Concordance Rate In Monozygotic Twins Research Articles

Cardiovascular Manifestations of Systemic Lupus Erythematosus: An Overview

Systemic Lupus Erythematosus(SLE) is a multisystem autoimmune disease with variable presentations. A proposed mechanism for the etiology of SLE involves the development of autoantibodies that result from a defect in apoptosis. The specific defect involves the “find-me” (adenosine triphosphate [ATP]/uridine triphosphate [UTP]) or “eat-me” (phosphatidylserine) signals activated upon release of red cell nuclei. In the absence of apoptosis, the nuclei break down, causing inflammation and contributing to the development of autoimmunity. Many signs and symptoms of SLE are caused by either circulating immune complexes or direct effects of antibodies on cells. A genetic predisposition for SLE exists, and the concordance rate in monozygotic twins is between 25% and 70%. If a mother has SLE, her daughter’s risk of developing the disease is 1:40, and her son’s risk is 1:250. The course of SLE consists of intermittent remissions punctuated by disease flares, and organ damage often progresses over time. Pericarditis is the most frequent cardiac manifestation; it can be documented by ECG, auscultation of a friction rub, or evidence of pericardial effusion. It usually responds to anti-inflammatory therapy and infrequently leads to tamponade. More serious cardiac manifestations are myocarditis and fibrinous endocarditis of Libman-Sacks. The endocardial involvement can lead to valvular insufficiencies, most commonly of the mitral or aortic valves, or embolic events. It has not been proven that glucocorticoid or other immunosuppressive therapies improve lupus myocarditis or endocarditis. Still, it is usual practice to administer a trial of high-dose steroids and appropriate supportive treatment for heart failure, arrhythmia, or embolic events. As discussed above, patients with SLE are at increased risk for myocardial infarction, usually due to accelerated atherosclerosis, which probably results from immune attack, chronic inflammation, and chronic oxidative damage to arteries.

The IL-17/IL-23 Axis and Its Genetic Contribution to Psoriatic Arthritis

Psoriatic arthritis (PsA) is a chronic inflammatory disease belonging to the family of spondyloarthropathies (SpA). PsA commonly aggravates psoriasis of the skin and frequently manifests as an oligoarthritis with axial skeletal involvement and extraarticular manifestations including dactylitis, enthesitis, and uveitis. The weight of genetic predisposition to psoriasis and PsA is illustrated by the concordance rates in monozygotic twins which clearly demonstrate that genomics is insufficient to induce the clinical phenotype. The association of PsA with several single nucleotide polymorphisms (SNPs) at the IL23R locus and the involvement of Th17 cells in the immunopathogenesis of PsA clearly put the IL-23/IL-17 axis in the spotlight. The IL-23 and IL-17 cytokines have a pivotal role in the chronic inflammation of the synovium in PsA and are also prominent in the skin lesions of those with PsA. In this review, we focus on the genetic association of the IL-23/IL-17 axis with PsA and the contribution of these master cytokines in the pathophysiology of the disease, highlighting the main cell types incriminated in PsA and their specific role in the peripheral blood, lesional skin and joints of patients. We then provide an overview of the approved biologic drugs targeting the IL-23/IL-17 axis and discuss the advantages of genetic stratification to enhance personalized therapies in PsA.

DNA methylation signatures of monozygotic twins clinically discordant for multiple sclerosis

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system with a modest concordance rate in monozygotic twins, which strongly argues for involvement of epigenetic factors. We observe highly similar peripheral blood mononuclear cell-based methylomes in 45 MS-discordant monozygotic twins. Nevertheless, we identify seven MS-associated differentially methylated positions (DMPs) of which we validate two, including a region in the TMEM232 promoter and ZBTB16 enhancer. In CD4 + T cells we find an MS-associated differentially methylated region in FIRRE. Additionally, 45 regions show large methylation differences in individual pairs, but they do not clearly associate with MS. Furthermore, we present epigenetic biomarkers for current interferon-beta treatment, and extensive validation shows that the ZBTB16 DMP is a signature for prior glucocorticoid treatment. Taken together, this study represents an important reference for epigenomic MS studies, identifies new candidate epigenetic markers, and highlights treatment effects and genetic background as major confounders.

