Twin Pairs Research Articles

Evaluating functional brain organization in individuals and identifying contributions to network overlap

Abstract Individual differences in the spatial organization of resting-state networks have received increased attention in recent years. Measures of individual-specific spatial organization of brain networks and overlapping network organization have been linked to important behavioral and clinical traits and are therefore potential biomarker targets for personalized psychiatry approaches. To better understand individual-specific spatial brain organization, this paper addressed three key goals. First, we determined whether it is possible to reliably estimate weighted (non-binarized) resting-state network maps using data from only a single individual, while also maintaining maximum spatial correspondence across individuals. Second, we determined the degree of spatial overlap between distinct networks, using test-retest and twin data. Third, we systematically tested multiple hypotheses (spatial mixing, temporal switching, and coupling) as candidate explanations for why networks overlap spatially. To estimate weighted network organization, we adopt the Probabilistic Functional Modes (PROFUMO) algorithm, which implements a Bayesian framework with hemodynamic and connectivity priors to supplement optimization for spatial sparsity/independence. Our findings showed that replicable individual-specific estimates of weighted resting-state networks can be derived using high-quality fMRI data within individual subjects. Network organization estimates using only data from each individual subject closely resembled group-informed network estimates (which was not explicitly modeled in our individual-specific analyses), suggesting that cross-subject correspondence was largely maintained. Furthermore, our results confirmed the presence of spatial overlap in network organization, which was replicable across sessions within individuals and in monozygotic twin pairs. Intriguingly, our findings provide evidence that overlap between 2-network pairs is indicative of coupling. These results suggest that regions of network overlap concurrently process information from both contributing networks, potentially pointing to the role of overlapping network organization in the integration of information across multiple brain systems.

Genetic and Environmental Causes of Variation in an Automated Breast Cancer Risk Factor Based on Mammographic Textures.

Cirrus is an automated risk predictor for breast cancer that comprises texture-based mammographic features and is mostly independent of mammographic density. We investigated genetic and environmental variance of variation in Cirrus. We measured Cirrus for 3,195 breast cancer-free participants, including 527 pairs of monozygotic (MZ) twins, 271 pairs of dizygotic (DZ) twins, and 1,599 siblings of twins. Multivariate normal models were used to estimate the variance and familial correlations of age-adjusted Cirrus as a function of age. The classic twin model was expanded to allow the shared environment effects to differ by zygosity. The SNP-based heritability was estimated for a subset of 2,356 participants. There was no evidence that the variance or familial correlations depended on age. The familial correlations were 0.52 (SE, 0.03) for MZ pairs and 0.16(SE, 0.03) for DZ and non-twin sister pairs combined. Shared environmental factors specific to MZ pairs accounted for 20% of the variance. Additive genetic factors accounted for 32% (SE = 5%) of the variance, consistent with the SNP-based heritability of 36% (SE = 16%). Cirrus is substantially familial due to genetic factors and an influence of shared environmental factors that was evident for MZ twin pairs only. The latter could be due to nongenetic factors operating in utero or in early life that are shared by MZ twins. Early-life factors, shared more by MZ pairs than DZ/non-twin sister pairs, could play a role in the variation in Cirrus, consistent with early life being recognized as a critical window of vulnerability to breast carcinogens.

The relationship of school performance with self-control and grit is strongly genetic and weakly causal

The non-cognitive skills self-control and grit are often considered predictors of school performance, but whether this relationship is causal remains unclear. We investigated the causality of this association using a twin design. Specifically, we evaluated the direct impact of self-control and grit on school performance, while controlling for genetic or environmental influences common to all three traits (i.e., confounding). Teachers of 4891 Dutch 12-year-old twin pairs (of which 3837 were complete pairs) completed a survey about school performance (school grades), self-control (ASEBA self-control scale), and the perseverance aspect of grit. Our analysis aimed to determine the direct impact of self-control and grit on school performance, while simultaneously controlling for genetic or environmental confounding. Establishing the regression relationship corrected for confounding supports the interpretation of the regression relationship as causal. In all analyses, we corrected for sex, rater bias of the teachers, and parental socioeconomic status. Initially, in the standard regression, self-control, and grit explained 28.4% of the school performance variance. However, allowing for genetic confounding (due to genetic pleiotropy) revealed that most of this association could be attributed to genetic influences that the three traits share. In the presence of genetic pleiotropy, the phenotypic regression of school performance on self-control and grit accounted for only 4.4% (i.e., the effect size association with the causal hypothesis). In conclusion, self-control and grit predict school performance primarily due to genetic pleiotropy, with a much smaller causal effect (R2 = 4.4%). This suggests that interventions targeting self-control and grit alone may yield limited improvements in school performance.

