A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes.

BACKGROUND & AIMS: The composition of the gastrointestinal microbiota is thought to have an important role in the etiology of inflammatory bowel diseases (IBDs) such as Crohn's disease (CD) and ulcerative colitis (UC). Interindividual variation and an inability to detect less abundant bacteria have made it difficult to correlate specific bacteria with disease. METHODS: We used 454 pyrotag sequencing to determine the compositions of microbial communities in feces samples collected from a cohort of 40 twin pairs who were concordant or discordant for CD or UC, and in mucosal samples from a subset of the cohort. The cohort primarily comprised patients who were in remission, but also some with active disease. RESULTS: The profiles of the microbial community differed with disease phenotypes; relative amounts of bacterial populations correlated with IBD phenotypes. The microbial compositions of individuals with CD differed from those of healthy individuals, but were similar between healthy individuals and individuals with UC. Profiles from individuals with CD that predominantly involved the ileum differed from those with CD that predominantly involved the colon; several bacterial populations increased or decreased with disease type. Changes specific to patients with ileal CD included the disappearance of core bacteria, such as Faecalibacterium and Roseburia, and increased amounts of Enterobacteriaceae and Ruminococcus gnavus. CONCLUSIONS: Bacterial populations differ in abundance among individuals with different phenotypes of CD. Specific species of bacteria are associated with ileal CD; further studies should investigate their role in pathogenesis.

Food protein-induced gastrointestinal syndromes in identical and fraternal twins.

BACKGROUND: It has been suggested that gene-environmental interactions play crucial roles in the development of allergy, especially in early life. Analysis of twin cases may provide novel insights into the pathogenesis and pathophysiology of allergy. Though several studies have indicated the importance of a genetic contribution to the expression of allergic diseases based on twin analyses, very few data are available regarding twins with Food Protein-Induced Gastrointestinal Syndrome (FPIGS). Two pairs of identical and fraternal twins with FPIGS are presented. CASE SUMMARY: The twins were born with no abnormalities and fed breast milk and supplemental formula. The identical twins developed vomiting and bloody stool simultaneously. The fraternal twins developed prolonged vomiting and loose stools at different times. Since their symptoms disappeared with when formula feeding was stopped, the symptoms were thought to indicate the presence of an allergy to cow's milk. The clinical symptoms and laboratory findings of the four patients were highly suggestive of FPIGS. The identical and fraternal twins showed very similar symptoms, including their onset and clinical courses. However, a substantial clinical disparity existed in the clinical features of the two pairs of twins. DISCUSSION: Comparisons of the twins' similarities and disparities suggest a profound genetic effect on the patients' clinical features, along with individual environmental factors. The prevalence of FPIGS is increasing, and it is now a major topic of public concern in Japan. Further accumulation of data on twins with FPIGS is needed to clarify the genetic contributions to this disease.

Monozygotic twins are discordant for chronic periodontitis: white blood cell counts and cytokine production after ex vivo stimulation.

OBJECTIVES: The aim of this study was to investigate the extent of concordance in the number of leucocytes and their cytokine secretion after ex vivo stimulation in a twin population discordant for the amount of periodontal breakdown. MATERIAL AND METHODS: Venous blood was collected from 18 adult twin pairs (10 monozygotic and eight dizygotic twins). Each twin pair consisted of a diseased twin (proband) and his/her co-twin. In venous blood, leucocytes were counted. The cytokines interleukin (IL)-1beta, IL-6, IL-8, IL-10 and IL-12p40 were assessed after stimulation of monocytic cells, while IL-13 and interferon (IFN)-gamma were determined after lymphocytic stimulation. RESULTS: In the study population as a whole, probands showed higher total numbers of leucocytes and lower IL-12p40 levels compared with their co-twins. In monozygotic twins, no difference was found in the leucocyte counts, but probands secreted more IL-6 than their co-twins; an opposite trend was found for IL-12p40. CONCLUSION: The results suggest that the observed discordance in periodontal breakdown in the studied monozygotic twin population may be related to the relatively high levels of IL-6 and the low levels of IL-12p40 secretion after ex vivo stimulation of whole-blood cell cultures. This cytokine secretion profile may be regarded as a risk indicator of periodontitis.