Discordance in monozygotic Parkinson's disease twins - continuum or dichotomy?

Differences in concordance rates between monozygotic and dizygotic twin pairs with Parkinson's disease (PD) have been used to estimate genetic influences in PD pathogenesis. We hypothesized that “discordance” may not in all cases adequately reflect the multifaceted disease manifestation of PD that involves a continuum from prodromal to definite PD. Deep clinical phenotyping, combining motor, nonmotor, and imaging modalities in five monozygotic, seemingly discordant twin pairs revealed motor and/or nonmotor features and/or nigral hyperechogenicity in all of the five putatively unaffected twins. In conclusion, our data suggest that concordance rates in monozygotic twins may be higher than previously appreciated.

Evaluation of the ISL1 gene in the pathogenesis of bladder exstrophy in a Swedish cohort

Bladder exstrophy is a congenital closure defect of the urinary bladder with a profound effect on morbidity. Although the malformation is usually sporadic, a genetic background is supported by an increased recurrence risk in relatives, higher concordance rates in monozygotic twins and several associated chromosomal aberrations. Recently, the ISL1 gene was presented as a candidate gene for bladder exstrophy and epispadias complex (BEEC) development in two different studies. In our study, we screened for genetic variants in the ISL1 gene in DNA from 125 Swedish patients using Sanger sequencing and array-CGH analysis. In addition, we evaluated ISL1 expression in RNA of human bladder during embryonic and fetal weeks 5–10 relative to that in lung tissue (week 9). In total, 21 single-nucleotide variants were identified, including a potentially novel missense variant, c.137C>G p.(Ala46Gly), substituting a conserved amino acid. This variant was inherited from an unaffected mother. No structural variants were identified. RNA sequencing revealed ISL1 mRNA expression during the critical time frame of human bladder development. In conclusion, we did not detect any known or likely pathogenic variants in the ISL1 gene in 125 Swedish BEEC patients, indicating that variation in the ISL1 gene is not a common genetic mechanism of BEEC development in the Swedish population.

Genetics of Tinnitus: Still in its Infancy.

Tinnitus is the perception of a phantom sound that affects between 10 and 15% of the general population. Despite this considerable prevalence, treatments for tinnitus are presently lacking. Tinnitus exhibits a diverse array of recognized risk factors and extreme clinical heterogeneity. Furthermore, it can involve an unknown number of auditory and non-auditory networks and molecular pathways. This complex combination has hampered advancements in the field. The identification of specific genetic factors has been at the forefront of several research investigations in the past decade. Nine studies have examined genes in a case-control association approach. Recently, a genome-wide association study has highlighted several potentially significant pathways that are implicated in tinnitus. Two twin studies have calculated a moderate heritability for tinnitus and disclosed a greater concordance rate in monozygotic twins compared to dizygotic twins. Despite the more recent data alluding to genetic factors in tinnitus, a strong association with any specific genetic locus is lacking and a genetic study with sufficient statistical power has yet to be designed. Future research endeavors must overcome the many inherent limitations in previous study designs. This review summarizes the previously embarked upon tinnitus genetic investigations and summarizes the hurdles that have been encountered. The identification of candidate genes responsible for tinnitus may afford gene based diagnostic approaches, effective therapy development, and personalized therapeutic intervention.

Editor's Choice – High Heritability of Liability to Abdominal Aortic Aneurysms: A Population Based Twin Study