Educational Attainment and Risk of All‐Cause Dementia, Vascular Dementia, and Alzheimer’s Disease – A Population‐Based Twin Study

AbstractBackgroundMost studies on the association between educational attainment and dementia have been conducted in unrelated individuals. Dementia‐discordant twin pairs can inform if the protective effect of education on dementia is evident when controlling for environmental and genetic effects. We investigated the association of educational attainment on all‐cause dementia, vascular dementia (VaD), and Alzheimer’s disease (AD) mortality in a population‐based sample of dizygotic (DZ) and monozygotic (MZ) pairs.MethodParticipants were from a population‐based longitudinal older Finnish Twin Cohort study with baseline questionnaire in 1975 (N = 29,784; mean age = 36.9±14.9years). Education was coded as <12 years versus ≥12 years. Registry‐based cause of death data until year 2020 was based on the International Classification of Diseases. We ran individual‐level cox proportional hazard models with sex as a covariate and conditional within‐twin‐pair models for education predicting all‐cause dementia, VaD, and AD mortality. We report hazard ratios (HR) with 95% confidence intervals (CI).ResultIn individual‐level analyses higher education was associated with a decreased risk of all‐cause dementia (HR = .935, 95%CI = .934;.936, p<.001) and VaD (HR = .638, 95%CI = .637;.640, p<.001), but with an increased risk of AD (HR = 1.276, 95%CI = 1.275;1.277, p<.001). In co‐twin analyses of discordant DZ and MZ twin pairs, co‐twins with higher education had lower – although non‐significant – risk of all‐cause dementia (N = 52, HR = .688, 95%CI = .319;1.481, p = .339) or AD (N = 36, HR = .600, 95%CI: .218;1.651, p = .323). Co‐twin analyses were not done for VaD due to small number of discordant pairs (N = 6).ConclusionThis large population‐based sample showed that higher education is related to lower risk of all‐cause dementia and VaD mortality. Unexpectedly, higher education was related to higher AD mortality, but discordant twin pair analyses were informative regarding this counterintuitive result. This case‐control design, controlling for genetic and environmental effects, did not support any causality from higher education to higher AD risk. Despite the large sample, twin pairs – especially MZ twins – discordant for dementia are rare. Meta‐ or mega‐analysis of multiple large twin studies is needed to clarify if secondary education is related to lower risk of dementia, VaD, and AD mortality when controlling for genetic effects.

Traumatic Brain Injury and Cognitive Aging Among Older Veteran Men – A Twin Study Accounting for Genetics and Medical Conditions

AbstractBackgroundTraumatic brain injury (TBI) is associated with increased risk of dementia, but whether TBI influences cognitive trajectories in later life is less clear. Identifying those at high‐risk of cognitive decline creates intervention opportunities to delay dementia. Since twins share many genes and environmental factors, we capitalize on the twin‐study design to investigate the association between lifetime TBI and cognitive decline.MethodParticipants (n = 8,662) members of the National Academy of Sciences‐National Research Council’s Twins Registry of World‐War‐II Male Veterans born between 1917‐1927 with self or proxy‐reported history of TBI and from one to four assessments over 12 years using the modified‐Telephone Interview for Cognitive Status (TICS‐m). We used linear random‐effects‐mixed models to examine the association between TBI and TICS‐m in the full sample and among co‐twins discordant for TBI. Additional TBI predictor variables included: number and severity (with/without loss‐of‐consciousness[LOC]) of TBI; and age of first TBI (age <25 vs 25+). Models were adjusted for age (centered‐at‐70‐years), age‐squared, education, wave, twin pairs and for lifestyle behaviors and medical conditions. In a subset, we assessed the impact of APOE on TICS‐m.ResultHistory of any TBI, TBI with LOC, and older age of TBI were associated with lower TICS‐m scores at 70‐years (p‐values<0.001). TBI with LOC, more than one TBI, and older age of TBI were associated with faster cognitive decline (p‐values<0.05). Among monozygotic twin pairs discordant for TBI (589 pairs), a history of TBI and having TBI at older age was associated with lower TICS‐m scores (p‐values<0.01); those with more than one TBI and TBI at older age showed greater cognitive decline (p‐values<0.05) compared to their cotwin without TBI. Across all twins, APOE‐e4 carriers with TBI, more than one TBI, TBI with LOC, and older age of TBI had lower TICS‐m scores and greater cognitive decline compared to APOE‐e4 non‐carriers.ConclusionThese findings support an association between TBI and lower cognitive score and more rapid cognitive decline in later life. The results in the monozygotic pairs, who share all genes and many exposures particularly in early life, provide evidence of a causal relationship between TBI and poorer late life cognitive outcomes.

