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Background: Hypertrophic cardiomyopathy is an autosomal dominant cardiac disease. The mechanisms that determine its variable expressivity are poorly understood. Epigenetics could play a crucial role in bridging the gap between genotype and phenotype by orchestrating the interplay between the environment and the genome regulation. In this study we aimed to establish a possible correlation between the peripheral blood DNA methylation patterns and left ventricular hypertrophy severity in patients with hypertrophic cardiomyopathy, evaluating the potential impact of lifestyle variables and providing a biological context to the observed changes., Methods and Results: Methylation data were obtained from peripheral blood samples (Infinium MethylationEPIC BeadChip arrays). We employed multiple pair-matched models to extract genomic positions whose methylation correlates with the degree of left ventricular hypertrophy in 3 monozygotic twin pairs carrying the same founder pathogenic variant ( MYBPC3 p.Gly263Ter). This model enables the isolation of the environmental influence, beyond age, on DNA methylation changes by removing the genetic background. Our results revealed a more anxious personality among more severely affected individuals. We identified 56 differentially methylated positions that exhibited moderate, proportional changes in methylation associated with left ventricular hypertrophy. These differentially methylated positions were enriched in regions regulated by repressor histone marks and tended to cluster at genes involved in left ventricular hypertrophy development, such as HOXA5 , TRPC3 , UCN3 , or PLSCR2 , suggesting that changes in peripheral blood may reflect myocardial alterations., Conclusions: We present a unique pair-matched model, based on 3 monozygotic twin pairs carrying the same founder pathogenic variant and different phenotypes. This study provides further evidence of the pivotal role of epigenetics in hypertrophic cardiomyopathy variable expressivity.

Blood biomarkers of multiple sclerosis (MS) can provide a better understanding of pathophysiology and enable disease monitoring. Here, we performed quantitative shotgun lipidomics on the plasma of a unique cohort of 73 monozygotic twins discordant for MS. We analyzed 243 lipid species, evaluated lipid features such as fatty acyl chain length and number of acyl chain double bonds, and detected phospholipids that were significantly altered in the plasma of co-twins with MS compared to their non-affected siblings. Strikingly, changes were most prominent in ether phosphatidylethanolamines and ether phosphatidylcholines, suggesting a role for altered lipid signaling in the disease., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: A variety of DNA-based methods have been applied to identify genetic markers of attention deficit hyperactivity disorder (ADHD), but the connection to RNA-based gene expression has not been fully exploited., Methods: Using well defined cohorts of discordant, monozygotic twins from the Michigan State University Twin Registry, and case-controlled ADHD cases in adolescents, the present studies utilized advanced single molecule RNA sequencing to identify expressed changes in whole blood RNA in ADHD. Multiple analytical strategies were employed to narrow differentially expressed RNA targets to a small set of potential biomarkers of ADHD., Results: RNA markers common to both the discordant twin study and case-controlled subjects further narrowed the putative targets, some of which had been previously associated with ADHD at the DNA level. The potential role of several differentially expressed genes, including ABCB5, RGS2, GAK, GIT1 and 3 members of the galactose metabolism pathway (GALE, GALT, GALK1) are substantiated by prior associations to ADHD and by established mechanistic connections to molecular pathways relevant to ADHD and behavioral control., Conclusions: The convergence of DNA, RNA, and metabolic data suggests these may be promising targets for diagnostics and therapeutics in ADHD.

Background and Aims: Studies of twins can reduce confounding and provide additional evidence about the causes of disease, due to within-pair matching for measured and unmeasured factors. Although findings from twin studies are typically applicable to the general population, few studies have taken full advantage of the twin design to explore the developmental origins of cardiometabolic health outcomes. We aimed to systematically review the evidence from twin studies and generate pooled estimates for the effects of early-life risk factors on later-life cardiometabolic health., Methods and Results: An initial search was conducted in March 2018, with 55 studies of twins included in the review. Risk of bias was assessed using the Newcastle-Ottawa Scale, and eligible studies were included in a meta-analysis, where pooled estimates were calculated. Twenty-six studies analysed twins as individuals, and found that higher birthweight was associated with lower SBP (β = -2.02 mmHg, 95%CI: -3.07, -0.97), higher BMI (β = 0.52 kg/m 2 , 95%CI: 0.20, 0.84) and lower total cholesterol (β = -0.07 mmol/L, 95%CI: -0.11, -0.04). However, no associations were reported in studies which adjusted for gestational age. Few of the included studies separated their analyses into within-pair and between-pair associations., Conclusions: Early-life risk factors were associated with cardiometabolic health outcomes in twin studies. However, many estimates from studies in this review were likely to have been confounded by gestational age, and few fully exploited the twin design to assess the developmental origins of cardiometabolic health outcomes., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Homozygous familial hypercholesterolemia (HoFH) is a rare, autosomal dominant disease that leads to premature cardiovascular disease (CVD). Since monozygotic twins share the intrauterine environment and have the same age and gene profile, they could represent a very special resource for the investigation of the causes and the natural course of FH. This report is a description of 36-year-old monozygotic twin brothers with almost identical early coronary artery involvement due to FH concomitant with high lipoprotein(a) (Lpa) levels and a review of the literature. Sequence analysis revealed that the twins were homozygous for the LDLR c.1060+10G>A (rs12710260) mutation and heterozygous for the LDLR c.542C>T (rs557344672) mutations. Both were also homozygous for the c.1060+7T>C (rs2738442) and c.1586+53A>G (rs1569372) mutations in the LDLR gene as well as c.4265A>T (rs568413) mutations in the APOB gene. In the literature, there are 7 twin cases with reported FH, but none with high Lpa levels. The HoFH twins in this case report had lower low-density lipoprotein (LDL) cholesterol levels than expected (before treatment 204 and 223 mg/dL), with almost identical coronary involvement. Both had an extremely high Lpa level (308 and 272 nmol/L) with a very low coronary calcium score (16 AU) and a good response to statins (>60%). There was a history of the first CVD event occurring at nearly the same age (32-34 years) in the family. This could be an important aspect of FH families as a result of the similar timing of cumulative LDL exposure exceeding the threshold of CVD events. In conclusion, this first report of monozygotic HoFH twins with elevated Lpa levels and almost identical early coronary artery involvement at the same age provides evidence to substantiate the hypothesis of lifetime cholesterol burden/exposure.