First degree relatives of patients with abdominal aortic aneurysm (AAA) have an increased risk of developing AAA; however, despite intensive investigation, the specific genetic factors involved in the development of the disease are still largely unknown. In twin studies the influence of genetic and environmental factors can be assessed by comparing concordance rates between monozygotic (MZ) and dizygotic (DZ) twins. Higher phenotypic similarity between MZ than DZ twins indicates a genetic attribution to the etiology. The objective of this study was to investigate the heritability of AAA among Danish twins using concordance rates and heritability estimates. The Danish Twin Registry was used to identify all Danish twin pairs (born 1880-1971) where both twins were alive on January 1, 1977. AAA cases were then identified using the National Patient Registry and the Registry of Cause of Death. Probandwise concordance rates were calculated and heritability estimated using structural equation modeling. The study identified 414 twins with AAA; 69.8% (289/414) were men and 30.2% (125/414) women. The probandwise concordance rate in MZ twins was 30% (95% CI 20.3-43.3%) compared with 12% (95% CI 7.0-20.1%) in DZ twins. In the heritability analysis 77% (95% CI 67-85%) of the total variance was explained by additive genetic components and 23% (95% CI 15-33%) was explained by non-shared environmental factors. The probandwise concordance rate was found to be 2.5 times higher in MZ compared with DZ twins. An overall heritability of 77% was determined.

Female Monozygotic Twins with Anorexia Nervosa

Anorexia nervosa (AN) is a serious eating disorder with higher morbidity and mortality rates. Higher concordance rates for monozygotic twins than for dizygotic twins have been shown in most twin studies. Symbiotic relationship between monozygotic twins makes it difficult to treat these patients. In this report, female monozygotic twins of AN with similar clinical features has been discussed comparing with other twins of AN in the literature.

AB040. Biomarkers for Autism: where are we now and what will the future bring?

Autism spectrum disorders (ASD) is a complex disorder in which both genes and environmental factors play important roles. ASD is characterized by a high concordance rate in monozygotic twins pointing to high heritability for this disorder. Notably, the sibling recurrence risk ratio (λs) is 22 for autism. Despite the high heritability clinical symptoms are markedly variable and multiple genetic factors including Mendelian mutations, copy number variations and common polymorphisms all contribute to the genetic load towards passing the clinical threshold to ASD. Indeed, multiple genetic loci have been with various degrees of certainty associated with this disorder. In addition to genetic factors environmental variables and epigenetic signatures are also important modifiers of susceptibility to ASD. For example, studies show that DNA methylation differences can occur in many loci across the genome of ASD subjects. Among biomarkers that have been examined in ASD are metabolic, oxidative stress, mitochondrial dysfunction, methylation, immune dysregulation, amino acids and neuropeptides, peripheral blood gene expression, digit ratio and dysbiosis (gut inflammation) among others. In my talk today after giving an overview (see above) of biomarkers in ASD, I will discuss my own group’s approach that includes both gene markers (serotonin transporter, OXTR and AVPR1a) as well as an innovative endophenotype biomarker approach to better understanding ASD. In a recent study we found that 2D:4D digit ratio (also a proposed marker for ASD) relationship to cognitive empathy (a core deficit in ASD) is dependent in normal subjects on an OXTR SNP linked to ASD in some studies. We have also shown that OXTR and AVPR1a gene polymorphisms are associated in normal subjects with cognitive and emotional empathy respectively. Notably, common polymorphisms in both genes are also associated with ASD. Similarly, the DRD4 gene shows a gender-sensitive association with cognitive empathy. In a parallel talk at this meeting I discuss in some detail how gene expression studies in lymphoblastoid cells may be a marker for ASD as well as personality traits. I will also discuss a finding with a colleague identifying a functional rare variant in autism using genome-wide screen for monoallelic expression. Altogether, our studies have revealed genetic and other biomarkers that jointly contribute to the social cognitive deficits that represent core diagnostic features of ASD. The biomarkers are not specific to ASD but nevertheless shed considerable light on the underlying common polymorphisms and multiple etiologies of this highly heritable disorder characterized by intellectual and social dysfunctions. One promising area of future studies of biomarkers in ASD is prenatal diagnosis using ultrasound.

