The genetic determinants of smoking

Dependence on tobacco, like many other drug dependencies, is a complex behavior with both genetic and environmental factors contributing to the variance. The heritability estimates for smoking in twin studies have ranged from 46 to 84%, indicating a substantial genetic component to smoking. Candidate gene studies have detected functional polymorphisms in genes coding for the cytochrome P450 enzymes, and variations in these genes that lead to more rapid nicotine metabolism have been implicated in smoking. Similarly, smoking has been associated with polymorphisms in dopaminergic genes that may influence the dopamine receptor number and/or function. Animal experiments have localized specific subunits of the nicotinic receptors that may mediate the reinforcing properties of nicotine and have investigated their role in nicotine dependence. However, environmental factors have also been found to contribute to the risk of initiation and persistence of smoking. We review the scientific evidence that supports a role for genetic influences on smoking, discuss the specific genetic and neurobiological mechanisms that may mediate susceptibility to nicotine dependence, identify possible gene/environmental interactions that may be important in understanding smoking behavior, and suggest directions for future research. Insights into the genetic contributions to smoking can potentially lead to more effective strategies to reduce smoking.     

Past,present and future of cardiovascular twin studies

The increasing burden of cardiovascular disorders highlights the crucial need to research efforts in the prevention and screening of heritable disorders or cardiovascular risk factors. Twin studies offer an opportunity to assess the influence of genetic and environmental factors and gene–environment interactions as well. Blood pressure and its components, arterial stiffness, carotid intima-media thickness were found to have a moderate heritability, whereas carotid plaque formation and coronary atherosclerosis seemed to be strongly genetically determined. These findings so far underlined the importance of identification of the specific genetic factors and prevention in high-risk individuals due to genetic transmission; therefore, further studies should investigate the benefits of a possible screening program. Beyond this “classical” model, monozygotic twin pairs discordant for a disease are important research opportunity since this method is able to assess the role of prenatal and postnatal environmental (epigenetic, stochastic) factors in the development of a disease. Longitudinal twin studies provide an ideal model to investigate the within-pair epigenetic drift (e.g. DNA methylation, histone modification) over time. In the future, these twin studies might unravel the underlying epigenetic changes associated with cardiovascular disease-risk biomarkers, which can help in the identification of those individuals who have higher risk for future cardiovascular disorders. Since in most twin studies a considerable role is found for unique environmental factors, the “traditional” concept of the deterministic role of individual-specific modifiable environmental factors, such as smoking, unhealthy nutrition or reduced physical activity, still remains important.     

Twin studies as a model for exploring the aetiology of autoimmune thyroid disease

Twins are an important resource for evaluating the relative contribution of genetic and environmental factors in determining a phenotype. During the last decades, a number of twin studies have investigated the aetiology of several phenotypes related to thyroid autoimmunity. Taken together, these studies have provided valid and unbiased information regarding the influence of genetic and environmental factors in the aetiology of autoimmune thyroid disease (AITD). The comparison of concordance rates between monozygotic (MZ) and dizygotic twins provides irrefutable evidence of a genetic component, and biometric twin modelling shows that approximately 75% of the total phenotypic variance in AITD is because of genetic effects. On the other hand, the lack of complete concordance in MZ twin pairs is proof of environmental and/or epigenetic factors also playing an important role. The impact of environmental triggers such as cigarette smoking, birth characteristics, infection with Yersinia enterocolitica, microchimerism and degree of X chromosome inactivation (XCI) has been evaluated by investigating AITD discordant twin pairs. These studies indicate that smoking, Y. enterocolitica infection and skewed XCI may be causally associated with clinically overt AITD, but not with the presence of thyroid autoantibodies in euthyroid subjects. Microchimerism, but not birth weight, might play a role in AITD. Twin studies offer several features that uniquely enhance our ability to localize genes and understand their function. Future twin studies should incorporate information on genetic, epigenetic and environmental variation thereby enhancing our ability to quantify the precise effect of specific risk factors.     