Fetal atrioventricular block is a rare pathology, mostly due to placental transmission of maternal SSA/Ro and SSB/La antibodies, and can lead to severe fetal or neonatal outcomes. We report a case of dichorionic, diamniotic twin pregnancy, with maternal SSA/Ro antibodies. Isolated complete atrioventricular block was diagnosed at 23 weeks in one fetus (Twin A), while the second fetus (Twin B) remained in normal sinus rhythm. Severe asymmetric intrauterine growth restriction occurred in Twin A. Delivery was by caesarean section at 32 + 2 weeks. Neonatal permanent pacemaker was inserted on the first day after birth in 1140 g neonate. Discordant heart block in twin pregnancy has already been reported in a few dichorionic pregnancies, but the pathway of discordant disease expression remains unclear. Extraction decision is a dilemma between cardiac failure prevention and prematurity associated twin morbidity. This case shows a successful pacing in a very low birth weight neonate., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Background: Alzheimer's disease results from a neurodegenerative process that starts well before the diagnosis can be made. New prognostic or diagnostic markers enabling early intervention into the disease process would be highly valuable. Environmental and lifestyle factors largely modulate the disease risk and may influence the pathogenesis through epigenetic mechanisms, such as DNA methylation. As environmental and lifestyle factors may affect multiple tissues of the body, we hypothesized that the disease-associated DNA methylation signatures are detectable in the peripheral blood of discordant twin pairs., Results: Comparison of 23 disease discordant Finnish twin pairs with reduced representation bisulfite sequencing revealed peripheral blood DNA methylation differences in 11 genomic regions with at least 15.0% median methylation difference and FDR adjusted p value ≤ 0.05. Several of the affected genes are primarily associated with neuronal functions and pathologies and do not display disease-associated differences in gene expression in blood. The DNA methylation mark in ADARB2 gene was found to be differentially methylated also in the anterior hippocampus, including entorhinal cortex, of non-twin cases and controls. Targeted bisulfite pyrosequencing of the DNA methylation mark in ADARB2 gene in 62 Finnish and Swedish twin pairs revealed that, in addition to the disease status, DNA methylation of this region is influenced by gender, age, zygosity, APOE genotype, and smoking. Further analysis of 120 Swedish twin pairs indicated that this specific DNA methylation mark is not predictive for Alzheimer's disease and becomes differentially methylated after disease onset., Conclusions: DNA methylation differences can be detected in the peripheral blood of twin pairs discordant for Alzheimer's disease. These DNA methylation signatures may have value as disease markers and provide insights into the molecular mechanisms of pathogenesis. We found no evidence that the DNA methylation marks would be associated with gene expression in blood. Further studies are needed to elucidate the potential importance of the associated genes in neuronal functions and to validate the prognostic or diagnostic value of the individual marks or marker panels.

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

Objectives: To explore the relative contributions of genetic and environmental influences on dental caries risk and to investigate fetal and developmental risk factors for dental caries., Methods: We recruited children from 250 twin pregnancies midgestation and collected demographic, health, and phenotypic data at recruitment, 24 and 36 weeks' gestational age, birth and 18 months, and 6 years of age. 25-hydroxyvitamin D was quantified in mothers at 28 weeks' gestation and in infants at birth. Dental caries and enamel defects were measured at six years of age. We compared concordance for the presence of any caries and advanced caries in monozygotic and dizygotic twin pairs. To investigate environmental risk factors for caries, we fitted multiple logistic regression models using generalized estimating equations to adjust for twin correlation., Results: A total of 345 twins underwent dental assessment, with 111 (32.2%) showing signs of any caries and 83 (24.1%) having advanced caries. There was no evidence of higher concordance in monozygotic twins compared with dizygotic twins, with a difference of 0.05 (95% confidence interval -0.14 to 0.25; P = .30) and 0.00 (95% confidence interval -0.26 to 0.26; P = .50) for any caries and advanced caries, respectively, suggesting that environmental factors, rather than genetics, are the predominant determinant of caries risk. After adjusting for potential confounders, lack of community water fluoridation, hypomineralized second primary molars, dichorionic placenta, and maternal obesity were associated with caries., Conclusions: Environmental rather than genetic factors drive dental caries risk and arise as early as prenatal life., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