High Heritability of Abdominal Aortic Aneurysms – A Population-based Twin-study

Introduction: It is well known that there is an increased risk of developing abdominal aneurysms (AAA) among first-degree relatives of AAA-patients; however, it is still uncertain how great a role genetics generally play in the development of the disease. In twin studies the influence of genetic and environmental factors can be assessed by comparing concordance rates between monozygotic (MZ) and dizygotic (DZ) twins. Higher phenotypic similarity between MZ than DZ twins indicates a genetic attribution to the etiology. The primary aim of this study was to investigate the heritability of AAA among Danish twins using concordance rates and heritability estimates. Secondary aims were to investigate possible differences between gender regarding age at diagnosis and prevalence. Methods: We identified all Danish twins with AAA using three different population-based registries: the National Hospital Patient Registry, the Registry of Cause of Death and the Danish Twin Registry, which were linked together using the Danish Civil Registration System. We calculated age at diagnosis and prevalence for both men and women, and proband-wise concordance rates. Heritability was estimated using tetrachoric correlations and structural ADCE-modelling. Results: We included 65 –820 twins (32 –910 pairs). We identified 414 twins with AAA; 69.8 % (289/414) were men and 30.2 % (125/414) women. Mean age at diagnosis was 69.7 years with no significant difference between men and women (69.6 vs. 70.0 years, p = 0.64). The prevalence across all zygosities was 0.87% in men and 0.39% in women. The proband-wise concordance rate in MZ twins was 30.6% (95% CI (confidence interval):20.3;43.3%) compared with 12.2% (95%CI:7.0;20.1%) in DZ twins. In the analysis of heritability 77% (95%CI:67;85%) of the total variance could be explained by additive genetic components. The rest of the variance could be explained by non-shared environmental factors, whereas genetic dominance and shared environmental factors were not needed to account for the observed variance. Conclusion: In this study we found more than a two times higher concordance rate in MZ twins compared with DZ twins, which indicates a genetic component in the development of AAA. Furthermore we found an overall heritability of 77 % meaning genetic variance accounts for more than ¾ of the total phenotypic variance. Prevalences were generally low with women accounting for about a third of the AAA-cases and we found no difference between genders regarding age at diagnosis.

Self-Reported Scoliosis is Not a Valid Method for Estimating Concordance Rates of Adolescent Idiopathic Scoliosis in a Danish Twin Population

Introduction The etiology of adolescent idiopathic scoliosis is still unclear and the true mode of inheritance has yet to be established. From the Danish twin cohort concordance rates in monozygotic twins have previously been reported to be 0.13 and in dizygotic twins 0. Studies on concordance in twin pairs provide a basis for analyzing the influence of genetic versus environmental factors. In this study, we wanted to validate if self-reported scoliosis is a valid method to establish incidence and concordance rates in a twin population. Patients and Methods All 46,418 twins registered in the Danish Twin Registry born from 1931 to 1982 were sent a questionnaire, which included questions about scoliosis. The questionnaire was returned by 34,944 (75.3%) representing 23,204 pairs. A total of 548 individuals representing 274 complete twin pairs, where at least 1 has self-reported scoliosis were invited to a clinical and a radiologic examination. Zygosity was established by genetic testing. Results A total of 182 individuals (33.2% of the cohort) participated. Overall, 128 of these individuals had self-reported scoliosis. The total number of participants consisted of 91 twin pairs, where one or both twins had scoliosis and 36 individuals whose twin did not want to participate. Overall, 35 individuals (27.3%) of the 128 participants with self-reported scoliosis presented a clinical and radiological confirmed curve. Of these were 5 twin pairs (four monozygotic pairs and one dizygotic pair) with scoliosis in both twins and 16 twin pairs with scoliosis in only 1 twin and 9 individuals where only one twin participated. Calculating concordance in twins with curves greater than 10 degrees, we found that the pairwise concordance rate was 0.4 (range, 0.12–0.74) for monozygotic and 0.05 (range, 0.01–0.25) for dizygotic twin pairs, probandwise concordance was 0.45 for monozygotic and 0.1 for dizygotic pairs. Conclusion Self-reported scoliosis in a Danish twin population is not a valid method to establish the true concordance rates. Although it is not statistically significant the differences in monozygotic and dizygotic pairs indicate that hereditary parameters have an impact.

Studying neurological disorders using induced pluripotent stem cells and optogenetics.