Twins as a tool for evaluating the influence of genetic susceptibility in thyroid autoimmunity

By means of large twin cohorts, it has been possible to provide relatively valid and unbiased data regarding the influence of genetic and to some extent epigenetic factors in the aetiology of thyroid autoimmunity. The comparison of concordance rates between monozygotic and dizygotic twins provides irrefutable evidence of a genetic component in the aetiology of both Graves’ disease and Hashimoto's thyroiditis, as well as for harbouring thyroid autoantibodies. Biometric modelling shows that approximately 75% of the total phenotypic variance in autoimmune thyroid disease is due to genetic effects. Despite the well known gender difference in the prevalence of autoimmune thyroid disease, the analyzes suggest that it is the same set of genes that operate in males and females. The lack of complete phenotypic concordance in monozygotic twin pairs indicates that also environmental and/or epigenetic factors are of importance. The impact of specific environmental and epigenetic exposures can be evaluated by investigating disease discordant twin pairs. Our studies show that skewed X chromosome inactivation is associated with clinically overt AITD but not with the presence of TPOAb in euthyroid individuals. It is now recognized that twin studies offer several features that uniquely enhance our ability to localize genes and understand their function. Future twin studies will incorporate information on genetic and epigenetic variation making it possible to quantify the precise effect of specific susceptibility genes and/or epigenetic variation on estimates of heritability.     

Genetic and environmental contributions to smoking

We estimate the magnitude of genetic and shared environmental contributions to risk of initiation and maintenance of smoking. Genetic models were fitted to data from 2 204 male-male monozygotic and 1 793 male-male dizygotic twin pairs from the Vietnam Era Twin Registry who responded to smoking questions on a 1987 mail and telephone survey. The best fitting model allowed for both genetic and shared environmental effects on smoking initiation, accounting for 50% and 30% of the variance in risk, but allowed for only genetic effects, (accounting for 70% of the variance in risk), on persistence in smoking among those who had become regular smokers. This finding of a major genetic influence on smoking persistence confirms similar results from studies in Scandinavia and Australia. The role of heritable traits such as nicotine sensitivity should be addressed in smoking prevention and cessation efforts.     

Gastroesophageal reflux disease in monozygotic and dizygotic twins.

BACKGROUND & AIMS: Gastroesophageal reflux disease (GERD) interferes with the quality of life and carries an increased risk for esophageal adenocarcinoma. We investigated genetic influence in the development of reflux. METHODS: We compared concordance for reflux in monozygotic (MZ) and dizygotic (DZ) twins. All twins age 55 and older in the nationwide Swedish Twin Registry were invited to participate. Data were collected by computer-assisted telephone interviews. Reflux disease was defined by symptomatic heartburn or acid regurgitation occurring at least weekly. RESULTS: A total of 2178 monozygotic, 3219 same-sex dizygotic, and 3014 unlike-sex dizygotic twin pairs provided information. Overall, 15.3% of the twins had reflux. In men, the intraclass correlation for reflux was 0.29 (95% confidence interval [CI], 0.15-0.43) for monozygotic and 0.13 (95% CI, 0.02-0.25) for dizygotic pairs. In women, the correlation was 0.33 (95% CI, 0.22-0.44) for monozygotic and 0.14 (95% CI, 0.04-0.24) for dizygotic pairs. For unlike-sex dizygotic pairs, the correlation was 0.06 (95% CI, -0.01 to 0.14). Concordance for reflux was not caused by inherited obesity or alcohol use; inherited smoking may be a minor factor. CONCLUSIONS: The increased concordance for reflux in monozygotic pairs, compared with dizygotic pairs, indicates genetic rather than shared environmental effects. Heritability accounted for 31% (23%-39%) of the liability to reflux disease in this population.     

功能性胃肠病的遗传机制——相关基因研究

功能性胃肠病(FGID)有一定程度的家族聚集现象,在孪生人群中的FGID流行病学研究显示,单卵孪生的共同患病率高于异卵孪生。这些现象提示,遗传因素改变个体对FGID的易感性以及相似环境致病因素下FGID的临床表现异质性。此文综述FGID遗传易感性方面的研究进展。     

Fasting plasma total ghrelin concentrations in monozygotic twins discordant for obesity

