Healthy Twins Research Articles

Dysbiosis in food allergy and implications for microbial therapeutics.

The increase in food allergy prevalence in recent years suggests that environmental factors, such as diet and intestinal microbiota, play contributory roles. In this issue of the JCI, Bao et al. compared twins that differed with respect to food allergies. The researchers analyzed sequences from microbe ribosomal RNA and profiled microbe metabolites, identifying health-associated microbes at the species level. In addition to revealing microbes from the Clostridia class enriched in healthy twins, the authors identified two commensal species (Phascolarctobacterium faecium and Ruminococcus bromii) related to the healthy fecal metabolome. This study advances the goal for next-generation probiotic therapies that effectively treat or prevent food allergy.

Genome-wide association study of non-tuberculous mycobacterial pulmonary disease

BackgroundThe prevalence of non-tuberculous mycobacterial pulmonary disease (NTM-PD) is increasing in South Korea and many parts of the world. However, the genetic factors underlying susceptibility to this disease remain elusive.MethodsTo...

Equivalent DNA methylation variation between monozygotic co-twins and unrelated individuals reveals universal epigenetic inter-individual dissimilarity

BackgroundAlthough the genomes of monozygotic twins are practically identical, their methylomes may evolve divergently throughout their lifetime as a consequence of factors such as the environment or aging. Particularly for young and healthy monozygotic twins, DNA methylation divergence, if any, may be restricted to stochastic processes occurring post-twinning during embryonic development and early life. However, to what extent such stochastic mechanisms can systematically provide a stable source of inter-individual epigenetic variation remains uncertain until now.ResultsWe enriched for inter-individual stochastic variation by using an equivalence testing-based statistical approach on whole blood methylation microarray data from healthy adolescent monozygotic twins. As a result, we identified 333 CpGs displaying similarly large methylation variation between monozygotic co-twins and unrelated individuals. Although their methylation variation surpasses measurement error and is stable in a short timescale, susceptibility to aging is apparent in the long term. Additionally, 46% of these CpGs were replicated in adipose tissue. The identified sites are significantly enriched at the clustered protocadherin loci, known for stochastic methylation in developing neurons. We also confirmed an enrichment in monozygotic twin DNA methylation discordance at these loci in whole genome bisulfite sequencing data from blood and adipose tissue.ConclusionsWe have isolated a component of stochastic methylation variation, distinct from genetic influence, measurement error, and epigenetic drift. Biomarkers enriched in this component may serve in the future as the basis for universal epigenetic fingerprinting, relevant for instance in the discrimination of monozygotic twin individuals in forensic applications, currently impossible with standard DNA profiling.

Gut microbiome signatures distinguish type 2 diabetes mellitus from non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is closely associated with type 2 diabetes mellitus (T2D), and these two metabolic diseases demonstrate bidirectional influences. The identification of microbiome profiles that are specific to liver injury or impaired glucose metabolism may assist understanding of the role of the gut microbiota in the relationship between NAFLD and T2D. Here, we studied a biopsy-proven Asian NAFLD cohort (n = 329; 187 participants with NAFLD, 101 with NAFLD and T2D, and 41 with neither) and identified Enterobacter, Romboutsia, and Clostridium sensu stricto as the principal taxa associated with the severity of NAFLD and T2D, whereas Ruminococcus and Megamonas were specific to NAFLD. In particular, the taxa that were associated with both severe liver pathology and T2D were also significantly associated with markers of diabetes, such as fasting blood glucose and Hb1Ac. Enterotype analysis demonstrated that participants with NAFLD had a significantly higher proportion of Bacteroides and a lower proportion of Ruminococcus than a Korean healthy twin cohort (n = 756). However, T2D could not be clearly distinguished from NAFLD. Analysis of an independent T2D cohort (n = 185) permitted us to validate the T2D-specific bacterial signature identified in the NAFLD cohort. Functional inference analysis revealed that endotoxin biosynthesis pathways were significantly enriched in participants with NAFLD and T2D, compared with those with NAFLD alone. These findings may assist with the development of effective therapeutic approaches for metabolic diseases that are associated with specific bacterial signatures.

Acute postpartum dyspnea: is it a simple or a complicated item?