Background: Familial hypercholesterolaemia (FH) is the most common inherited metabolic disease with an autosomal dominant mode of inheritance. It is characterised by raised serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c), leading to premature coronary artery disease. Children with FH are subjected to early and enhanced atherosclerosis, leading to greater risk of coronary events, including premature coronary artery disease. To the best of our knowledge, this is the first report of a pair of monochorionic diamniotic identical twins with a diagnosis of heterozygous FH, resulting from mutations in both LDLR and ABCG8 genes., Case Presentation: This is a rare case of a pair of 8-year-old monochorionic diamniotic identical twin, who on family cascade screening were diagnosed as definite FH, according to the Dutch Lipid Clinic Criteria (DLCC) with a score of 10. There were no lipid stigmata noted. Baseline lipid profiles revealed severe hypercholesterolaemia, (TC = 10.5 mmol/L, 10.6 mmol/L; LDL-c = 8.8 mmol/L, 8.6 mmol/L respectively). Their father is the index case who initially presented with premature CAD, and subsequently diagnosed as FH. Family cascade screening identified clinical FH in other family members including their paternal grandfather who also had premature CAD, and another elder brother, aged 10 years. Genetic analysis by targeted next-generation sequencing using MiSeq platform (Illumina) was performed to detect mutations in LDLR, APOB100, PCSK9, ABCG5, ABCG8, APOE and LDLRAP1 genes. Results revealed that the twin, their elder brother, father and grandfather are heterozygous for a missense mutation (c.530C > T) in LDLR that was previously reported as a pathogenic mutation. In addition, the twin has heterozygous ABCG8 gene mutation (c.55G > C). Their eldest brother aged 12 years and their mother both had normal lipid profiles with absence of LDLR gene mutation., Conclusion: A rare case of Asian monochorionic diamniotic identical twin, with clinically diagnosed and molecularly confirmed heterozygous FH, due to LDLR and ABCG8 gene mutations have been reported. Childhood FH may not present with the classical physical manifestations including the pathognomonic lipid stigmata as in adults. Therefore, childhood FH can be diagnosed early using a combination of clinical criteria and molecular analyses.

Background: The fasting-state serum bile acid profile in nonalcoholic fatty liver disease (NAFLD) has been reported to differ when nonalcoholic steatohepatitis is compared to nonalcoholic fatty liver. However, there are few data comparing changes in NAFLD vs non-NAFLD, or whether the bile acid profile differs according to the degree of fibrosis., Aim: To examine the serum bile acid profile across the entire spectrum of NAFLD., Methods: We performed a cross-sectional analysis of two complementary cohorts: a Twin and Family cohort of 156 participants, and a biopsy-proven-NAFLD cohort of 156 participants with fasting bile acid profiling using liquid chromatography/mass spectrometry., Results: In the Twin and Family cohort (mean age 46.3 years and body mass index (BMI) 26.6 kg/m 2 ), 36 (23%) participants had NAFLD (magnetic resonance imaging proton density fat fraction ≥ 5%). Higher chenodeoxycholyl conjugates (9.0% vs 6.5%, P = 0.019) and lower glycohyocholate (1.2% vs 3.6%, P < 0.001) were observed in NAFLD compared to non-NAFLD-controls. In the biopsy-proven-NAFLD cohort (mean age 49.8 years, BMI 32.0 kg/m 2 ), no differences in total bile acid were seen between nonalcoholic fatty liver vs nonalcoholic steatohepatitis. The total unconjugated bile acid significantly decreased across nonalcoholic steatohepatitis categories (P = 0.044). The distribution of stage of fibrosis was F0: 42.3%, F1: 32.7%, F2: 10.3%, F3: 8.3% and F4: 6.4%. The total serum bile acid increased with increase in fibrosis stage (P < 0.001). The primary conjugated bile acid proportion increased (P < 0.001) whereas unconjugated bile acid (P = 0.006), unconjugated cholyl (P < 0.001) and chenodeoxycholyl conjugates (P < 0.002) significantly decreased with increase in liver fibrosis stage., Conclusions: Fasting-state serum bile acid profile alterations are seen across the entire spectrum of NAFLD. The total serum bile acids did not differ significantly between NAFLD vs non-NAFLD and nonalcoholic fatty liver vs nonalcoholic steatohepatitis, but were significantly perturbed progressively as liver fibrosis increases., (© 2018 John Wiley & Sons Ltd.)

Our report details the workup and management of a 43-year-old woman with an identical twin who presented with 2 years of virilization and secondary amenorrhea. Serum total testosterone was elevated. An MRI did not identify adnexal or adrenal pathology. Subsequent ovarian vein sampling demonstrated unilateral testosterone elevation. The patient underwent laparoscopic unilateral oophorectomy resulting in the diagnosis of Sertoli-Leydig cell tumor (SLCT). Although SLCT is a rare sex-cord ovarian tumor, it is associated with endometrial hyperplasia and malignancy. Our goals are to review the workup of androgen-secreting tumors and discuss the clinical importance of the DICER1 mutation in the context of SLCT. In this case, an identical twin underwent DICER1 testing which was one of the essential steps in her clinical management.

