HLA-DR allele frequencies autoimmuneliver diseases. Finally, the role of a mutation in the CC chemokine receptor 5(CCR5) in viral immunity is presented by Ahlenstiel et al. (2009).

In complex diseases some results from different studies have been conflicting.The different results reported in the literature on the association of variousgenetic polymorphisms with a particular disease may be due to various factorssuch as the multifactorial nature of the disease, its diverse clinical forms aswell as factors such as ethnicity, race, gender and environmental factors, andmany reports of association may not be reproducible under different condi-tions. A great deal of interest exists on identifying potential genetic markersor risk factors in many different diseases, so it is important that these markersare well established and, more importantly, confirmed. Therefore, while somestudies reports negative results, i.e. the lack of an association between thesegene variants and disease, such results are also biologically significant.

One example of these studies is by Noack et al. (2009). Last, there may besituations in which while a particular genetic polymorphism is associatedwith a particular disease, that polymorphism may not be the functional one,i.e., the one causing a potential aberration, which may be a factor in the dis-ease itself. Rather, the association of that polymorphism with disease may bedue to its linkage disequilibrium with another polymorphism, which happensto be the truly functional one. An example of such a situation is described byMorozumi et al. Finally, we would like to thank Dr. DeMichele for a nicereview of the effects of genetic polymorphisms on the outcome of breast andovarian cancer (Kim, Hagemann, and De Michele, 2009).

Declaration of Interest: The author reports no conflicts of interest. The authoralone is responsible for the content and writing of the paper.

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Genetic Polymorphisms and Immune Responses 201

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