Ghrelin is a hormone that is involved in the regulation of food intake. Neuronal, endocrine, and genetic factors have been shown to regulate plasma ghrelin levels; but the determinants of fasting ghrelin concentrations are not yet fully understood. The main aim was to explore the roles of adiposity and genetic differences in determining fasting plasma total ghrelin levels. We measured total ghrelin levels in a population of 23 monozygotic twin pairs discordant for obesity. In addition, 2 variants of ghrelin gene, namely, Arg51Gln and Leu72Met, were genotyped in 3 populations of monozygotic twin pairs: 23 obesity-discordant, 43 lean-concordant, and 46 obesity-concordant twin pairs. In discordant twins, lean co-twins had higher fasting plasma total ghrelin levels (950 pg/mL, SD = 328 pg/mL) than obese twins (720 pg/mL, SD = 143 pg/mL; P = .003). Arg51Gln-polymorphism of the ghrelin gene was equally distributed between the twin groups. However, there were significant differences in genotype frequencies at the Leu72Met polymorphism between the discordant and obese-concordant groups (P = .003) and between the discordant and lean-concordant groups (P = .011), but not between the 2 concordant groups. In the discordant group, there were fewer Met carriers (4%) than among the obese (17%) or the lean-concordant groups (15%). Plasma total ghrelin levels are affected by acquired obesity independent of genetic background. The Leu72 allele is particularly common among monozygotic twins discordant for obesity, suggesting that this ghrelin allele is more permissive in the regulation of energy balance. The ghrelin gene may thus play a role in the regulation of variability of body weight, such that Leu72 allele carriers are more prone to weight variability in response to environmental factors.     

The genetics of smoking related behavior: a brief review

Smoking behavior is influenced by both genetic and environmental factors. Many years of twin and adoption studies have demonstrated that heritability is at least 50% for both smoking initiation and smoking persistence. Furthermore, the extent to which genetic and environmental factors contribute to smoking behavior in men is significantly different from that in women. It has been reported that polymorphisms of candidate genes, such as cytochrome P450, dopamine receptor and transporter, and serotonin transporter genes, are associated with smoking behavior. However, many of these reports have not yet received independent confirmation. Based on the results from genome-wide linkage and association analyses on different subject populations, 15 loci located on 8 chromosomes were reported to harbor susceptibility genes for nicotine and other substances of abuse. It is expected that a newly completed human genome sequence, as well as advances in genomic technologies such as genotyping and array analysis, will greatly enhance progress toward the identification of genes associated with smoking behavior.     

Heritability of plasma sex hormones and hormone binding globulin in adult male twins

Plasma sex hormone concentrations have been used as biomarkers in epidemiological studies of many conditions including cancer, obesity, bone density, and coronary heart disease. The objective of this analysis was to estimate genetic and nongenetic influences on endogenous sex hormones (testosterone, estradiol, estrone, and SHBG) in a large sample of 532 adult white male twins (134 monozygotic and 132 dizygotic twin pairs) from the National Heart, Lung, and Blood Institute Twin Study. Participants were aged 59-70 yr at the time of plasma collection, and hormone concentrations were determined with RIA. Genetic models were fitted by the method of maximum likelihood. Testosterone and SHBG concentrations have substantial genetic variation, with additive genetic factors accounting for 57 and 68% of the total phenotypic variation, respectively. In contrast, variation in estrone (37% shared environmental and 63% individual specific environmental effects) and estradiol concentrations (25% genetic effect, 44% shared environmental effects, and 31% individual specific environmental effects) were largely influenced by nongenetic factors. Assessment of the relative contribution of genetic and nongenetic influences on hormone concentrations may help in the search for genes underlying variation and covariation in complex traits affected by plasma sex hormone concentrations.     

The relative importance of genetic and environmental factors in the aetiology of thyroid nodularity: a study of healthy Danish twins

BACKGROUND: A large proportion of healthy, euthyroid, nongoitrous individuals have thyroid nodules. The aetiology of these ultrasonographically detected morphological abnormalities is largely unknown. Factors such as age, gender, iodine intake, smoking and parity are associated with nodularity of the thyroid. Whether there is a genetic susceptibility is unclear. AIM: To gain insight into the aetiology of thyroid nodularity by investigating a large cohort of healthy euthyroid monozygotic and dizygotic twins. DESIGN: A cross-sectional twin study. PARTICIPANTS: A representative sample of self-reported healthy twin pairs was identified through the Danish Twin Registry. A total of 520 individuals divided into 104 monozygotic (MZ), 107 dizygotic same sex (DZ) and 49 opposite sex (OS) twin pairs were investigated. MEASUREMENTS: Probandwise concordance and tetrachoric correlations. Quantitative genetic modelling was used to elucidate the relative importance of genetic and environmental effects for the variation in the liability of nodularity. RESULTS: A higher concordance rate for thyroid nodularity was found in MZ twins [0.57 (95% CI 0.36-0.76)] than in DZ twins [0.36 (95% CI 0.17-0.56, P = 0.074)]. The same was true for tetrachoric correlations: 0.67 (95% CI 0.34-0.87) in MZ twins and 0.17 (CI - 0.28-0.56, P = 0.053) in DZ twins. The difference, although not significant, was more pronounced for multiple nodules than for solitary nodules. Controlling for covariates (age, gender and smoking habits), it was calculated that genetic factors accounted for 67% (95% CI 35-87%) and environmental factors for 33% (95% CI 13-65%) of the individual differences in the liability to thyroid nodularity. CONCLUSIONS: This study suggests that genetic factors are of aetiological importance for thyroid nodularity in clinically healthy and euthyroid individuals, and indicates a difference in the aetiology of solitary and multiple thyroid nodules.     