We aim to examine if circulating micro-RNA and cytokine levels associate with dementia diagnosis and cognitive scores. To test our hypothesis, we use plasma donated from 48 monozygotic twin pairs in 1997 and 46 micro-RNAs and 10 cytokines were quantified using microfluidic RT-qPCR and multiplex solid-phase immunoassays, respectively. Micro-RNA and cytokine profiling were examined for associations with dementia diagnoses in a longitudinal registry study or with cognitive scores at baseline. Thirty-six micro-RNAs and all cytokines were detected consistently. Micro-RNA profiles associate with diagnoses and cognitive scores at statistically significant levels while cytokine only showed trends pointing at chronic inflammation in twins having or developing dementia. The most notable findings were decreased miR-106a and miR-210, and increased miR-106b expression in twins with a dementia diagnosis. This pioneering evaluation of micro-RNA and cytokine and dementia diagnosis suggests micro-RNA targets in vasculogenesis, lipoprotein transport, and amyloid precursor protein genes.

Microdeletions of 20q11.2 are rare but have been associated with characteristic clinical findings. A 1.6 Mb minimal critical region has been identified that includes three OMIM genes: GDF5, EPB41L1, and SAMHD. Here we describe a male monozygotic, monochorionic-diamniotic twin pair with discordant phenotypes, one with multiple findings that overlap with those reported in 20q11.2 deletions, and the other unaffected. Microarray analysis revealed mosaicism for a 363 Kb deletion encompassing GDF5 in the peripheral blood of both twins, which was confirmed by FISH. Subsequent FISH on buccal cells identified the deletion only in the affected twin. The blood FISH findings were interpreted as representing chimerism resulting from anastomosis and the blood exchange between the twins in utero. The implications of this finding are discussed, as is the contribution of GDF5 to the associated clinical findings of 20q11.2 deletions., (© 2017 Wiley Periodicals, Inc.)

Determination of the soluble fms-like tyrosine kinase-1 to placental growth factor ratio (sFlt-1/PlGF) in the maternal serum is expected to aid in the monitoring and decision-making process of women at risk for placental dysfunction. We report two cases of placental mesenchymal dysplasia (PMD) with sFlt-1/PlGF correlation. The first case is a dichorionic twin pregnancy with one fetus affected by PMD and Beckwith-Wiedemann syndrome in which a high value of sFlt-1/PlGF was found, coinciding with acute maternal and fetal wellbeing decline at 31 weeks. The second case corresponds to a singleton pregnancy diagnosed of PMD with normal sFlt-1/PlGF and favorable outcome.

Background: Intrauterine growth restriction (IUGR) is a risk factor for developing metabolic syndrome later in life. We explored whether adipokine concentrations in cord blood (CB) and on day 3 (D3) were related to impaired fetal growth and lipids in IUGR twins., Patients and Methods: Thirty-six discordant (birth weight [BW] discordance ≥20% calculated in relation to the heavier co-twins) and 42 concordant (BW discordance ≤ 10%) twin pairs were included., Results: In IUGR twins, both adiponectin/BW and triglyceride (TG) levels were significantly higher, while total cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol were lower in CB. On D3, both leptin and HDL-C levels were significantly lower and TG levels were significantly higher in IUGR twins. In the discordant group, the alterations in lipids were not related to any adipokine., Conclusions: IUGR is related to lower leptin level and proatherogenic lipid profile (higher TG and lower HDL-C), which are not influenced by adipokine at birth.

Lower vitamin D serum levels are linked to increased melanoma risk and poorer survival. Naevus counts are associated with both melanoma risk and survival and to leucocyte telomere length. Vitamin D is also linked to telomere biology with higher levels of vitamin D in individuals with longer leucocyte telomere length despite adjusting for age. Using the TwinsUK data, we explored the association between naevus count, leucocyte telomere length and vitamin D serum levels. Increasing vitamin D levels were associated with increasing naevus count: serum levels were 73.3 nmol/l in individuals with less than 50 naevi compared to 78.8 nmol/l in individuals with more than 50 naevi (p?=?0.002). In the final regression model, using naevus count as a continuous variable, vitamin D remained associated with higher naevus counts despite adjustment for age, weight, height, season of sampling and twin relatedness (p?=?0.02). Further adjustment for leucocyte telomere length, decreased the magnitude of the association but it remained significant so leucocyte telomere length is not the sole driver of this association. Having large numbers of naevi is associated with higher vitamin D serum levels.

