Diseases come in various types and subtypes and they all possess diverse underlying mechanisms. A common factor in all of them is the influence of the genetic background that is unique to every individual. The presence of susceptibility genes and modifier genes in our genome provides insights into the way our bodies respond to disease-causing factors and the complicated gene-gene interactions that take place resulting in varying outcomes. This review discusses the dynamics and complexities of susceptibility genes and modifier genes with the goal of comparing and determining their importance in disease occurrence and expression, using examples of colorectal cancer and breast cancer. It is seen that a broader view that includes both groups of these genes is essential for tackling diseases. Early and accurate detection is a key factor in improving outcomes while treating diseases. By furthering studies on susceptibility genes and modifier genes, personalized risk assessment and prognostic precision could be achieved.
Introduction
The etiology and pathogenesis of a disease are important aspects that drive the direction of diagnosis and therapy targeted at the disease. It is even more important to study what steer these aspects, which is why it is crucial to study susceptibility genes and modifier genes. Genetic disorders can be inherited or sporadic. Every genetic disease is affected by a multitude of factors other than the mutations in the disease-causing gene itself, such as epigenetics, environment, modifier genes, etc. This, in a way, has led to monogenic disorders take a shift towards sharing the term ‘multifactorial disorders’ presenting complex traits which are commonly limited to diseases like cancers and diabetes (Dipple & McCabe, 2000). It is important to note that this is exclusively in the sense that it is not just one gene, but multiple other modifying factors contributing to the clinical presentation of the disease and not the absolute cause.
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Due to the genetic heterogeneity of the human body, there is a genetic component playing an indirect role in some element of every disease. It also causes phenotypic variations by influencing disease expression in the affected individuals (Dipple & McCabe, 2000; Fanous & Kendler, 2005). Thus, this review will talk about the genes affecting this process where they influence the occurrence and expression of diseases. This could be due to the numerous ways in which complex pathways are linked in the body. Genes that increase the likelihood of developing a disease and make an individual susceptible to that disease are called susceptibility genes. Their presence is not essential for developing a disease, unlike disease-causing genes. Genes that target other genes and affect different aspects of a disease and cause a modification in disease expression are called modifier genes. They can affect disease-causing genes, susceptibility genes, or any other gene involved in the disease mechanism.
In this review, first, I will be going through the basic properties of modifier genes and susceptibility genes, along with their properties and complexities. Then I will talk about the identification strategies used to detect them. Finally, I attempt to explore the dynamics of both susceptibility genes and modifier genes in the same disease, taking examples of colorectal cancer and breast cancer. Overall, the focus of this review is to compare the roles of susceptibility genes and modifier genes in the development and progress of a disease to further aid in creating improved strategies for diagnosis and treatment by being able to form more accurate predictions regarding the chances of developing a disease, its course, and severity upon using genetic screening and testing methods.
Modifier genes
Modifier genes are those genes that ‘modify’ other target genes. These modifier genes, as well as their target genes, can originate from mutations that are spontaneous or induced, or from natural allelic variants (Riordan & Nadeau, 2017). In the context of genetic diseases, this ‘modification’ could be in terms of severity, onset, and subset of disease. They are responsible for the presence of varying clinical heterogeneity in a disease. They provide answers to why different phenotypes arise due to different genetic backgrounds, even in monogenic disorders following simple Mendelian genetics, where the same mutation is causing the same disease but with a difference in certain features or ‘modifications’.
Their effects can be “subtle or profound”, for e.g., subtle enough to cause just a slight change in the onset of the disease, or profound enough to change the penetrance to an extent that the individual with the causal gene may not even develop the disease (Riordan & Nadeau, 2017). To be certain that the effects observed are solely due to modifier genes, the effects need to be observed on different genetic backgrounds in similar environments while considering the same genotype (Nadeau, 2001). Modifier genes have effects on different phenotypic aspects such as penetrance, expressivity, dominance, and pleiotropy (Figure 1).