Does heredity determine the allergy manifestation or the sensitisation to a specific allergen?

BACKGROUND: The role of genetics in allergy development is well accepted. However, studies could not delineate the mode of inheritance or what is specifically being inherited. The purpose of this study was to determine the effect of genetics on the development of allergy manifestation, serum IgE level, and sensitization to specific allergens. METHODS: Fifty-eight twin sets (age 7 months to 11 years) were evaluated for allergy by medical history, family history, physical examination, serum total IgE level, and percutaneous testing to selected common allergens. RESULTS: In 25 monozygotic (MZ) sets, concordance of atopy was significantly higher than in 33 dizygotic (DZ) sets (84.6% vs 62.5%). The age at onset tended to be earlier when the mother was allergic than when the father was (23.5 months vs 30.5 months). When both twins were allergic, the intra-pair difference in age at onset was within <6 months in 50% of MZ sets versus 31.8% in DZ sets. Total IgE level in twins showed a very strong correlation in MZ sets (r 0.92), but only a moderate correlation among DZ sets (r 0.57). Skin test positivity to specific allergens did not show a significant concordance between twins in either group. CONCLUSION: Our study indicates that the genetic influence was strongest on the inheritance of IgE phenotype, the development of the atopic tendency, the age of onset, and to some extent on the specific allergy manifestation. The effect seemed less on determining the specific offending allergen(s), suggesting possible roles of epigenetic and environmental factors.

Genetic and environmental contributions to allergen sensitization in a Chinese twin study.

BACKGROUND: Allergic disease is on the rise worldwide. Effective prevention of allergic disease requires comprehensive understanding of the factors that contribute to its intermediate phenotypes, such as sensitization to common allergens. OBJECTIVE: To estimate the degree of genetic and environmental contributions to sensitization to food and aeroallergens. METHODS: Sensitization was defined as a positive skin prick test to an allergen. We calculated the zygosity-specific concordance rates and odds ratios (ORs) for sensitization to food and aeroallergens in 826 Chinese twin pairs [472 monozygotic (MZ) and 354 dizygotic (DZ)] aged 12-28 years. We also applied structural equation modelling procedures to estimate genetic and environmental influences on sensitization. RESULTS: The concordance rates and risk of sensitization in one twin given the presence vs. the absence of sensitization in the other twin were higher in MZ twins than those in DZ twins. However, a large number of MZ twins were discordant in sensitization to common allergens. These observations suggest both genetic and environmental factors influence sensitization. Consistently, the estimated heritability and individual environmental components of the liability to sensitization ranged from 0.51 to 0.68 and 0.32 to 0.49, respectively, based on the best-fitted structural equation model. We also observed high phenotypic correlations between sensitization to two aeroallergens (cockroach and dust mite: 0.83) and two food allergens (peanut and shellfish: 0.58), but only moderate correlations for the pairs between sensitization to a food and an aeroallergen (0.31-0.46). The shared genetic and environmental factors between paired sensitizations contribute to the observed correlations. CONCLUSION: We demonstrated that sensitization to common food and aeroallergens were influenced by both genetic and environmental factors. Moreover, we found that paired allergen sensitizations might share some common sets of genes and environmental factors. This study underscores the need to further delineate unique and/or pleiotropic genetic and environmental factors for allergen sensitization.

The relative importance of genetic and environmental effects for the early stages of thyroid autoimmunity: a study of healthy Danish twins.

OBJECTIVE: In euthyroid individuals, autoantibodies to thyroid peroxidase (TPOab) and thyroglobulin (Tgab) are regarded as early markers of thyroid autoimmunity. Family and twin studies suggest that development of thyroid autoantibodies in first-degree relatives of patients with autoimmune thyroid disease is under genetic influence. We aimed to estimate the relative importance of genetic and environmental effects for the presence of thyroid autoantibodies in euthyroid subjects. METHODS: A representative sample of healthy twin pairs was identified through the Danish Twin Registry; 1372 individuals, divided into 283 monozygotic (MZ), 285 dizygotic same sex (DZ), and 118 opposite sex twin pairs were investigated. Serum TPOab and serum Tgab were measured. Proband-wise concordance and intraclass correlations were calculated, and quantitative genetic modelling was performed. RESULTS: Probandwise concordance and intraclass correlations were consistently higher for MZ than for DZ twin pairs indicating genetic influence. Genetic components (with 95% confidence intervals) accounted for 73% (46-89%) of the liability of being thyroid antibody positive. Adjusting for covariates (age, TSH and others), the estimate for genetic influence on serum TPOab concentrations was 61% (49-70%) in males and 72% (64-79%) in females. For serum Tgab concentrations, the estimates were 39% (24-51%) and 75% (66-81%) respectively. CONCLUSIONS: Early markers of thyroid autoimmunity appear to be under strong genetic influence. The analyses suggest that it is the same set of genes that operate in males and females. However, complex mechanisms such as dominance and/or epistasis may be involved.