Environmental epidemiology and risk factors for autoimmune disease

It has long been recognized that environmental influences play an important role in the risk of developing chronic rheumatic disease. Defining specific pathogenic environmental mediators that may trigger the development or progression of autoimmune disease remains a focus of increasing investigative effort. Factors promoting disease may not be identical to factors that influence the severity or progression of the disorder. Human monozygotic twin studies, animal studies, and genetic models demonstrate that genetic influences strongly determine whether one will develop autoimmunity, however, genes affecting the metabolism of exogenous agents that may trigger disease expression have only recently drawn attention. In this article the authors review recent reports that advance our understanding of previously recognized environmental risk factors and challenge accepted beliefs that increased estrogenic exposures predate the incidence of autoimmune disorders, systemic lupus erythematosus in particular.     

Genetic and environmental influences on symptomatic gallstone disease: a Swedish study of 43,141 twin pairs

The contribution of hereditary and environmental factors to the pathogenesis of symptomatic gallstone disease is still unclear. We estimated the relative importance of genetic and environmental factors by analyzing a large population of twins. For this purpose, the Swedish Twin Registry was linked with the Swedish inpatient-discharge and causes of death registries for symptomatic gallstone disease and gallstone surgery-related diagnoses in 43,141 twin pairs born between 1900 and 1958. Concordance rates, correlations, and odds ratios were calculated for males, females, monozygotic, and dizygotic twins, respectively, as well as for twin pairs of opposite sex. Structural equation modeling techniques were used to estimate the contributions of genetic effects as well as shared and non-shared environmental factors to the development of symptomatic gallstone disease. We found that concordances and correlations were higher in monozygotic compared with dizygotic twins, both for males and females. Of note, there were no significant sex differences in heritability. In the full model, genetic effects accounted for 25% (95% CI, 9%-40%), shared environmental effects for 13% (95% CI, 1%-25%), and unique environmental effects for 62% (95% CI, 56%-68%) of the phenotypic variance among twins. In conclusion, our results show heritability to be a major susceptibility factor for symptomatic gallstone disease, consistent with results from previous, much smaller studies.     

A population-based study of chronic autoimmune hypothyroidism in Danish twins

Hashimoto's thyroiditis (HT), atrophic thyroiditis (AT), and Graves' disease are autoimmune thyroid diseases in which genetic factors are suspected to play an important role in disease susceptibility. In a recent population-based twin study we rendered it probable that a substantial part of the susceptibility to Graves' disease is attributable to genetic factors. At present there are no population-based twin studies supporting such a genetic influence in the etiology of HT/AT. To elucidate whether there is a genetic influence in the etiology of HT/AT, we studied the distribution of HT/AT in a population-based sample of 2945 Danish female-female twin pairs (5890 individuals) born between 1953 and 1972. Information on hypothyroidism was obtained from a nationwide questionnaire survey in 1994. Information from hospitals, out-patient clinics, general practitioners, and specialists was sought to verify the diagnosis. The overall prevalence of autoimmune hypothyroidism was 0.41% (24 of 5890). The prevalence did not differ between monozygotic and dizygotic twins (0.42% and 0.40%, respectively). The crude proband-wise concordance rates were significantly higher for monozygotic compared to dizygotic twin pairs: 0.55 (95% confidence interval, 0.23-0.83) vs. 0.0 (95% confidence interval, 0.0-0.25; P = 0.01). All of the healthy cotwins (n = 15) of twins with clinically overt autoimmune hypothyroidism were biochemically euthyroid. Overall, regardless of zygosity 53% (8 of 15) of the healthy cotwins were positive for antithyroid antibodies. The prevalence of autoantibodies among the monozygotic cotwins was 80% (4 of 5) and 40% (4 of 10) among dizygotic cotwins (P = 0.36). In conclusion, the higher concordance rate in monozygotic compared to dizygotic pairs indicates that genetic factors play a role in the etiology of HT/AT among Caucasian women living in areas with borderline iodine deficiency. However, the fact that the concordance rate among MZ twins was below 1 suggests that environmental factors also are of etiological importance.     