The CHECH study: A prospective pregnancy cohort study on CHemical exposure and children's health in Tianjin, China

The CHemical Exposure and Children's Health (CHECH) study is an ongoing pregnancy cohort study in Tianjin, China. This paper describes the background, aim and the study design, which can be followed by future researchers to design and conduct similar studies. The abundance and the potential adverse health outcomes of endocrine disrupting chemicals (EDCs) is concerning. More notably, developing fetuses and infants are more vulnerable to EDCs exposure. The CHECH study aims to investigate the importance of early life exposure to multiple EDCs (phthalates and their metabolites, bisphenol A and their substitutes, perfluorinated compounds and poly brominated diphenyl ethers) for multiple health outcomes in Chinese children, namely sexual development, neurodevelopment, metabolism and growth, as well as asthma and allergy. A total of 2238 pregnant women were recruited in Tianjin from May 2017 to April 2021 with a response rate of 90 %. Among these women, 2255 children were born with available information, including 47 pairs of twins. Urine samples were collected from pregnant women and children, while air and dust samples were obtained from the home environment during pregnancy and infancy periods. Information on children's health was gathered through physical examinations and questionnaires. The CHECH study, which collected exposure information and health outcomes at multiple time points, will contribute to the understanding of prenatal exposure to EDCs and their impact on children's health, thereby facilitating the development of risk assessments aimed at reducing exposure and associated health risks.

The heritability of subjective cognitive complaints in older Australian twins

AbstractBackgroundSubjective cognitive complaints (SCCs) may be a precursor to mild cognitive impairment (MCI) and dementia. This study aimed to examine the heritability of SCCs, and the influence of personality and mood on the relationship between SCCs and memory performance.MethodThe heritability of SCCs were examined in 306 twin pairs using structural equation modelling. Genetic, environmental, and phenotypic correlations between SCCs and memory performance, personality, and mood scores were determined.ResultSCCs were low to moderately heritable. Mood appeared to be related to SCCs by an environmental correlation, whereas memory performance was related to SCCs by a genetic correlation. SCCs had a significant amount of both genetic and environmental variances not explained by memory performance, personality, or mood.ConclusionOur results suggest that SCCs are influenced both by a person’s mood and their memory performance, and that these determinants are not mutually exclusive. Much of the genetic and environmental components to SCCs were specific to SCCs, with the specific factors yet to be determined.

SFM Fetal Therapy Practice Guidelines: Fetal Reduction

AbstractThe indications of fetal reduction can be multifetal reduction (MFR) or selective fetal reduction. In MFR, the objective is to reduce the number of fetuses, whereas in selective fetal reduction the abnormal fetus is targeted for reduction. Reduction in the monochorionic twin pairs resulted in the most favorable pregnancy outcome among triplets and should be recommended whenever fetal reduction is an option. Selective termination by potassium chloride injection is contraindicated with monochorionic gestations because death of the unaffected twin occurs in 80 to 100% of cases. The standard operating procedures discuss various aspects of fetal reduction in detail like indications, consent, procedural details, risks and complications, and follow-up. It also gives a report template that can be used in your clinical practice.

Evaluating the Impact of Maternal Exposure to Ozone on Twin Fetal Growth in China.