Target genes in Alzheimer's disease (AD) have been identified. In monozygotic twins discordant for AD we analysed the expression of selected genes, and their possible regulation by epigenetic mechanisms in peripheral blood mononuclear cells, possibly useful to discover biomarkers. Amyloid precursor protein, sirtuin 1 and peptidyl prolyl isomerase 1 gene expressions were highly up-regulated in the AD twin versus the healthy one. Consistently with sirtuin 1 role in controlling acetylation status, we observed a substantial reduction of the acetylation on histone 3 lysine 9, associated with gene transcription in the AD twin. Noteworthy in the AD twin we also observed an increased gene expression in two histone deacetylases (HDACs) isoforms: HDAC2 and HDAC9. A general DNA hypomethylation of all gene promoters studied was also observed in both twins. Our results unravel transcriptional and epigenetic differences potentially helpful to better understand environmental factors and phenotypic differences in monozygotic twins., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: Human leucocyte antigen (HLA)-DRB1*13 alleles are associated with protection from anticitrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA). It is, however, unknown at which phase of disease development (seroconversion, ACPA maturation, disease onset or outcome) these alleles are most important. We therefore examined the effect of HLA-DRB1*13 on: ACPA presence (systemic autoimmunity associated with RA) in individuals with and without RA, on ACPA characteristics and on clinical outcome measures., Methods: The effect of HLA-DRB1*13 on ACPA presence in subjects with or without RA (non-RA) was assessed in the Swedish twin registry (n=10 748). ACPA characteristics were studied in patients with ACPA-positive RA from the Swedish Epidemiological Investigation of RA (EIRA, n=1224) and the Dutch Leiden Early Arthritis Clinic (EAC, n=441). Disease activity at inclusion and disease outcome (disease-modifying antirheumatic drugs (DMARD)-free sustained remission and radiographic progression) was assessed in patients with RA from the EAC., Results: HLA-DRB1*13 is associated with protection from ACPA-positive RA (prevalence 16% vs 28% in ACPA-negative non-RA), but not with significant protection from ACPA in individuals without RA (prevalence: 22%, p value 0.09). HLA-DRB1*13 is associated with lower ACPA-levels (EIRA: 447 U/ml versus 691 U/ml, p value= 0.0002) and decreased citrullinated epitope recognition (EIRA: p<0.0001). No association between HLA-DRB1*13 and disease activity or outcome was found., Conclusions: These data indicate that HLA-DRB1*13 mainly affects the onset of ACPA-positive RA in ACPA-positive non-RA individuals. In RA, HLA-DRB1*13 influences ACPA characteristics but not the disease course. This implies that therapeutic strategies aimed at emulating the HLA-DBR1*13 protective effect may be most effective in ACPA-positive healthy individuals at risk for RA., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Hypoxia is the primary stimulus for the production of erythropoietin (EPO) in both fetal and adult life. Here, we investigated fetal plasma EPO concentrations in monochorionic (MC) twin pregnancies with selective intrauterine growth restriction (sIUGR) and abnormal umbilical artery (UA) Doppler. We diagnosed sIUGR in presence of (1) birth-weight discordance >20% and (2) either twin with a birth weight <10th percentile. An abnormal UA Doppler was defined as a persistent absent-reverse end diastolic flow (AREDF). The intertwin EPO ratio was calculated as the plasma EPO level of the smaller (or small-for-gestational-age) twin divided by the EPO concentration of the larger (or appropriate-for-gestational-age (AGA)) twin. Thirty-two MC twin pairs were included. Of these, 17 pairs were normal twins (Group 1), seven pairs were twins with sIUGR without UA Doppler abnormalities (Group 2), and eight pairs were twins with sIUGR and UA Doppler abnormalities (Group 3). The highest EPO ratio was identified in Group 3 (p < .001) but no significant differences were observed between Groups 1 and 2. Fetal hemoglobin levels did not differ significantly in the three groups, and fetal EPO concentration did not correlate with gestational age at birth. We conclude that fetal plasma EPO concentrations are selectively increased in MC twin pregnancies with sIUGR and abnormal UA Doppler, possibly as a result of uncompensated hypoxia.

Objective: Twin neonates have a higher risk of respiratory complications, such as respiratory distress syndrome (RDS) and transient tachypnea of the newborn (TTN), than singleton neonates. The purpose of this study was to evaluate the relationship between the cortisol levels in the umbilical cord and neonatal RDS/TTN in twin pregnancies., Methods: We analyzed data obtained from 106 neonates (53 twin pairs), comprising 33 dichorionic twin (DCT) and 20 monochorionic twin (MCT) gestations. All infants were delivered via scheduled cesarean section without labor. We measured the cortisol levels in umbilical vein blood using enzyme-linked immunosorbent assay., Results: The cortisol levels in the umbilical vein were significantly lower in the RDS/TTN group than in the no RDS/TTN group (p = 0.004). The umbilical cortisol levels in the TTN group were between the values observed in the RDS group and no RDS/TTN group. We subsequently analyzed the cut-off cortisol values for RDS/TTN and observed higher accuracy in the DCTs than in the MCTs., Conclusions: Neonates who develop RDS/TTN have significantly lower cortisol levels in the umbilical cord at birth than no RDS/TTN neonates in twin pregnancies. When applying these data in clinical practice, physicians should pay attention to differences based on chorionicity.

Objective: The objective of this study is to investigate the effect of second trimester anemia on maternal and perinatal outcomes in twin pregnancies., Methods: A retrospective population-based study was conducted, comparing maternal and neonatal outcomes in women carrying twins, with second trimester anemia (defined as hemoglobin < 10 g/dl) to those without anemia (defined as hemoglobin > or equal to 10 g/dl). Deliveries occurred in a tertiary medical center in 2013., Results: During the study period, there were 307 twin deliveries. Hemoglobin levels were available for 247 (80.4%) twins; 66 (26.7%) of these had anemia (<10 g/dl) during the second trimester. Women with second trimester anemia had a higher parity (p=0.03), and needed more blood transfusions than those with hemoglobin level > or equal to 10 g/dl (OR = 1.6; 95% CI 1.11-2.43, p < 0.001). No significant differences were noted between the groups regarding other obstetrical outcomes or regarding perinatal outcomes., Conclusion: Second trimester anemia in women carrying twins is associated with a high parity and increases the risk for blood transfusions. However, in our population, maternal anemia in twin gestations does not increase the risk for adverse perinatal outcome.