Penetrance. Penetrance refers to the number of individuals affected out of all the individuals carrying the disease-causing allelic variant. Modifications in penetrance cause an increase or decrease in the penetrance of the target gene, causing the development of disease in some individuals carrying the same mutant gene while preventing it in some. For example, in sickle cell anemia which is caused by a mutation in the -globin (HBB) gene, various sub-phenotypes are observed, which are partly caused by different allelic variants and partly by modifier genes (Steinberg and Sebastiani, 2012 as cited in Riordan & Nadeau, 2017).
Expressivity. Expressivity refers to the severity of traits in the phenotype of affected individuals. Modifier genes can cause an increase or decrease in the severity, to the extent that affected and unaffected individuals seem indistinguishable. For e.g., in hypertrophic cardiomyopathy (HCM), an autosomal dominant disease, variations in the phenotypic expression of hypertrophy signified by the magnitude of left ventricular mass index have been observed in affected family members carrying the same mutation in the myosin-binding protein C (MyBPC) gene, which could be explained by the effect of modifier genes (Marian, 2002).
Dominance. Dominance refers to the dosage of the target gene required for the phenotypic traits to be expressed. Dominance modifications can cause the same trait to be inherited in a dominant, semi-dominant or recessive manner depending on the genetic background. For e.g., in individuals with hereditary hemochromatosis, homozygotes of the mutant allele develop more severe symptoms in comparison to heterozygotes (Broderick et al., 2007 as cited in Talseth-Palmer, Wijnen, Grice, & Scott, 2013; Merryweather-Clarke et al., 2003 as cited in Riordan & Nadeau, 2017).
Pleiotropy. Pleiotropy refers to the range of phenotypes that arise only due to the presence and effect of modifier genes on the target gene, including novel phenotypes, in affected individuals. For e.g., in Bardet-Biedl syndrome (BBS) or Meckel-Gruber syndrome (MKS), seizures are not usually seen, but in individuals having mutations in both the genes MK1 (Meckel syndrome type 1) and BBS1, BBS9 or BBS10, seizures are seen to occur, which could be considered as a novel phenotype (Leitch et al., 2008 as cited in Riordan & Nadeau, 2017).
Susceptibility genes
Genes that are known to cause a predisposition to a specific disease in individuals are called susceptibility genes. They can be both hereditary and sporadic. They are not necessary for the development of the disease, but they are considered to confer increased susceptibility towards the disease. Also, their presence does not indicate any guarantee of developing the disease and the chances could vary tremendously. In studies related to schizophrenia, it has been suggested that susceptibility alleles could confer risk based on the genetic and environmental background in varying amounts like Quantitative trait loci (QTL) (Fanous & Kendler, 2005).
Susceptibility genes remain surrounded by complexities when it comes to their properties and mechanisms. They may or may not contribute to disease pathogenesis (Miller & Kwok, 2001, as cited in McCarthy, Smedley, & Hide, 2003). In monogenic disorders like cystic fibrosis, the disease-causing gene is known. However, in multigenic diseases, like cancer, a single gene is not responsible for the disease and hence, even susceptibility genes could impart a greater contribution towards pathogenesis in those cases. For e.g., Rb gene is a susceptibility gene for various cancers, but being a tumor suppressor gene, it also has a role in disease pathogenesis.
Identification methods
Modifier genes and susceptibility genes have been studied using common methods, which consist of associating genetic variations to different phenotypes to determine the genotype-phenotype relations. Initially, they were studied through linkage analysis in families having many affected individuals. Although they were successful for Mendelian traits, they were useful only for high-penetrance genes and detecting common variants having smaller effects was difficult (Aloraifi, Boland, Green, & Geraghty, 2015).
The candidate gene approach came into use, where variants from candidate genes that were selected based on biologically related functions with the disease were tested. This approach required prior knowledge of the processes involving the candidate genes in the specific disease. Then, the genetic variants and haplotypes in correlation with the particular phenotype would be analyzed (Marian, 2002).