Neurological disorders are amongst the most widely studied human aliments. Yet, they are also one of the most poorly understood. Although most of these disorders are polygenic, genotype still plays an important role in their etiologies. For example, in schizophrenia and autism spectrum disorders, there is a 40–60% concordance rate in monozygotic twins, with 60–90% heritability (Burmeister et al., 2008). However, the mechanisms by which multiple genes and their genomic variations influence the phenotypes of the disorders remain to be understood. The complexities of the disorders are further compounded by the individual rarity of the genomic variations and their variable penetrance (Cook and Scherer, 2008). Thus, conventional disease modeling, such as gene knockout in cells or in animals, to attain the desired disease genotype may not be the most suitable platform for tackling most neurological disorders.

Schizophrenia: a consequence of gene-environment interactions?

Schizophrenia is a multi-factorial disease characterized by a high heritability and environmental risk factors (e.g., social stress and cannabis use). It is the combined action of multiple genes of small effect size (Owen et al., 2005) and a number of environmental risk factors (McGrath et al., 2004), which causes the development of this mental disorder (Mackay-Sim et al., 2004). This is conceptualized in the “Two-Hit Hypothesis” of schizophrenia, which predicts that genetic and environmental risk factors interactively (GxE interaction) cause the development of the disorder (Bayer et al., 1999; Caspi and Moffitt, 2006). GxE interactions occur when the expression of an individual's genetic predisposition is dependent on the environment they are living in or when environmental influences on a trait differ according to an individual's genome (Tsuang et al., 2004). Human studies have confirmed that nature and nurture are both important in the development of schizophrenia: the concordance rate in monozygotic twins is only around 50% (Tsuang et al., 2001) and genome wide association studies fail to identify major genetic candidates for schizophrenia (Sanders et al., 2008) suggesting an important role of environmental factors in the development of this disorder.

Epigenetics of Multiple Sclerosis: An Updated Review

Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease characterized with autoimmune response against myelin proteins and progressive axonal loss. The heterogeneity of the clinical course and low concordance rates in monozygotic twins have indicated the involvement of complex heritable and environmental factors in MS pathogenesis. MS is more often transmitted to the next generation by mothers than fathers suggesting an epigenetic influence. One of the possible reasons of this parent-of-origin effect might be the human leukocyte antigen-DRB1*15 allele, which is the major risk factor for MS and regulated by epigenetic mechanisms such as DNA methylation and histone deacetylation. Moreover, major environmental risk factors for MS, vitamin D deficiency, smoking and Ebstein-Barr virus are all known to exert epigenetic changes. In the last few decades, compelling evidence implicating the role of epigenetics in MS has accumulated. Increased or decreased acetylation, methylation and citrullination of genes regulating the expression of inflammation and myelination factors appear to be particularly involved in the epigenetics of MS. Although much less is known about epigenetic factors causing neurodegeneration, epigenetic mechanisms regulating axonal loss, apoptosis and mitochondrial dysfunction in MS are in the process of identification. Additionally, expression levels of several microRNAs (miRNAs) (e.g., miR-155 and miR-326) are increased in MS brains and potential mechanisms by which these factors might influence MS pathogenesis have been described. Certain miRNAs may also be potentially used as diagnostic biomarkers in MS. Several reagents, especially histone deacetylase inhibitors have been shown to ameliorate the symptoms of experimental allergic encephalomyelitis. Ongoing efforts in this field are expected to result in characterization of epigenetic factors that can be used in prediction of treatment responsive MS patients, diagnostic screening panels and treatment methods with specific mechanism of action.

Genetic background of febrile seizures

Febrile seizures (FSs) occur in children older than 1 month and without prior afebrile seizures in the absence of a central nervous system infection or acute electrolyte imbalance. Their pathogenesis is multifactorial. The most relevant familial studies evidence an occurrence rate ranging from 10% to 46% and median recurrence rate of 36% in children with positive familial history for FS. The main twin studies demonstrated a higher concordance rate in monozygotic twins with FS than in dizygotic ones. Linkage studies have proposed 11 chromosomal locations responsible to FS attributed to FEB1 to FEB11. Population-based association studies have shown at least one positive association for 14 of 41 investigated genes with FS. The proinflammatory cytokine interleukin 1β (IL-1β) was the most investigated and also gene associated with susceptibility to FS. A possible role in the overlapping of epilepsy and FS was found for 16 of 36 investigated genes. SCN1A, IL-1β, CHRNA4, and GABRG2 were the most commonly involved genes in this context. The genetic background of FS involves the regulation of different processes, including individual and familial susceptibility, modulation of immune response, and neuronal excitability and interactions with exogenous agents such as viruses.