Unlike singletons, twins require attention not only to the birth weight of the fetuses but also to discordance (i.e., the differences between weights) because twin growth discordance is a significant factor contributing to perinatal mortality and morbidity in twin pregnancies. However, the impact of maternal air pollution exposure on twin growth discordance has rarely been investigated. We examined the association of long-term ozone exposure during preconception and pregnancy with the birth weight of twins and twin growth discordance among 35,795 twins from the National Free Preconception Health Examination Project between January 2010 and December 2019. Linear mixed-effect models and random-effect logistic regression models were used to examine the associations of ozone exposure with the birth weight-related outcomes (i.e., birth weight of twins and within-pair birth weight difference) and risk of twin growth discordance, respectively, after adjustment for demographic characteristics and lifestyle. We found that an interquartile range (IQR) increase (15 μg/m3) in ozone exposure during the entire pregnancy was associated with a reduction (-28.96g, 95% confidence interval [CI]: -46.37, -11.56) in the total birth weight of twins, and ozone had a more pronounced impact on the birth weight of the smaller fetuses (-18.28 g, 95% CI: -27.22, -9.34) compared to the larger fetuses (-9.88 g, 95% CI: -18.84, -0.92) in twin pregnancies. An IQR increase in ozone exposure during the entire pregnancy was associated with a significant increase (8.41 g, 95% CI: 4.13, 12.69) in the within-pair birth weight difference; the odds ratio (OR) of twin growth discordance related to ozone exposure increased by 9% (OR = 1.09, 95% CI: 1.01, 1.18). However, no consistently significant associations were observed for ozone exposure during prepregnancy. Male-male twin pairs and those who were born prematurely appeared to be more susceptible to ozone exposure than their counterparts. Long-term ozone exposure during pregnancy was associated with twin growth discordance, and our findings provide reference data for future studies.

Cardiometabolic Effects of Omnivorous vs Vegan Diets in Identical Twins

Increasing evidence suggests that, compared with an omnivorous diet, a vegan diet confers potential cardiovascular benefits from improved diet quality (ie, higher consumption of vegetables, legumes, fruits, whole grains, nuts, and seeds). To compare the effects of a healthy vegan vs healthy omnivorous diet on cardiometabolic measures during an 8-week intervention. This single-center, population-based randomized clinical trial of 22 pairs of twins (N = 44) randomized participants to a vegan or omnivorous diet (1 twin per diet). Participant enrollment began March 28, 2022, and continued through May 5, 2022. The date of final follow-up data collection was July 20, 2022. This 8-week, open-label, parallel, dietary randomized clinical trial compared the health impact of a vegan diet vs an omnivorous diet in identical twins. Primary analysis included all available data. Twin pairs were randomized to follow a healthy vegan diet or a healthy omnivorous diet for 8 weeks. Diet-specific meals were provided via a meal delivery service from baseline through week 4, and from weeks 5 to 8 participants prepared their own diet-appropriate meals and snacks. The primary outcome was difference in low-density lipoprotein cholesterol concentration from baseline to end point (week 8). Secondary outcome measures were changes in cardiometabolic factors (plasma lipids, glucose, and insulin levels and serum trimethylamine N-oxide level), plasma vitamin B12 level, and body weight. Exploratory measures were adherence to study diets, ease or difficulty in following the diets, participant energy levels, and sense of well-being. A total of 22 pairs (N = 44) of twins (34 [77.3%] female; mean [SD] age, 39.6 [12.7] years; mean [SD] body mass index, 25.9 [4.7]) were enrolled in the study. After 8 weeks, compared with twins randomized to an omnivorous diet, the twins randomized to the vegan diet experienced significant mean (SD) decreases in low-density lipoprotein cholesterol concentration (-13.9 [5.8] mg/dL; 95% CI, -25.3 to -2.4 mg/dL), fasting insulin level (-2.9 [1.3] μIU/mL; 95% CI, -5.3 to -0.4 μIU/mL), and body weight (-1.9 [0.7] kg; 95% CI, -3.3 to -0.6 kg). In this randomized clinical trial of the cardiometabolic effects of omnivorous vs vegan diets in identical twins, the healthy vegan diet led to improved cardiometabolic outcomes compared with a healthy omnivorous diet. Clinicians can consider this dietary approach as a healthy alternative for their patients. ClinicalTrials.gov Identifier: NCT05297825.

On the co-nucleation of adjoining twin pairs at grain boundaries in hexagonal close-packed materials

This work addresses the formation of adjoining twin pairs (ATPs) at grain boundaries (GBs) in hexagonal close-packed (hcp) metals from the perspective of the co-nucleation (CN) of pairs of deformation twins. A continuum defect mechanics model is proposed to investigate the energetic feasibility of the CN of ATPs resulting from the dissociation of GB dislocations. Application of the model to a set of GBs in Mg reveals that CN is largely preferred over the nucleation of a single twin variant for low misorientation angle GBs, which is consistent with previous experimental analyses. The CN events are subsequently analyzed considering the GB character, and the twin system alignment (m′) and Schmid factors to obtain better insights into the conditions governing the formation of ATPs via CN. The likelihood of CN even at low m′ values reveals that CN events could be responsible for the formation of ATP pairs in these scenarios.