Age-related changes on platelet membrane: a study on elderly and centenarian monozygotic twins

Cellular senescence is a biological process associated with aging and longevity. Successful aging is believed to be related to the ability to cope with different environmental stresses. The objective of this study was to investigate if cellular senescence is associated with platelet membrane modifications on subjects of different age, in particular on monozygotic twins and if these changes might be affected by both genetic components and environmental factors. The work was performed on 81 monozygotic twin pairs of different age. Platelet membranes from centenarian twins showed: decreased both basal lipid peroxide levels and membrane fluidity compared with elderly subjects; Na(+)/K(+)-ATPase activity and SA content are similar to those evaluated in young group, suggesting one of their important roles in the successful aging. We concluded that platelet membranes from centenarians show deeper structural and functional modifications than in elderly subjects and that these changes might play a protective role against oxidative damage. No statistical difference in biochemical parameters was observed between two sibpairs in each twin pair highlighting that environmental factors (diet, life-style) affect age-related platelet membrane changes less than their common genetic component. Thus genetic factors might play an important role in the mechanisms at the basis of successful aging.     

Long-term bone loss in men: effects of genetic and environmental factors.

OBJECTIVE: To identify environmental factors associated with bone loss in adult male twins and to determine the extent to which shared environmental characteristics affect estimates of the genetic influence on bone loss. DESIGN: A 16-year cohort study. SETTING: A midwestern university hospital. PARTICIPANTS: One hundred and eleven male veterans of World War II or the Korean conflict, born between 1916 and 1927. All were twins, with the sample comprising 48 pairs and 15 persons whose twin brothers were deceased or seriously ill. MEASUREMENTS: Bone mass and environmental characteristics (cigarette smoking, alcohol consumption, physical activity, dietary calcium intake, use of thiazide diuretics) measured at baseline and 16 years later. RESULTS: Rates of radial bone loss averaged 0.45% per year. Those who both smoked and used alcohol at levels greater than the median for the population had a rate of bone loss (10% in 16 years) twice the rate of those who were below the median level for both variables (5% bone loss, P = 0.003). Rates of bone loss were correlated within twin pairs, and these correlations were diminished 25% to 35% by adjustments for environmental influences on bone loss. However, statistically significant within-pair correlations remained (r = 0.4), which did not differ between monozygotic and dizygotic twin pairs after adjustments for smoking, alcohol use, dietary calcium intake, and exercise. CONCLUSIONS: Bone loss in men during mid-life is determined, at least in part, by environmental factors, including smoking, alcohol intake, and, possibly, physical activity. Rates of bone loss were similar within twin pairs, apparently because of a shared environment.     

Genetics of fibrin clot structure: a twin study

Coronary artery thrombosis following plaque rupture is an important feature of myocardial infarction, and studies have highlighted the role of coagulation in this condition. Although genetic and environmental influences on the variance in coagulation protein concentrations have been reported, there are no data on the heritability of structure/function of the final phenotype of the coagulation cascade, the fibrin clot. To assess genetic and environmental contributions to fibrin structure, permeation and turbidity studies were performed in 137 twin pairs (66 monozygotic, 71 dizygotic). The environmental influence (e2) on pore size (Ks) (e2 = 0.61 [95% confidence interval (CI), 0.45-0.80]) and fiber size (e2 = 0.54 [95% CI, 0.39-0.73]) was greater than the heritability (h2 = 0.39 [95% CI, 0.20-0.55] and 0.46 [95% CI, 0.27-0.62], respectively). After correction for fibrinogen levels, the environmental effect persisted for Ks (e2 = 0.61), but genetic influence assumed a greater importance in determining fiber size (h2 = 0.73). Multivariate analysis revealed an overlap in the influence of genetic and environmental factors on fibrinogen levels, Ks, and fiber size. Factor XIII B subunit showed environmental and genetic correlation with fibrinogen and fiber size and a genetic correlation with Ks. The results indicate that genetic and environmental influences are important in determining fibrin clot structure/function.     