Background: Peripartum cardiomyopathy (PPCM), like spontaneous coronary artery dissection (SCAD), is a disease that affect healthy women and occur in the days before and after delivery. Case Presentation: We discuss the case of a 26-year-old woman, already a mother of a boy, who gave birth to two healthy twin girls by cesarean section. Two hours after delivery, the woman suddenly developed acute dyspnea and chest pain, which had angina pectoris features and was permanent. Her electrocardiogram showed sinus tachycardia at 125 beats per minute, with no specific ST- segment deviation at 12 precordial (on the ECG), but also right and posterior leads. Echocardiography showed a significant reduction in left ventricular systolic performance, with an estimated LVEF (Left Ventricular Ejection Fraction) of approximately 25%-30%, and significant hypokinesis in the mid-distal part of the interventricular septum and the apex of the left ventricle. Her blood examination revealed an increase in troponin-T high sensitivity (0.245 ng/ml), with a mild parallel increase in creatine phosphokinase, as well as the MB (isoenzyme of CPK, the most specific indicator for the myocardial infarction diagnosis) form (383 and 52 IU/l, respectively). The NT-pro BNP (N-terminal pro Brain Natriuretic Peptide) was mildly increased, too, at 1280 pg/ml. The chest pain remained until the next 36 hours when it gradually disappeared, as the dyspnea, too. She was completely recovered until the 10th day of hospitalization. The patient underwent coronary computed tomography angiography, which showed 0 Agatston coronary artery calcium score units. However, in the middle of the left anterior descending (LAD) artery, after the protrusion of the second diagonal branch, an eccentric 7 mm non-calcified lesion was observed, which caused mild stenosis (1%-24%). Conclusion: PPCM and SCAD are related to young healthy women and occur in the peripartum period. However, in some cases, their clinical picture may overlap, making the diagnosis challenging.

Cardioautonomic control in healthy singleton and twin pregnancies.

In conjunction with significant cardiovascular adaptation, changes in cardioautonomic balance, specifically greater sympathetic activation and vagal withdrawal, are considered normal adaptations to healthy singleton pregnancy. Cardiovascular adaptation to twin pregnancy is more profound than that of singleton pregnancies; however, the changes in cardioautonomic control during multifetal gestation are unknown. To address this gap, beat-by-beat blood pressure (photoplethysmography) and heart rate (lead II electrocardiogram) were measured continuously in 25 twin pregnancies and 25 singleton pregnancies (matched for age, prepregnancy body mass index, and gestational age) during 10 min of rest. Data extracted from a 3- to 5-min period were used to analyze heart rate variability (HRV), blood pressure variability (BPV), cardiovagal baroreflex gain, and cardiac intervals as indicators of cardioautonomic control. Independent t tests were used to determine statistical differences between groups (α = 0.05), and the false rate discovery was determined to adjust for multiple comparisons. Resting heart rate was greater in twin compared with singleton pregnancies (91 ± 10 vs. 81 ± 10 beats/min; P = 0.001), but blood pressure was not different. Individuals with twin pregnancies had lower HRV, evidenced by lower standard deviation of R-R intervals (32 ± 11 vs. 47 ± 18 ms; P = 0.001), total power (1,035 ± 810 vs. 1,945 ± 1,570 ms2; P = 0.004), and high frequency power (224 ± 262 vs. 810 ± 806 ms2; P < 0.001) compared with singleton pregnancies. There were no differences in cardiac intervals, BPV, and cardiovagal baroreflex gain between groups. Our findings suggest that individuals with twin pregnancies have greater sympathetic and lower parasympathetic contributions to heart rate and that cardiac, but not vascular, autonomic control is impacted during twin compared with singleton pregnancy.NEW & NOTEWORTHY Individuals with healthy twin pregnancies had lower overall heart rate variability compared with those with singleton pregnancies at similar gestational ages. These results suggest a greater sympathetic and reduced parasympathetic contribution to cardiac control in twin pregnancies. Baseline heart rate was elevated, while arterial pressure and spontaneous cardiovagal baroreflex gain were not different between groups. This was result of the upward resetting of the cardiovagal baroreflex during healthy twin pregnancy, thus maintaining arterial pressure.