Attention-deficit/hyperactivity disorder symptoms and subsequent cardiometabolic disorders in adults: investigating underlying mechanisms using a longitudinal twin study

BackgroundEmerging research suggests that attention-deficit/hyperactivity disorder (ADHD) increases the risk for cardiovascular (CVDs) and metabolic disorders (i.e., cardiometabolic disorders) in adulthood. Yet, available studies are scarce and have mainly been focused on individuals receiving clinical ADHD diagnoses. We aimed to investigate the prospective associations of ADHD symptoms in young and mid-adulthood with subsequent cardiometabolic disorders and the underlying mechanisms.MethodsWe studied 10,394 twins from the Swedish Twin Registry (STR), born between 1958 and 1985 without previous medical history of cardiometabolic disorders. They provided self-assessment of ADHD symptoms (score range 0–36) via a validated, DSM-IV-based scale in a web-based questionnaire/telephone interview within the Study of Twin Adults: Genes and Environment (STAGE), in 2005–2006 (aged 19–47 years), and were followed until the end of 2018 (33–59 years) to identify incident clinical diagnoses/medication prescriptions for cardiometabolic disorders acquired from Swedish national registers. We used Cox regression models to investigate the associations between ADHD symptoms score and cardiometabolic outcomes, with and without adjustment for relevant covariates, and a co-twin control design to study familial confounding.ResultsA one-unit increase in the level of ADHD symptoms was associated with a 2% increase in the rate of CVDs (hazard ratio [HR] = 1.02, 95% confidence interval 1.01–1.04) and a 3% increase in the rate of metabolic disorders (HR = 1.03, 1.02–1.05), after adjusting for birth year and sex. The associations were no longer significant after adjusting for educational attainment, lifestyle factors, and comorbid psychiatric disorders. The associations remained significant after adjusting for familial factors shared by dizygotic twin pairs but became nonsignificant after adjusting for factors shared by monozygotic twin pairs. However, the strength of the associations attenuated significantly in monozygotic twins compared to dizygotic twins for CVDs only, suggesting genetic confounding.ConclusionsADHD symptom score is associated with a higher risk for cardiometabolic disorders, which may be explained by lower educational attainment, adverse lifestyle factors, and psychiatric comorbidities. Moreover, the associations appear to be partly confounded by shared genetic factors, especially for CVDs. Further research is needed to investigate the identified associations at the level of individual cardiometabolic disorders and to follow-up participants until a more advanced older age.

Genetic and environmental influences on early-age susceptibility and initiation of nicotine-containing product use: A twin-pairs study.

Nicotine-containing products (NCPs) such as electronic nicotine delivery systems (ENDS) are increasingly common throughout the landscape of youth use of nicotine-containing products (NCP), and have overtaken traditional cigarette smoking modalities. This study seeks to examine the genetic and environmental influences on liability for susceptibility and initiation of ENDS and other NCPs among US children. Data were drawn from 886 monozygotic (MZ) and dizygotic (DZ) twin pairs aged 9-10 years in the Adolescent Brain & Cognitive Development (ABCD) study at the baseline during 2016-2018. Heritability (h2) measured the proportion of the total phenotypic variation attributable to genes. Variance component models were utilized to analyze influences from the common environment (c2) and unique environmental factors (e2), taking into account correlations within twin pairs. The national sample included 50% females, 69.5% of non-Hispanic Whites, 12.8% of non-Hispanic Blacks, and 11.6% of Hispanics, with a mean age of 121.5 months. The twin sets were 60% DZ and 40% MZ. Heritability was low for NCP susceptibility (h2=0) and moderate for NCP initiation (h2=39%, p=0.02). The variance associated with NCP susceptibility was primarily influenced by environmental factors, especially one's unique factors (c2=37%, p<0.0001 vs e2=63%, p<0.0001). In contrast, the variance associated with NCP initiation was split across common and unique environmental factors (c2=32%, p=0.02 vs e2=29%, p=0.02). In the era with ENDS use surging among youth, NCP initiation remains to be a heritable trait with joint influence from the environment. NCP susceptibility is largely influenced by environmental factors, especially unique environments. Continued assessment of gene × environment interaction can better inform future youth NCP interventions.

Polygenic risk of obesity and BMI trajectories over 36 years: A longitudinal study of adult Finnish twins.