With advancements in sequencing technology, genome-wide associations studies (GWAS) are the more commonly used approach these days. This approach does not require any prior knowledge regarding the biology of the disease and allows for the detection of genetic variants associated with a particular trait across the entire genome (Marian, 2002). This method allows the detection of more common variants having smaller effects, which are considered to be behind the cause of complex multifactorial diseases, along with environmental factors. GWAS can be performed using different technologies such as single-nucleotide polymorphism (SNP) arrays or whole-genome sequencing (WES) (Aloraifi et al., 2015; Tam et al., 2019).
Susceptibility genes and Modifier genes in Colorectal cancer and Breast cancer as examples
There are many types of colorectal cancers (CRCs), one of the most common ones being hereditary non-polyposis cancer (HNPCC) (Ma et al., 2018; Stoffel et al., 2015 as cited in Liu & Tan, 2019). Lynch syndrome is an autosomal dominant genetic disorder which is caused by germline mutations in genes involved in DNA mismatch repair (MMR). In some studies, Lynch syndrome and HNPCC have been used synonymously, but HNPCC can be of two types – one that consists of mutations in the DNA MMR genes and microsatellite instability (MSI), as a result of Lynch syndrome (Boland et al., 2008 as cited in Carethers & Stoffel, 2015), and one where the DNA MMR genes are unaffected (Carethers & Stoffel, 2015). Here, we will consider the case of HNPCC with underlying Lynch syndrome.
Around 40 susceptibility genes linked to hereditary CRCs have been found (Stoffel et al., 2015; Chubb et al., 2015 as cited in Liu & Tan, 2019), and the major ones associated with HNPCC are MLH1, MSH2, MSH6, and PMS2 which are part of the DNA MMR system (Peltomaki & Vansen, 2004 as cited in Liu & Tan, 2019). The risk for developing CRC in HNPCC patients having MLH1 and MSH2 mutations was found to be 22-74% and those having MSH6 or PMS2 mutations was 10-22% and 15-20% respectively (Engel et al., 2014 as cited in Liu & Tan, 2019). The epithelial cell adhesion molecule (EPCAM) gene is also considered a susceptibility gene for HNPCC as germline deletions in this gene have been seen to cause MSH2 silencing via hypermethylation of its promoter (Boesch et al., 2018 as cited in Liu & Tan, 2019). Other gene mutations seen to be involved in CRC susceptibility include BUB1, MUTYH, SMAD4 (DeRycke et al., 2017 as cited in Liu & Tan, 2019). The recently detected mutations in these genes of HNPCC are listed in Table 1.Differences in disease expression have led to the search for modifier genes, however, only a few studies have shown convincing results due to problems of sample size and replicability. Most searches were conducted based on the candidate gene approach and selected genes involved in xenobiotic clearance, cell cycle control, DNA repair, immunological function, and growth factors (Talseth-Palmer et al., 2013).
One interesting finding has been regarding a polymorphism in the gene for enzyme Telomerase reverse transcriptase (hTERT) being associated with an earlier onset of cancer and/or development of polyps in epithelial cancers and this effect being absent in older patients above 45, suggests a modifier effect that diminishes as telomeres shorten with age. (Djojosubroto et al., 2003 as cited in Talseth-Palmer et al., 2013). Another gene considered as a potential modifier gene is of the growth factor IGF-1. This has been suggested by the correlation between the presence of a CA-repeat polymorphism near the IGF-1 promoter and the age of onset of CRC in patients with Lynch syndrome (Zecevic et al., 2006 as cited in Talseth-Palmer et al., 2013). The methylenetetrahydrofolate reductase (MTHFR) gene related to haemochromatosis (HFE), the hereditary iron overload disorder, has also been identified as a modifier gene for CRC risk. In Lynch syndrome patients, MTHFR variants were seen to affect disease expression as it was observed that compound heterozygotes of two functional polymorphisms (C677T and A1298C) experienced a delay in the age of disease onset hereditary hemochromatosis patients with a polymorphism in HFE, specifically homozygous for one that causes a substitution of a tyrosine for a cysteine residue at position 282 (C282Y). They had a chance of developing CRC 3 times higher compared to controls (Broderick et al., 2007 as cited in Talseth-Palmer et al., 2013).