Genetic factors in self-reported snoring and excessive daytime sleepiness: a twin study

Subjects in this study included 1,560 intact male-male twin pairs (818 monozygotic [MZ], 742 dizygotic [DZ]) of mean age (+/- SD) 74.2 +/- 2.8 yr. The Epworth Sleepiness Scale (ESS) was used to assess daytime sleepiness and standardized questionnaires assessed snoring. Multivariate genetic model fitting was used to estimate the contribution of genetic and nongenetic (environmental) influences to the variation and covariation of obesity with snoring and daytime sleepiness. In this sample, 26% were habitual snorers, 18% reported excessive daytime sleepiness (ESS > or = 11), and 29% were obese (body mass index [BMI] > or = 28). By using structural equation modeling, we estimated that genetic factors accounted for 64% of the variance in obesity, 40% of the variance in daytime sleepiness, and 23% of the variability in self-reports of snoring. We found a significant genetic correlation between obesity and snoring and between obesity and excessive daytime sleepiness (EDS), although for the most part the genetic variance in snoring and sleepiness was nonoverlapping with the genetic variance for obesity. We conclude from these data that self-reported symptoms of snoring and daytime sleepiness in older men have a genetic basis that is largely independent of genes associated with obesity.     

Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment

BACKGROUND & AIMS: There is growing evidence that the interplay of genetic susceptibility and environmental factors leads to primary biliary cirrhosis (PBC). In particular, family members of an infected individual have up to a 100-fold higher risk of developing PBC. Although concordant rates for identical twins in other autoimmune diseases range between 25% and 50%, there are no such data on PBC. Accordingly, we evaluated the concordance of PBC in a genetically defined population of twin sets and evaluated the clinical characteristics between concordant subjects. METHODS: We identified 16 pairs of twins within a 1400-family cohort followed up by several centers worldwide, evaluated the diagnosis of PBC in all individuals, and determined the zygosity of sets reported as identical by the analysis of 2 highly variable HLA class II regions and 5 short tandem repeats. RESULTS: Eight of 16 sets of twins were monozygotic. In 5 of 8 monozygotic twin sets, both individuals had PBC (pairwise concordance rate, 0.63). Among the dizygotic twins (n = 8), no set was found to be concordant for PBC. Interestingly, the age at onset of disease was similar in 4 of 5 concordant sets of monozygotic pairs; however, there were differences in natural history and disease severity. CONCLUSIONS: The concordance rate of PBC in identical twins is among the highest reported in autoimmunity. However, discordant pairs were identified. The data show not only the role of genetics but also emphasize that either epigenetic factors and/or environment play a critical role.     

Genetic and environmental factors in monozygotic twins with Crohn's disease and their first-degree relatives: a case report

BACKGROUND/AIMS: Familial Crohn's disease has shown concordance concerning location and clinical type of the disease especially among monozygotic twins. Susceptibility to Crohn's disease is both based on genetic and environmental factors. We investigated polymorphisms of CARD15, TLR4, and OCTN, and environmental factors in a monozygotic twin pair with Crohn's disease and their first-degree relatives. METHODS: 22-year-old monozygotic female twins with ileocolonic Crohn's disease and their healthy brother and parents were examined. DNA samples from patients and relatives were genotyped for CARD15, TLR4,and OCTN polymorphisms. ASCA and p-ANCA analyses were performed. Additionally, patients and relatives filled out a questionnaire concerning multiple environmental factors. RESULTS: Both twins presented in the same year with identical Vienna Classification phenotypes: stenotic behavior (B2) and localization in terminal ileum and colon (L3). Both carried a CARD15 R702W variant, but had normal alleles in TLR4 and OCTN. They were smokers since the age of 15, used oral contraceptives and had undergone appendectomy. The healthy father and brother were CARD15 R702W positive, were non-smokers and had not undergone appendectomy. CONCLUSION: This case report is the first to describe complete concordance in CARD15 status, phenotypic appearance, and smoking, appendectomy and oral contraceptive use in a pair of monozygotic twins with CD.