Genetic factors in nickel allergy evaluated in a population-based female twin sample.

Environmental exposures are important for development of allergic contact dermatitis, but genetic factors have been proposed to be of additional importance for contact sensitization. Recently genetic factors were shown to be of significance for hand eczema. In this study, a sample of twins recruited on the basis of hand eczema has been evaluated with respect to influence of genetic factors on development of nickel sensitization. A total of 1076 individual twins were patch tested and underwent clinical examination, and in the final genetic statistical analysis 630 females were available, of which 146 had a positive patch test to nickel. The aggregation of nickel allergy among twin pairs was measured by the casewise concordance and the twin odds ratio. The twin odds ratio were adjusted for effects of risk factors known to be associated with nickel allergy, namely, wet work, atopic dermatitis, and self-reported hand eczema. There was a small tendency for larger odds ratio among monozygotic twins than among dizygotic twins, which was not statistically significant. As a result of the statistical analysis, it is concluded that allergic nickel contact dermatitis is mainly caused by environmental and only to a lesser degree genetic factors. The selection of twins on the basis of hand eczema may theoretically influence the prevalence of nickel allergy and concordance estimates, which should be considered before extrapolating the data to a random population-based twin sample.

A long-term competent chimeric immune system in a dizygotic dichorionic twin.

We present here a rare case that involved the long-term coexistence of 2 mature, functional, and equilibrated immune systems in a single child after fetofetal transfusion between dizygotic twins. A dichorionic diamniotic pregnancy complicated by twin anemia-polycythemia sequence resulted in the demise of 1 twin. The detection of abnormal vessels on the dichorionic plate strongly suggested the existence of functional vascular anastomoses leading to blood chimerism in the survivor. Genetic, phenotypic, and immunologic analyses at 2 years revealed chimeric lymphoid and myeloid cells in the surviving twin, although no tissue mosaicism was detected, which indicates that early transfusion led to mutual immune tolerance.

Aggregation of thyroid autoantibodies in twins from opposite-sex pairs suggests that microchimerism may play a role in the early stages of thyroid autoimmunity.

CONTEXT: Microchimerism is the presence of small populations of cells from one individual in another genetically distinct individual. This phenomenon can arise from pregnancy, blood transfusion, or bidirectional cell trafficking between twins in utero. Microchimerism has recently been proposed to play a role in the pathogenesis of thyroid autoimmunity. In that case, twins from opposite-sex pairs (OS) should have an increased risk of thyroid autoantibodies (TA). AIM: The aim of the study was to compare the frequency of TA in twin individuals from OS and monozygotic (MZ) twin pairs. DESIGN: This was a case-control study of 240 individuals (120 females and 120 males) from OS twin pairs (cases) and 568 control individuals from MZ pairs (284 females and 284 males). METHODS: Antibodies toward thyroid peroxidase (TPOAb), thyroglobulin (TgAb), and the TSH receptor (TSHRAb) were measured and considered positive if greater than 60 U/ml, greater than 60 U/ml, and greater than 1.0 U/liter, respectively. RESULTS: The frequency of TPOAb, TgAb, and TSHRAb among female cases was 15.0, 5.0, and 4.2%, respectively, which was higher than the corresponding prevalences in the female control population: 7.4% (P = 0.018), 1.1% (P = 0.023), and 0.7% (P = 0.026), respectively. However, when corrected for the number of phenotypes studied (TPOAb, TgAb, TSHRAb, and any thyroid antibody), the association remained significant only in the combined group, P(corrected) = 0.012. Essentially similar results were obtained in males. CONCLUSION: Both female and male twins from OS pairs, as opposed to MZ pairs, have an increased frequency of TA, indicating a potential role of microchimerism in developing TA.