The impact of online brain training exercises on experiences of depression, anxiety and emotional wellbeing in a twin sample

This study assessed the effectiveness of cognitive and emotional brain training and transfer effects to wellbeing and depression and anxiety symptoms. 352 healthy adult twins were randomised to a training group where they were asked to play brain training games over a 30-day period, or a waitlist control group. This study focused on the impact of the brain training on explicit and implicit emotional cognition, and analysed effects using both Intention-To-Treat (ITT) and Per-Protocol (PP) approaches. Both analyses revealed significant training effects for improvement in the explicit identification of fear expressions (ITT: p < 0.001, d = 0.33; PP training 3 h+: p < 0.001, d = 0.55), and a reduction in implicit bias for anger expressions amongst males (ITT: p < 0.001, d = 0.94; PP training 3 h+: p = 0.04, d = 0.90). Female participants also showed improvements in implicit bias for happy expressions (ITT: p = 0.003, d = 0.34; PP training 3 h+: p = 0.03, d = 0.47). Improvements resulting from training in emotional cognition did not directly improve wellbeing, depression or anxiety symptoms. Regression modelling also suggested training improvements in emotional cognition yielded no indirect transfer effects for the mental health and wellbeing measures. The results suggest brain training in healthy populations has potential for improving emotional cognition, but the subsequent impact on improving wellbeing and mental health symptoms is still equivocal.

Urinary Sodium and Potassium Levels and Blood Pressure in Population with High Sodium Intake.

The purpose of this study was to examine the association of urinary sodium-to-creatinine ratio and potassium-to-creatinine ratio with blood pressure in a cross-sectional study comprising Korean adults who participated in the Healthy Twin Study. The participants consisted of 2653 men and women in the Healthy Twin Study aged ≥19 years. Participants’ urinary excretion of sodium, potassium, and creatinine was measured from overnight half-day urine samples. Food intake was assessed using a validated food frequency questionnaire. We examined systolic and diastolic blood pressures according to sodium- or potassium-to-creatinine ratios using the generalized linear model. We determined food groups explaining high urinary sodium- or potassium-to-creatinine ratio using the reduced rank regression and calculated sodium- or potassium-contributing food score. We observed that systolic blood pressure was higher among men and women in the highest quintile of urinary sodium-to-creatinine ratio or sodium-to-potassium ratio than it was in the lowest quintile. Geometric means (95% CIs) of the lowest and the highest quintiles of systolic blood pressure (mmHg) were 113.4 (111.8–115.0) and 115.6 (114.1–117.2; P for trend = 0.02), respectively, for sodium-to-creatinine ratio. The association between urinary sodium-to-creatinine and systolic blood pressure was more pronounced among individuals whose body mass index (BMI) was less than 25 kg/m2 (P for interaction = 0.03). We found that vegetables, kimchi and seaweed intake contributed to high sodium intake and a sodium-contributing food score were associated with increased blood pressure. In our study, we identified the food groups contributing to high sodium intake and found that high urinary sodium levels were associated with increasing blood pressure among Korean adults.

Longitudinal retinal layer changes in preclinical Alzheimer's disease.

PurposeSeveral studies found reduced retinal thickness on optical coherence tomography (OCT) in Alzheimer’s disease (AD), even in preclinical stages, labelling this technique of interest as biomarker. In this study, we examine retinal thickness changes in preclinical AD, as defined by cognitively normal individuals with amyloid‐beta (Aβ) on positron emission tomography (PET).MethodsFor this monocentre study, 145 cognitively healthy monozygotic twins aged ≥ 60 were included from the Netherlands Twin Register taking part in the EMIF‐AD PreclinAD study. At baseline, participants underwent [18F] flutemetamol PET that was visually rated for cortical Aβ. Binding potential was calculated as continuous measure for Aβ. Optical coherence tomography (OCT) was performed at baseline and after 22 months to assess changes in total and individual inner retinal layer thickness in the macular region (ETDRS circles) and peripapillary retinal nerve fibre layer thickness. Differences in rate of change between amyloid‐beta positive and negative individuals and associations between binding potential and change in retinal thickness were evaluated.ResultsSixteen participants (11%) were positive for Aβ. Change in retinal thickness did not differ in any region between Aβ+ and Aβ− individuals. A positive association between binding potential and change in inner plexiform layer thickness was observed in the inner macular ring (beta = 1.708, CI = 0.575 to 2.841, p = 0.003).ConclusionAβ+ individuals did not differ in rate of change of any retinal layer compared to controls, but higher binding potential at baseline was associated with less IPL thinning over time. Optical coherence tomography (OCT) as a longitudinal screening tool for preclinical AD seems limited, but IPL changes offer leads for further research.