This study investigated 36-year BMI trajectories in twins whose BMI in young adulthood was below, within, or above their genetically predicted BMI, with a focus on twin pairs with large intrapair BMI differences (within-pair ΔBMI ≥ 3 kg/m2 ). Together, 3227 like-sexed twin pairs (34% monozygotic) were examined at age ~30 years in 1975 and followed up in 1981, 1990, and 2011. An individual's observed BMI in 1975 was considered within (±2.0), below (<-2.0), or above (>+2.0) genetically predicted BMI, measured by a polygenic risk score of 996,919 single nucleotide polymorphisms. In monozygotic and dizygotic twin pairs with large intrapair BMI differences, the co-twin with a higher observed BMI in 1975 deviated above predicted BMI more frequently (~2/3) than the co-twin with a lower BMI deviated below prediction (~1/3). Individuals below, within, and above prediction in 1975 reached, respectively, normal weight, overweight, and obesity by 2011, with a mean BMI increase of 4.5 (95% CI: 4.3-4.8). Categorizing BMI as below, within, or above polygenic risk score-predicted BMI helps identifying individuals who have been resistant or susceptible to weight gain. This may provide new insights into determinants and consequences of obesity.

Impedance cardiogram based exploration of cardiac mechanisms in post-traumatic stress disorder during trauma recall.

Post-traumatic stress disorder (PTSD) is an independent risk factor for developing heart failure; however, the underlying cardiac mechanisms are still elusive. This study aims to evaluate the real-time effects of experimentally induced PTSD symptom activation on various cardiac contractility and autonomic measures. We recorded synchronized electrocardiogram and impedance cardiogram from 137 male veterans (17 PTSD, 120 non-PTSD; 48 twin pairs, 41 unpaired singles) during a laboratory-based traumatic reminder stressor. To identify the parameters describing the cardiac mechanisms by which trauma reminders can create stress on the heart, we utilized a feature selection mechanism along with a random forest classifier distinguishing PTSD and non-PTSD. We extracted 99 parameters, including 76 biosignal-based and 23 sociodemographic, medical history, and psychiatric diagnosis features. A subject/twin-wise stratified nested cross-validation procedure was used for parameter tuning and model assessment to identify the important parameters. The identified parameters included biomarkers such as pre-ejection period, acceleration index, velocity index, Heather index, and several physiology-agnostic features. These identified parameters during trauma recall suggested a combination of increased sympathetic nervous system (SNS) activity and deteriorated cardiac contractility that may increase the heart failure risk for PTSD. This indicates that the PTSD symptom activation associates with real-time reductions in several cardiac contractility measures despite SNS activation. This finding may be useful in future cardiac prevention efforts.

Safety of omalizumab in chronic urticaria during pregnancy: a real-life study.

Managing a pregnant patient with chronic spontaneous urticaria (CSU) is often challenging. Recent data have shown that most CSU treatments in pregnant patients are second-generation H1 antihistamines (sgAHs), while data on the safety of omalizumab are scant. To evaluate, in a routine clinical practice setting, the efficacy and safety of omalizumab in patients with severe CSU refractory to sgAHs who either became pregnant during treatment or who started the drug during pregnancy. We conducted a retrospective study of women aged ≥ 18 years who were pregnant, who received one or more doses of omalizumab at any time during their pregnancy or who were taking omalizumab at the time of, or in the 8 weeks before, conception. Twenty-nine pregnant patients were evaluated: 23 (79%) conceived a child while taking omalizumab (group A), while 6 (21%) started omalizumab treatment during pregnancy (group B). Among patients in group A, we observed 23 births (21 liveborn singletons and 1 liveborn twin pair) and 1 miscarriage. Fifteen (65%) patients discontinued omalizumab after confirming their pregnancy, while eight (35%) were exposed to omalizumab during their entire pregnancy. In group B, omalizumab was introduced at a mean (SD) 10.83 (3.60) weeks' gestation and all patients were exposed to it until the end of pregnancy. In this group, there were seven liveborn infants (five singletons and one twin pair). No adverse events, pregnancy complications or congenital anomalies in newborns were recorded in either group. Omalizumab for CSU treatment before and during pregnancy does not appear to have negative effects on maternal or fetal outcomes.