Objective: Small-for-gestational-age (SGA) neonates (birth weight <10th centile) are at higher risk of altered glucose homeostasis compared to appropriate for gestational age (AGA) neonates. The aim of this matched case-control study was to estimate the incidence of hypoglycaemia and/or hyperglycaemia in monochorionic (MC) twins with selective intrauterine growth restriction (sIUGR)., Methods: We included all MC twins with sIUGR (2002-2013). Neonates in the SGA group were matched with their AGA co-twin. We recorded the occurrence of hypoglycaemia and hyperglycaemia in the first 48 h after birth and studied the association with SGA., Results: In this retrospective study were 126 twin pairs included. The incidence of hypoglycaemia in the SGA group and AGA group was 29.6% and 17.4%, respectively, hyperglycaemia occurred in 8.7% of the SGA neonates and in 2.6% of the AGA co-twins. Multivariate analysis showed an independent association of SGA with hypoglycaemia (OR 1.97, CI 1.23-3.18, p ≤ 0.01), but not with hyperglycaemia (OR 2.57, CI 1.64-10.28, p = 0.182). Low gestational age (GA) at birth (OR 1.65, CI 1.09-2.48, p = 0.02) showed an independent association with hyperglycaemia., Conclusions: The risk of hypoglycaemia is almost twofold higher in SGA neonates compared to their MC AGA twins. Low GA appeared to be an independent risk factor for hyperglycaemia in SGA neonates.

Objective: To evaluate the diagnostic accuracy of middle cerebral artery peak systolic velocity (MCA-PSV) Doppler measurements in prediction of hemoglobin levels in twin anemia-polycythemia sequence (TAPS)., Methods: This study involved a consecutive cohort comprising monochorionic twin pregnancies complicated by TAPS managed at three European fetal medicine centers between 2005 and 2013. The accuracy of MCA-PSV, measured immediately prior to fetal hemoglobin (Hb) measurement by fetal or cord blood sampling, for prediction of anemia and polycythemia was assessed using 2 × 2 tables., Results: A total of 116 measurements (74 recorded in donors and 42 in recipients) from 43 twin pregnancies complicated by TAPS were available for analysis. MCA-PSV multiples of the median (MoM) values correlated well with Hb levels (r = - 0.86; P < 0.001). The sensitivity of MCA-PSV ≥ 1.5 MoM to predict severe anemia (Hb deficit > 5 SD below the mean) in TAPS donors was 94% (95% CI, 85-98%); specificity was 74% (95% CI, 62-83%); positive and negative predictive values were 76% (95% CI, 65-85%) and 94% (95% CI, 83-98%), respectively. The sensitivity of MCA-PSV ≤ 1.0 MoM to predict polycythemia (Hb level > 5 SD above the mean) in TAPS recipients was 97% (95% CI, 87-99%); specificity was 96% (95% CI, 89-99%); positive and negative predictive values were 93% (95% CI, 81-97%) and 99% (95% CI, 93-100%), respectively., Conclusion: MCA-PSV measurement has high diagnostic accuracy for predicting abnormal Hb levels in fetuses with TAPS., (Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.)

Introduction: Several circulating metabolites derived from bacterial protein fermentation have been found to be inversely associated with renal function but the timing and disease severity is unclear. The aim of this study is to explore the relationship between indoxyl-sulfate, p-cresyl-sulfate, phenylacetylglutamine and gut-microbial profiles in early renal function decline., Results: Indoxyl-sulfate (Beta(SE) = -2.74(0.24); P = 8.8x10-29), p-cresyl-sulfate (-1.99(0.24), P = 4.6x10-16), and phenylacetylglutamine(-2.73 (0.25), P = 1.2x10-25) were inversely associated with eGFR in a large population base cohort (TwinsUK, n = 4439) with minimal renal function decline. In a sub-sample of 855 individuals, we analysed metabolite associations with 16S gut microbiome profiles (909 profiles, QIIME 1.7.0). Three Operational Taxonomic Units (OTUs) were significantly associated with indoxyl-sulfate and 52 with phenylacetylglutamine after multiple testing; while one OTU was nominally associated with p-cresyl sulfate. All 56 microbial members belong to the order Clostridiales and are represented by anaerobic Gram-positive families Christensenellaceae, Ruminococcaceae and Lachnospiraceae. Within these, three microbes were also associated with eGFR., Conclusions: Our data suggest that indoxyl-sulfate, p-cresyl-sulfate and phenylacetylglutamine are early markers of renal function decline. Changes in the intestinal flora associated with these metabolites are detectable in early kidney disease. Future efforts should dissect this relationship to improve early diagnostics and therapeutics strategies.