Γονικότητα και διδυμία: Μία διπλή πρόκληση

Ιn the present paper the transition to parenthood of twins and the developmental process of the relationship between parents and their twins from the prenatal period up to adolescence are described and discussed. Our interest is focused on the distinctiveness of this relationship and the issues arising in every developmental step of twins. It is a double challenge for parents. On the one hand they should respond effectively to their role as parents and on the other hand they should simultaneously face the needs of two different children, with all the difficulties involved. In the present work the significance of the twins’ differentiation by their parents while they are still in the prenatal period, is emphasized as it is an important issue for the prevention of comparison, tension or jealousy that are harmful to the twin bond. The realisation that every twin child is different brings out the developmental advantages of twinship (companionship, empathy, cooperation etc) and diminishes the stereotypical view summarized in the phrase “for problem see twin”, which is being questioned by contemporarynaturalistic studies on the subject. Identifying the developmental advantages of twinship is a critical factor for the growth of emotionally healthy twins who respect and appreciate themselves and their relationship.

MRI-visible dilated perivascular spaces in healthy young adults: A twin heritability study.

We investigated the narrow‐sense heritability of MRI‐visible dilated perivascular spaces (dPVS) in healthy young adult twins and nontwin siblings (138 monozygotic, 79 dizygotic twin pairs, and 133 nontwin sibling pairs; 28.7 ± 3.6 years) from the Human Connectome Project. dPVS volumes within basal ganglia (BGdPVS) and white matter (WMdPVS) were automatically calculated on three‐dimensional T2‐weighted MRI. In univariate analysis, heritability estimates of BGdPVS and WMdPVS after age and sex adjustment were 65.8% and 90.2%. In bivariate analysis, both BGdPVS and WMdPVS showed low to moderate genetic correlations (.30–.43) but high shared heritabilities (71.8–99.9%) with corresponding regional volumes, intracranial volumes, and other regional dPVS volumes. Older age was significantly associated with larger dPVS volume in both regions even after adjusting for clinical and volumetric variables, while blood pressure was not associated with dPVS volume although there was weak genetic correlation. dPVS volume, particularly WMdPVS, was highly heritable in healthy young adults, adding evidence of a substantial genetic contribution in dPVS development and differential effect by location. Age affects dPVS volume even in young adults, while blood pressure might have limited role in dPVS development in its normal range.

Genetic and environmental effects on lumbar posture, flexibility and motion control in healthy adults

BackgroundAlthough alterations in posture, flexibility, and motion control of the lumbar spine are associated with low back pain, the underlying interplay between genetic and environmental influences on these traits remains unclear. The aim of this study is to investigate the extent to which genetics and the environment influence lumbar lordosis, flexibility, and motion control. DesignThe present cross-sectional and observational study employed the classic twin design with structural equation models. MethodsAn inertial measurement unit with a wireless movement analysis system, the ViMove (DorsaVi, Melbourne, Australia) was used to measure lumbar lordosis, flexibility, and motion control during range of motion and functional tests. Intraclass correlation was used to determine twin resemblance for the traits. Heritability (genetic influence on trait variation) of lumbar lordosis, flexibility and motion control was estimated from 52 healthy twins, 34 monozygotic and 18 dizygotic using age and sex adjusted univariate genetic models. ResultsA strong heritability estimate was found in lumbar lordosis (77%, 95% confidence interval [CI]: 38%–91%) in standing, followed by lumbar flexibility (67%, 95% CI: 32%–85%) in the sagittal plane. No significant intraclass correlations were found in monozygotic twin pairs for lumbar motion control or in dizygotic twin pairs during the hurdle step and in-line lunge test. ConclusionGenetic factors appear to have a substantial influence on lumbar lordosis and lumbar sagittal flexibility. Lumbar motion control may be more influenced by environmental factors.