GWAS has resulted in the identification of numerous loci associated with CRC risk and some SNPs have been studied for risk modifier effects, such as rs16892766 on chromosome 8q23.3 and rs3802842 on chromosome 11q23.1 (Wijnen, 2009 et al., 2009 as cited in Talseth-Palmer et al., 2013), but further studies on their functional effects are required.
Breast cancer (BC) is the most common cancer affecting women. In the case of hereditary breast cancers, BRCA1 and BRCA2 genes have been widely studied and identified as susceptibility genes with a high penetrance. Mutations in these genes are inherited in an autosomal dominant manner and are associated with causing a 60-85% chance of developing BC (Ripperger, Gadzicki, Meindl, & Schlegelberger, 2009). Loss of expression of BRCA1 and BRCA2 are observed in 30-40% of sporadic breast cancers as well (Paul & Paul, 2014).
BC has come to be considered as a polygenic disease, where multiple genes collectively contribute to increased susceptibility and development of the disease. Many susceptibility genes conferring moderate risk as well as low risk have been identified (Wendt & Margolin, 2019). Table 2 shows some of these identified genes.
Increased risks of BC were also observed in cases of Lynch syndrome. This could be due to the dysfunction caused in the DNA repair system common in both (Vasen et al., 2001 as cited in Ripperger et al., 2009). Most genes involved in breast cancers are involved in maintaining genetic stability through DNA repair and tumor suppression. Hence, mutations would cause a malfunction in these processes which would, in turn, lead to oncogenesis.
Variations in the penetrance estimates for carriers of BC-associated mutations have been observed, causing a need to search for BC modifiers (Milne & Antoniou, 2016). Although environmental influence and low sample size make it difficult to study modifier genes in humans, studies have found a few low-penetrance BC polymorphisms to act as modifier genes in carriers of BRCA1/2 mutations. Some examples include the SNPs 135G>C in RAD51, rs2981582 in FGFR2 and rs889312 in MAP3K1 carriers of BRCA2 mutations, rs3803662 in TOX3 in carriers of mutations in both BRCA1 and BRCA2 (Kadouri et al., 2004; Antoniou et al., 2007 as cited in Ripperger et al., 2009).
An analysis
Susceptibility genes provide a way to estimate the chances of developing a disease, but modifier genes can even affect susceptibility genes. They also have varying effects on different aspects of the disease, that change the overall perception of the disease. This is why both need to be considered for the prediction of diagnosis and prognosis.
They can be used utilized in several ways. A model to help determine the risk for colorectal cancer has been developed using 27 common CRC susceptibility loci identified using GWAS (Hsu et al., 2015). A therapeutic approach has been proposed for sickle cell anemia based on targeting genes that repress a modifier gene of the severity of the disease, fetal hemoglobin (HbF), as HbF is also used in the treatment of adult patients (Lanzkron et al., 2008 as cited in Riordan & Nadeau, 2017).
Interestingly, susceptibility genes can act as modifier genes and modifier genes can also confer susceptibility in some cases. In monogenic cardiac arrhythmia, some modifier genes are themselves seen to confer susceptibility as well. (Schwartz et al., 2013 as cited in (Schwartz, Crotti, & George, 2018). This goes to show that instead of simply classifying genes into distinct categories, we need to take into consideration the existence of heterogeneous gene action. Studies also suggest the existence of ‘pseudo-modifier’ which are genes that influence the susceptibility of a particular subtype of a disease. They act as modifiers by modifying the symptoms of the disease to give rise to its subtype (Bergen, Maher, Fanous, & Kendler, 2010).
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