Objective: Intrauterine growth restriction (IUGR) and prenatal exposure to oxidative stress are thought to lead to increased risks of cardiovascular disease later in life. The objective of the present study was to document whether cord blood oxidative stress biomarkers vary with the severity of IUGR and of vascular disease in the twin pregnancy model in which both fetuses share the same maternal environment., Methods: This prospective cohort study involved dichorionic twin pairs, with one co-twin with IUGR. Oxidative stress biomarkers were measured in venous cord blood samples from each neonate of 32 twin pairs, and compared, according to severity of IUGR (IUGR <5th percentile), Doppler anomalies of the umbilical artery and early onset IUGR (in the second trimester) of the growth restricted twin., Results: Oxidized Low-Density Lipoproteins (oxLDL) and Malondialdehyde (MDA) concentrations were increased proportionally in cases of severe IUGR. OxLDL concentrations were also increased in cases of IUGR with Doppler anomaly., Conclusion: Our data indicate that severe IUGR, is related to a derangement in redox balance, illustrated by increased venous cord blood oxidative stress biomarkers concentrations. Severe IUGR and IUGR with abnormal Doppler can be translated into conditions with intense oxidative stress.

Context: The interindividual variability in thyroid hormone function parameters is much larger than the intraindividual variability, suggesting an individual set point for these parameters. There is evidence to suggest that environmental factors are more important than genetic factors in the determination of this individual set point., Objective: This study aimed to quantify the effect of genetic factors and (fetal) environment on the early postnatal blood T4 concentration., Methods: This was a classical twin study comparing the resemblance of neonatal screening blood T4 concentrations in 1264 mono- and 2566 dizygotic twin pairs retrieved from the population-based Netherlands Twin Register. Maximum-likelihood estimates of variance explained by genetic and environmental influences were obtained by structural equation modeling in data from full-term and preterm twin pairs., Results: In full-term infants, genetic factors explained 40%/31% of the variance in standardized T4 scores in boys/girls, and shared environment, 27%/22%. The remaining variance of 33%/47% was due to environmental factors not shared by twins. For preterm infants, genetic factors explained 34%/0% of the variance in boys/girls, shared environment 31%/57%, and unique environment 35%/43%. In very preterm twins, no significant contribution of genetic factors was observed., Conclusion: Environment explains a large proportion of the resemblance of the postnatal blood T4 concentration in twin pairs. Because we analyzed neonatal screening results, the fetal environment is the most likely candidate for these environmental influences. Genetic influences on the T4 set point diminished with declining gestational age, especially in girls. This may be due to major environmental influences such as immaturity and nonthyroidal illness in very preterm infants.

Aim: The purpose of this study was to prospectively estimate the incidence of spontaneous twin anemia-polycythemia sequence (TAPS) in monochorionic-diamniotic twin pregnancies., Methods: We prospectively examined umbilical cord hemoglobin (Hb) and reticulocyte count of consecutive monochorionic-diamniotic twin pregnancies delivered at Seirei Hamamatsu General Hospital from December 2006 to September 2013. We excluded cases of twin-twin transfusion syndrome, intrauterine fetal demise, and missing data (Hb and reticulocyte count missing from the medical record). TAPS was diagnosed using the postnatal criteria of intertwin Hb difference >8.0 g/dL and reticulocyte count ratio >1.7. Acute feto-fetal hemorrhage was defined as Hb difference >7 g/dL and reticulocyte count ratio <1.7., Results: A total of 185 monochorionic-diamniotic twin pregnancies were included in this study. Three fulfilled the diagnostic criteria for postnatal TAPS, and one fulfilled the diagnostic criteria for acute feto-fetal hemorrhage., Conclusion: The incidence of spontaneous TAPS in monochorionic-diamniotic twin pregnancies was 1.6% (3/185) at Seirei Hamamatsu General Hospital., (© 2014 The Authors. Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology.)

Objective: To perform clinical and genetic analysis of a family with familial hypobetalipoproteinemia in which the proband had been diagnosed with diabetes mellitus., Methods: Direct sequencing was performed on candidate genes such as APOB, PCSK9, and ANGPTL3. The effect of the mutant gene on lipid profile was investigated using biochemical methods., Results: A novel mutation Y344S in ANGPTL3 was identified but no variants were found in PCSK9 or APOB. Lipid profiles showed the levels of TG, TC, and LDL-C to be significantly lower in Y344S carriers than in non-carriers in this family. The levels of HDL-C and plasma concentrations of ANGPTL3 showed no significant differences. Western blot analysis revealed that the mutant ANGPTL3 proteins could not be secreted into the medium., Conclusion: A novel mutation Y344S was found in ANGPTL3 gene in two diabetic patients with familial hypobetalipoproteinemia. The family study and genetic analysis suggest that this set of gene mutation may be a genetic basis for the lipid phenotypes, and may become a vascular protective factor in the probands with high risk of atherosclerosis., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Pseudohypoparathyroidism (PHP) is associated with compromised signal transductions via PTH receptor (PTH-R) and other G-protein-coupled receptors including GHRH-R. To date, while GH deficiency (GHD) has been reported in multiple patients with PHP-Ia caused by mutations on the maternally expressed GNAS coding regions and in two patients with sporadic form of PHP-Ib accompanied by broad methylation defects of maternally derived GNAS differentially methylated regions (DMRs), it has not been identified in a patient with an autosomal dominant form of PHP-Ib (AD-PHP-Ib) accompanied by an STX16 microdeletion and an isolated loss of methylation (LOM) at exon A/B-DMR. We studied 5 4/12-year-old monozygotic twins with short stature (both -3.4 SD) and GHD (peak GH values, <6.0 μg/L after arginine and clonidine stimulations). Molecular studies revealed maternally derived STX16 microdeletions and isolated LOMs at exon A/B-DMR in the twins, confirming the diagnosis of AD-PHP-Ib. GNAS mutation was not identified, and neither mutation nor copy number variation was detected in GH1, POU1F1, PROP1, GHRHR, LHX3, LHX4, and HESX1 in the twins. The results, in conjunction with the previous finding that GNAS shows maternal expression in the pituitary, suggest that GHD of the twins is primarily ascribed to compromised GHRH-R signaling caused by AD-PTH-Ib. Thus, resistance to multiple hormones including GHRH should be considered in AD-PHP-Ib.