Birth weight is associated with adolescent brain development: A multimodal imaging study in monozygotic twins.

Previous research has shown that the prenatal environment, commonly indexed by birth weight (BW), is a predictor of morphological brain development. We previously showed in monozygotic (MZ) twins associations between BW and brain morphology that were independent of genetics. In the present study, we employed a longitudinal MZ twin design to investigate whether variations in prenatal environment (as indexed by discordance in BW) are associated with resting‐state functional connectivity (rs‐FC) and with structural connectivity. We focused on the limbic and default mode networks (DMNs), which are key regions for emotion regulation and internally generated thoughts, respectively. One hundred and six healthy adolescent MZ twins (53 pairs; 42% male pairs) followed longitudinally from birth underwent a magnetic resonance imaging session at age 15. Graph theoretical analysis was applied to rs‐FC measures. TrackVis was used to determine track count as an indicator of structural connectivity strength. Lower BW twins had less efficient limbic network connectivity as compared to their higher BW co‐twin, driven by differences in the efficiency of the right hippocampus and right amygdala. Lower BW male twins had fewer tracks connecting the right hippocampus and right amygdala as compared to their higher BW male co‐twin. There were no associations between BW and the DMN. These findings highlight the possible role of unique prenatal environmental influences in the later development of efficient spontaneous limbic network connections within healthy individuals, irrespective of DNA sequence or shared environment.

Doppler Velocimetry of the Ophthalmic Artery Behavior in Twin Pregnancy.

Our main objective was to evaluate the ophthalmic artery Doppler behavior in twin pregnancies and compare with singleton pregnancies. We studied 64 healthy twin pregnant women between 12 to 38 weeks of gestation. Resistance index (RI), pulsatility index (PI), and peak ratio (PR) were determined. The control group consisted of 289 singletons. Linear regression analysis was performed to evaluate the association between gestational age and the ophthalmic indexes. Student t test was used to compare the means and standard deviation of the Doppler indexes. There was a decrease in RI and PI and an increase in PR with advancing gestational age (ρ < 0.0001, 0.0052, and 0.0033). The means ± SDs for RI, PI, and PR were 0.77 ± 0.07, 1.79 ± 0.46, and 0.53 ± 0.12, in women with twin pregnancies and 0.75 ± 0.05, 1.88 ± 0.43, and 0.52 ± 0.10 in singletons. No significant difference was found between the PI and PR values, but significant difference was found in the RI values between the groups (P = 0.0332). We concluded that there are no significant differences in ophthalmic artery behavior in twins and the same reference values established in singleton pregnancies can be applied for PI and PR indexes in the evaluation of twin pregnancies. These indexes were the best to evaluate twin pregnancies.

Novel variant in NSDHL gene associated with CHILD syndrome and syndactyly- a case report

BackgroundCongenital hemidysplasia with ichthyosiform erythroderma and limb defects also known as CHILD syndrome is an X-linked dominant, male lethal genodermatosis with a prevalence of 1 in 100,000 live births. Mutations in NSDHL gene located at Xq28 potentially impair the function of NAD(P) H steroid dehydrogenase-like protein and is responsible for its pathogenesis.Case presentationThe proband was a 9-month-old twin (T2) girl with a healthy twin sister (T1) of Sri Lankan origin born to non-consanguineous parents. She presented with right sided continuous icthyosiform erythroderma and ipsilateral limb defects and congenital hemidysplasia since birth. Notably the child had ipsilateral hand hypoplasia and syndactyly. There were other visceral abnormalities. We performed whole exome sequencing and found a novel heterozygous variant (NSDHL, c.713C > A, p.Thr238Asn).ConclusionWe report a novel missense variant in the NSDHL gene that resides in a highly-conserved region. This variant affects the NAD(P) H steroid dehydrogenase-like protein function via reduction in the number of active sites resulting in the CHILD syndrome phenotype and syndactyly.