Symposium 2-1The autoimmunome: Similarities and differences among genetic susceptibility to common immune-related diseases.

Autoimmune disorders arise when physiological tolerance to "self" antigens is lost. Although several mechanisms may be involved in this pathogenic process, dysregulation of T-cell and B-cell activation and of pathways leading to inflammation are logical candidates. Susceptibility to autoimmune diseases has been associated with multiple factors including genetics, epigenetics, and the environment. While the modest concordance rate in monozygotic twins suggests that environmental factors are major players in most autoimmune diseases, increased heritability within families and the decrease in risk with the degree of relatedness all argue in favor of genetic factors. With the advent of high-throughput genomics, massive amounts of genetic data are being produced and reported on a monthly basis. Although considerable insight has been gained from each of these individual studies, a detailed comparative analysis will likely identify both unique and common pathways operating in autoimmunity.More than 40 genome-wide association studies (GWAS) have been published to date in several autoimmune diseases (AID) and hundreds of common variants have been identified that confer risk or protection. While statistical adjustments are essential to refine the list of potential associations with each disease, valuable information can be extracted by the systematic collection of moderately significant variants present in more than one trait. While involvement of the MHC region in chromosome 6p21 is not in question for most AID, the complex genetic architecture of this locus poses a significant analytical challenge. On the other hand, by considering the contribution of non-MHC-related genes, similarities and differences among AID can be readily computed thus gaining insights into possible pathogenic mechanisms. For example, statistically significant excess sharing of non-MHC genes was found between type I diabetes (T1D) and all other AID studied, a result also seen for RA. A smaller but significant degree of sharing was observed for multiple sclerosis (MS), Celiac disease (CeD) and Crohn's disease (CD). We have developed a bioinformatics tool called iCTNet (integrated Complex Traits networks), that enables downloading and visualization of large volumes of data and the relationships among the different data types, information that is not typically available for the general user. The most recent version of iCNet (scheduled to be released in Spring 2014) includes data from genome-wide association studies, OMIM, protein interactions, tissue expression, drug targets, drug side effects, and miRNA targets among other data types. During my presentation I will describe practical examples of how this tools may facilitate the biological interpretation of large throughput data in human immune-related diseases and how this can help to generate new hypotheses for drug repositioning strategies. Using this class of approaches the unique genetic landscape for each autoimmune disease can start to be defined. Furthermore, this kind of analysis may set the basis for more targeted and rational therapeutic approaches.

Genetic and Epigenetic Factors in Etiology of Diabetes Mellitus Type 1

Diabetes mellitus type 1 (T1D) is a complex disease resulting from the interplay of genetic, epigenetic, and environmental factors. Recent progress in understanding the genetic basis of T1D has resulted in an increased recognition of childhood diabetes heterogeneity. After the initial success of family-based linkage analyses, which uncovered the strong linkage and association between HLA gene variants and T1D, genome-wide association studies performed with high-density single-nucleotide polymorphism genotyping platforms provided evidence for a number of novel loci, although fine mapping and characterization of these new regions remains to be performed. T1D is one of the most heritable common diseases, and among autoimmune diseases it has the largest range of concordance rates in monozygotic twins. This fact, coupled with evidence of various epigenetic modifications of gene expression, provides convincing proof of the complex interplay between genetic and environmental factors. In T1D, epigenetic phenomena, such as DNA methylation, histone modifications, and microRNA dysregulation, have been associated with altered gene expression. Increasing epidemiologic and experimental evidence supports the role of genetic and epigenetic alterations in the etiopathology of diabetes. We discuss recent results related to the role of genetic and epigenetic factors involved in development of T1D.