The fetus, not the mother, elicits maternal immunologic rejection: lessons from discordant dizygotic twin placentas.

AIMS: Our objective was to elucidate the pathogenesis of twin discordance in four dizygotic pregnancies where only one of the twins had IUGR due to chronic villitis. METHODS: We identified four cases of dizygotic twin placentas over a period of four years with evidence of chronic villitis. There was no clinical or pathologic evidence of TORCH, bacterial infection, preeclampsia or autoimmune disorders. Placentas were weighed, processed for histologic examination and stained with CD45RO (clone UCHL1) mouse monoclonal antibody, which identifies T-cells. RESULTS: All placentas were dichorionic, with two being fused. Birth weight differences were 29%, 41%, 17% and 10%. Villitis was more marked in the placenta of the twin that weighed less and correlated with the degree of weight discordance. On examining the junction between the fused dichorionic placentas, the chorionic villi from the smaller twin contained numerous T-cells, whereas the villi associated with the less affected twin, showed little to no T-cells. CONCLUSION: We describe a series of dizygotic twin placentas where the more severe the chronic villitis, the more affected the placenta and fetus. Since the maternal environment was constant for each of these twins, differences in villitis severity appears to be attributable to differences in the ability of each placenta to induce a maternal immune response.

Heritability estimates of innate immunity: an extended twin study.

Cytokines are key players in numerous inflammatory processes. Demonstration of a heritable component in the variation of cytokine production would indicate that simultaneous occurrence of conditions might be caused by a heritable inflammatory characteristic. We applied an extended twin study approach to assess heritability estimates of interleukin (IL)-1beta, IL-1ra, IL-10, IL-6, and TNF-alpha production capacity after ex vivo stimulation with lipopolysaccharide. Cytokine production capacity was assessed in 42 monozygotic pairs, 52 dizygotic pairs, one trizygotic triplet, 33 single twins, and 83 additional siblings. Heritability estimates were derived from variance decomposition models using maximum likelihood estimation. For all cytokines, over 50% of the variance was genetically determined. IL-1ra and TNF-alpha had the lowest heritability estimate of 53%. Estimates for IL-6 and IL-10 were 57 and 62%, respectively. IL-1beta had the highest estimate of 86%. We conclude that the production of cytokines is under tight genetic control.

Expression of beta-cell autoimmunity does not differ between potential dizygotic twins and siblings of patients with type 1 diabetes.

Twin studies help to elucidate the contribution of genes and environment to type 1 diabetes (T1DM). The Diabetes Prevention Trial-1 (DPT-1) tested for anti-islet autoantibodies: 34,765 non-diabetic non-twin siblings of patients with T1DM, and 896 non-diabetic potential twins of patients with T1DM. Zygosity (being monozygotic [MZ] or dizygotic [DZ]) was unknown except for 357 non-diabetic subjects with opposite gender to their diabetic twin, who must be DZ. Expression of cytoplasmic islet cell (ICA), GAD65, ICA512 and insulin autoantibodies in 357 different-sex (DZ) potential non-diabetic twins of T1DM patients was, respectively, 4.5%, 4.7%, 3.0% and 2.4%, which was lower than in 539 same-sex potential non-diabetic twins (including MZ and DZ) of T1DM patients for ICA (7.8%, p < 0.05), GAD65 (13.4%, p < 0.0001) and ICA512 (6.5%, p < 0.03). In contrast, expression of ICA, GAD65, ICA512 and insulin autoantibodies was not significantly different in different-sex (DZ) potential twins versus all siblings (respectively, 4.2%, 4.8%, 2.2%, 2.5%), different-sex siblings (3.9%, 4.9%, 2.2%, 2.5%) or same-sex siblings (4.4%, 4.7%, 2.2%, 2.5%) of T1DM patients. In conclusion, anti-islet autoimmunity is not increased in non-diabetic DZ twins of T1DM patients compared to non-diabetic siblings of T1DM patients, suggesting that the greater environmental sharing by twins does not increase risk of anti-islet autoimmunity.