Genetic and shared environmental risk factors do not lead to eosinophil activation in healthy twins of IBD patients

Objective To examine the role of eosinophils in the pre-diagnostic phase of inflammatory bowel disease (IBD), we studied the influence of genetic and shared environmental risk factors in a twin cohort of IBD. Material and methods We analysed eosinophil derived neurotoxin (EDN) and eosinophil cationic protein (ECP) in faecal samples from twin pairs with Crohn’s disease (n = 37) or ulcerative colitis (n = 21) and from external healthy controls (n = 44). Eosinophils stained with eosinophil peroxidase (EPO) were quantified in rectal biopsies. Ratios with 95% confidence intervals were calculated. Results Twins with Crohn’ disease displayed higher levels of EDN (Ratio = 2.98, 1.65–5.37) and ECP (Ratio 1.83, 1.24–2.70) than their healthy siblings. Levels did not differ between healthy twin-siblings and external controls (EDN, Ratio = 1.52, 0.79–2.94 and ECP, Ratio = 0.93, 0.56–1.54). Higher levels of EDN (Ratio = 2.43, 1.13–5.24) and ECP (Ratio = 1.53, 0.92–2.53) were observed among twins with ulcerative colitis vs their healthy siblings. Levels did not differ between healthy twin-siblings and external controls (EDN, Ratio = 1.08, 0.51–2.25 and ECP, Ratio = 1.29, 0.74–2.26). Using intra-class correlation coefficient (ICC), we found no agreement in levels of EDN or ECP in discordant pairs, except for ECP in monozygotic Crohn’s disease pairs (ICC = 0.63). In contrast, agreement was observed in monozygotic pairs concordant for Crohn’s disease (EDN, ICC = 0.67 and ECP, ICC = 0.66). The number of eosinophils in rectum was increased in twins with ulcerative colitis vs their healthy sibling (Ratio = 2.22, 1.50–3.27). Conclusions Activation of eosinophils in IBD seems to be a consequence of inflammation rather than an effect of genetic and shared environmental risk factors alone.

Heritability of macular ganglion cell inner plexiform layer thickness as determined by optical coherence tomography: the Healthy Twin Study

PurposeTo evaluate genetic influence on macular ganglion cell inner plexiform layer (GCIPL) thickness.MethodsMacular GCIPL thickness was measured with optical coherence tomography in nine macular subfields defined by the E TDRS....

Changes in cognitive functions in a girl with severe acquired hypothyroidism in comparison to the healthy twin sister.

Not required for Clinical Vignette.

Genetic and environmental determinants of variation in the plasma lipidome of older Australian twins.

The critical role of blood lipids in a broad range of health and disease states is well recognised but less explored is the interplay of genetics and environment within the broader blood lipidome. We examined heritability of the plasma lipidome among healthy older-aged twins (75 monozygotic/55 dizygotic pairs) enrolled in the Older Australian Twins Study (OATS) and explored corresponding gene expression and DNA methylation associations. 27/209 lipids (13.3%) detected by liquid chromatography-coupled mass spectrometry (LC-MS) were significantly heritable under the classical ACE twin model (h2 = 0.28-0.59), which included ceramides (Cer) and triglycerides (TG). Relative to non-significantly heritable TGs, heritable TGs had a greater number of associations with gene transcripts, not directly associated with lipid metabolism, but with immune function, signalling and transcriptional regulation. Genome-wide average DNA methylation (GWAM) levels accounted for variability in some non-heritable lipids. We reveal a complex interplay of genetic and environmental influences on the ageing plasma lipidome.

The impact of vitamin D supplementation on VDR gene expression and body composition in monozygotic twins: randomized controlled trial

Vitamin D supplementation is widely used. However, there is no consensus on the use and dosage of this supplement and the existing recommendations arise from studies based on the benefits that this nutrient can facilitate in bones. In addition, individual genetics can influence the response to supplementation, therefore, research involving monozygotic twins aims to reduce these differences in phenotypic responses. The objective of this randomised controlled study is to examine the effect of vitamin D supplementation on body composition and the expression of the vitamin D receptor (VDR) mRNA. An intervention was performed through supplementation with cholecalciferol at the concentration of 2000 IU in 90 healthy adult monozygotic twins (male or female pairs) for 2 months. The findings showed that serum vitamin D concentration increased by 65% and VDR gene expression sixty times (p = 0.001). Changes in body composition parameters were observed regarding body fat and lean mass. Our results indicate that an increase in serum vitamin D concentration may have potential therapeutic implications.