DNA methylation profiles in type 1 diabetes twins point to strong epigenetic effects on etiology

Type 1 diabetes (T1D) shows ∼40% concordance rate in monozygotic twins (MZ) suggesting a role for environmental factors and/or epigenetic modifications in the etiology of the disease. The aim of our study was to dissect the contribution of epigenetic factors, particularly, DNA methylation (DNAm), to the incomplete penetrance of T1D. We performed DNAm profiling in lymphocyte cell lines from 3 monozygotic (MZ) twin pairs discordant for T1D and 6 MZ twin pairs concordant for the disease using HumanMethylation27 BeadChip. This assay assesses the methylation state of 27,578 CpG sites, mostly located within proximal promoter regions. We identified 88 CpG sites displaying significant methylation changes in all T1D-discordant MZ twin pairs. Functional annotation of the genes with distinct CpG methylation profiles in T1D samples showed differential DNAm of immune response and defense response pathways between affected and unaffected twins. Integration of DNAm data with GWAS data mapped several known T1D associated genes, HLA, INS, IL-2RB, CD226, which showed significant differences in DNAm between affected and unaffected of twins.Our findings suggest that abnormalities of DNA methylation patterns, known to regulate gene transcription, may be involved in the pathogenesis of T1D.

Virus infection, antiviral immunity, and autoimmunity

As a group of disorders, autoimmunity ranks as the third most prevalent cause of morbidity and mortality in the Western World. However, the etiology of most autoimmune diseases remains unknown. Although genetic linkage studies support a critical underlying role for genetics, the geographic distribution of these disorders as well as the low concordance rates in monozygotic twins suggest that a combination of other factors including environmental ones are involved. Virus infection is a primary factor that has been implicated in the initiation of autoimmune disease. Infection triggers a robust and usually well-coordinated immune response that is critical for viral clearance. However, in some instances, immune regulatory mechanisms may falter, culminating in the breakdown of self-tolerance, resulting in immune-mediated attack directed against both viral and self-antigens. Traditionally, cross-reactive T-cell recognition, known as molecular mimicry, as well as bystander T-cell activation, culminating in epitope spreading, have been the predominant mechanisms elucidated through which infection may culminate in an T-cell-mediated autoimmune response. However, other hypotheses including virus-induced decoy of the immune system also warrant discussion in regard to their potential for triggering autoimmunity. In this review, we discuss the mechanisms by which virus infection and antiviral immunity contribute to the development of autoimmunity.

Heritability and Familial Aggregation of Diverticular Disease: A Population-Based Study of Twins and Siblings

Little is known about the role of heritable factors in diverticular disease. We evaluated the contribution of heritable factors to the development of diverticular disease diagnosed at a hospitalization or outpatient visit. Using nationwide patient registries, we identified 142,123 incident cases of diverticular disease diagnosed at a hospitalization (1977-2011) or an outpatient hospital visit (1995-2011) in Denmark, including cases in 10,420 index siblings and 923 twins. We calculated standardized incidence ratios for siblings versus the general population and concordance rates for monozygotic versus dizygotic twin pairs as measures of relative risk (RR). The RR for diverticular disease in siblings of index cases was 2.92 (95% confidence interval [CI], 2.50-3.39) compared with the general population. The RRs were similar irrespective of the sex of the sibling or index case and were particularly strong in siblings of hospitalized cases and cases that underwent surgery. The proband-wise concordance rate for monozygotic twins was double that of dizygotic twins (0.16 [95% CI, 0.11-0.22] vs 0.07 [95% CI, 0.05-0.11], respectively). The RR of diverticular disease in one twin when the other had diverticular disease was 14.5 (95% CI, 8.9-23) for monozygotic twins compared with 5.5 (95% CI, 3.3-8.6) for dizygotic twins. Associations were stronger in female monozygotic twins compared with male twins (tetrachoric correlation, 0.60 [95% CI, 0.49-0.70] vs 0.33 [95% CI, 0.13-0.51]; P = .03 in an analysis stratified by sex and zygosity). We estimate that 53% (95% CI, 45%-61%) of susceptibility to diverticular disease results from genetic factors. Based on a population-based study in Denmark, genetic factors appear to contribute to development of diverticular disease.