Concomitant coronary artery disease development in identical twins: a case report and a systematic literature review

Abstract Case summary: Two 47-year-old monozygotic male twins presented to a tertiary hospital with chest pain (having a 3-month difference in their presentation). They were both smokers without any other standard modifiable risk factor or positive family history. Coronary angiograms of both twins demonstrated concordant coronary anatomy and obstructive CAD in two major epicardial coronary vessels with nearly identical lesions. Lipoprotein(a) [lp(a)] levels were substantially elevated in both twins (170 and 120 mg/dl respectively). Aiming to explain the almost identical CAD observed, next-generation whole-exome sequencing analyses were performed; however, no disease-causing CAD- or lp(a)-related mutation could be identified. Background The occurrence of CAD is strongly affected by genetic, epigenetic and environmental factors. Currently, a growing yet heterogeneous body of evidence reports the development of concomitant CAD in identical twins; however, no systematic approach has been attempted so far to gather and quantify the existing evidence. Methods A systematic literature review was conducted by searching for original studies in PubMed, WebOfScience and Scopus databases through February 28, 2023 to identify every study reporting the incidence of CAD in monozygotic twin pairs according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and predetermined eligibility criteria (https://doi.org/10.17605/OSF.IO/TWXKP). Results Our search yielded 28 eligible studies encompassing a total of 37 monozygotic twin pairs suffering from CAD and presenting (simultaneously most of them) with acute coronary syndrome (mean age of presentation: 46 years, male percentage: 78%). Coronary angiograms demonstrated lesion and anatomy concordance at a 86% and 79% of the twin pairs, respectively. Concordance of the standard modifiable (environmental) cardiovascular risk factors was identified in at least 75% of the twin pairs, whereas only 4 genetic polymorphisms were identified (i.e., erythrocyte/leucocyte, ACE, LDLR, APOB genes and HLA polymorphisms). Conclusion This is the first systematic literature review of studies reporting identical twin pairs who suffer concomitantly from CAD. Most pairs shared similar environmental risk factors; however, their premature CAD could not be sufficiently explained in most cases leading us to speculate underlying (non-recognized) epigenetic interplay. Monozygotic twin studies -unbiased by age effects- can provide insights into CAD heritability on the grounds of their ability to disentangle the traditional dyad of genetic and environmental factors. Given the limited evidence on disease-causing mutations in the eligible studies, future twin studies are warranted to shed light on non-investigated genetic polymorphisms [such as lp(a)-related single nucleotide polymorphisms] and investigate the within-pair epigenetic drift through novel biomarkers of epigenetic regulation.PRISMA flow diagram of the reviewConcordance of CAD-related risk factors

Epigenetic study of the differential phenotypic expression of a hypertrophic cardiomyopathy-related pathological variant at MYBPC3 in a cohort of monozygotic twins

Abstract Introduction Hypertrophic cardiomyopathy (HCM) is a inherited cardiac disease with a variable penetrance and expressivity. Epigenetics orchestrates the interplay between the environment and the molecular changes that lead to the development of the pathological phenotype. It is of great interest to identify the changes that determine the magnitude of left ventricular hypertrophy (LVH) in patients carrying a given pathogenic variant. Methods In this work, we used peripheral blood samples from a cohort of three homozygous twin pairs carrying the p.Gly263Ter pathogenic variant at MYBPC3 gene to suppress the underlying genetic effect and isolate the role of DNA methylation in its divergent phenotypic expressivity. Results We found a poorer life-style and a more anxious personality among the more severely affected patients. Using a pair-matched model corrected by cell type proportions, a total of 2486 differentially methylated positions (DMP) were extracted with moderate but proportional methylation changes to the LVH of the patients. DMP were enriched in functional regions controlled by repressor histone marks (H3K27me3, H3K9me3) and tended to colocalise forming differentially methylated regions (DMR) across genes mainly related to homophilic surface adhesion molecules and Ca2+ transport. Strikingly, many affected genes were found to be involved in LVH development, such as PLSCR2, ELMO3, TRIM68, HOXA5, UCN3, PCDHGA3, PAX8-AS1, suggesting that the analysis of blood samples could be able to recapitulate alterations at cardiac tissue level. Furthermore, the relationship of the observed changes with the development of the pathology was successfully validated with an external cohort of peripheral blood samples from healthy patients. Further studies are needed to validate the observed changes at cardiac tissue and to verify their causal role. Conclusions In this cohort of monozygotic twins we were able to identify promising epigenetic peripheral blood changes that relate to the expressivity of the HCM. Anxious personalities and lifestyle divergences could lie behind our findings. DNA methylation changes tend to locate at key positions related to cell-to-cell communication and Ca2+ metabolism, as well as at other loci already described to regulate LVH and stress.

Abstract 13063: Gut Microbiota-Derived Metabolites and Cardiometabolic Traits: Findings From a Monozygotic Twin Study

Introduction: Microbial metabolites are small chemical compounds produced by gut microbiota when it breaks down food, chemicals, or other environmental exposures. These metabolites serve as signaling molecules between the host and gut microbiota and regulate numerous aspects of host physiology, immunity, and metabolism. Hypothesis: Gut dysbiosis is associated with cardiometabolic disorders via alterations in microbial metabolites. Aims: To identify gut-microbiota-derived metabolites associated with cardiometabolic traits. Methods: Using hydrophilic interaction liquid chromatography (HILIC), we measured the relative abundances of 62 food and gut-microbiota-derived metabolites in plasma sample of 46 complete monozygotic twin pairs (34 female-female pairs, 12 male-male pairs, mean age 36.2) enrolled in the Mood and Methylation Study (MMS), an observational study designed to identify biomarkers associated with depressive symptoms using a twin design. Information for cardiometabolic traits, including body mass index, waist circumference, blood glucose, HbA1c, insulin, triglycerides, total cholesterol, HDL and LDL, was collected using standard questionnaires or laboratory methods. The association of each metabolite with cardiometabolic trait was examined by a linear mixed-effects model, adjusting for age, sex, smoking, drinking, and depressive symptoms. The co-twin correlation was accounted for by including twin pair as a random effect in the model. Results: After correction for multiple testing by false discovery rate (FDR&lt;0.05), 15 microbial metabolites were significantly associated with one or more cardiometabolic traits. Of these, 7 glycerophospholipids (e.g., PC(32:1), PC(34:4), PE(38:6)) and 2 sphingomyelins (i.e., SM(d36:1), SM(d36:2)) were positively, whereas betaine, creatinine, urea, pipecolic acid, N1, N12-diacetylspermine, and 3-chloro-L-tyrosine were negatively associated with LDL, triglycerides, total cholesterol, and HbA1c. Conclusions: Our results revealed novel microbial metabolites associated with cardiometabolic traits and support their potentially important role in mediating the interactions between gut microbiota and host pathophysiology.

Abstract 16300: Genetic Influences on Cardiovascular Deaths During Various Follow-Up Lengths in the 45-Year Longitudinal Twin Study

Background: Genetic factors are known to affect cardiovascular and coronary heart death. The more deaths occur during the longer follow-up period in a longitudinal study. However, it is unclear whether follow-up lengths affect genetic influences on the mortality from total cardiovascular (CVD) and coronary heart diseases (CHD). Objective: To determine genetic influences on the mortality from CVD and CHD over various years of follow-up in the 45-year longitudinal National Heart, Lung, and Blood Institute (NHLBI) Twin Study. Method: A total of 1024 middle-aged, white male, veteran twins (512 pairs), including 253 monozygotic and 261 dizygotic twin pairs, were initially enrolled during 1969-1973 and then followed up on vital status and causes of death through December 31, 2015. Tetrachoric correlation coefficients were estimated for CHD and CVD death at 20, 30, and 45 years of follow-up, respectively. Genetic and environmental influences on the death were quantified using the best-fitting structural equation model selected with the smallest Akaike's Information Criterion value and the parsimony rule. Results: The age at death ranged from 43.9 to 97.3 years over a 45-year follow-up. Tetrachoric correlation coefficients in dizygotic twins were less than half of that in monozygotic twins over 20, 30, and 45 years of follow-up for CVD but over 20 and 30 years for CHD, respectively. Dominant genetic factors explained 40% (95% CI 5% ~ 68%), 39 % (16% ~ 59%), and 24% (4% ~ 43%) of variation in CVD death over 20, 30, and 45 years of follow-up, respectively, while the remaining variation in CVD death was explained by unique environmental factors during each follow-up period. For CHD death, unique environmental factors explained all variation over 20 and 45 years of follow-up. By contrast, dominant genetic factors explained 26% (95% CI -6% ~ 53%) variation in CHD death over 30 years of follow-up while the remaining variation was explained by unique environmental factors. Conclusion: Dominant genetic factors consistently influence cardiovascular mortality over 20 to 45 years of follow-up, implying a twin study of cardiovascular death can control for genetic confounding during this period.