Unlabelled: We report the course of dicygotic twins born preterm after 29 (4)/7 weeks of gestation due to congenital Parvovirus B19 infection causing fetal hydrops with severe anemia in one infant in whom intrauterine transfusion was impossible to perform and high levels of viremia in both infants. After being discharged, they were readmitted at 3 months of age with critical aplastic crisis. Therapy with intravenous immunoglobulin infusion resulted in decreasing viremia followed by stable hemoglobin levels in both infants., Conclusion: Intravenous immunoglobulin treatment of congenital pure red cell aplasia due to Parvovirus B19 infection in preterm infants seems to be effective to introduce viral remission and to normalize erythropoiesis.

Aim: This article is a systematic review of the literature to establish the detection rate and false-positive rate of the combined test for the screening of trisomy 21 in twins., Material and Methods: We conducted a literature search (MEDLINE, EMBASE and ScienceDirect and Cochrane) to identify studies between 1995 and 2013 that provided data on the combined test in twins. Selected studies included data on maternal age, number of fetuses affected by Down syndrome, test strategy, sensitivity and specificity of the test., Results: The combined test in twins had a pooled sensitivity of 0.893 [95% confidence interval (CI) 0.797-0.947] and a pooled specificity of 0.946 (95% CI 0.933-0.957). The performance of the test was good (summary receiver operating characteristic area under the curve: 0.817). In dichorionic twins, sensitivity and specificity were 0.862 (95% CI 0.728-0.936) and 0.952 (95% CI 0.942-0.96), respectively. In monochorionic twins, the sensitivity and specificity were 0.874% (95% CI 0.526-0.977) and 0.954% (95% CI 0.943-0.963), respectively., Conclusions: The results of this meta-analysis show that the accumulative evidence on the performance of the combined test in twin pregnancies is good. Nowadays, it seems to be the best first-trimester screening test available for twin pregnancies., (© 2014 John Wiley & Sons, Ltd.)

Objective: Because of lack of evidence, we aimed to examine to what degree low-grade systemic inflammation and coronary heart disease (CHD) death shared common genetic and environmental substrates., Approach and Results: From the 41-year prospective National Heart, Lung, and Blood Institute Twin Study, we included 950 middle-aged male twins at baseline (1969-1973). Low-grade systemic inflammation was measured with plasma levels of interleukin-6 (IL-6) and C-reactive protein. Univariate and bivariate structural equation models were used, adjusted for a risk score for CHD death. The score-adjusted heritability was 19% for IL-6, 27% for C-reactive protein, and 22% for CHD death. The positive phenotypic correlation of IL-6 with CHD death (radjusted=0.27; 95% confidence interval [CI], 0.08-0.43) was driven by additive genetic factors (contribution [relative contribution], 0.30 [111%]) but attenuated by unique environment (-0.03 [-11%]). The genetic correlation between IL-6 and CHD death was 0.74 (95% CI, 0.21-1.00), whereas the unique environmental correlation was -0.05 (95% CI, -0.35 to 0.25). The proportion of genetic variance for CHD death shared with that for IL-6 was 74%. The phenotypic correlation of C-reactive protein with CHD death (radjusted=0.10; 95% CI, -0.02 to 0.22) was explained by additive genetic factors (0.20 [149%]) but was attenuated by the unique environment (-0.09 [-49%]). The genetic correlation of C-reactive protein with CHD death was 0.63 (95% CI, -0.07 to 1.00), whereas the unique environmental correlation was -0.07 (95% CI, -0.29 to 0.17)., Conclusions: Low-grade systemic inflammation, measured by IL-6, and long-term CHD death share moderate genetic substrates that augment both traits., (© 2014 American Heart Association, Inc.)

Introduction: Neuroticism is an important marker of vulnerability for both mental and physical disorders. Its link with multiple etiological pathways has been studied before. Inflammatory markers have been demonstrated to predict similar mental and physical disorders as neuroticism. However, currently no study has focused on the shared genetic background of neuroticism and inflammatory markers. In the present study we will focus on the phenotypic and genetic relationship between neuroticism and three commonly used inflammatory markers: C-reactive protein (CRP), fibrinogen and Immunoglobulin-G (IgG)., Material and Methods: The study was conducted in 125 Dutch female twin pairs. For each participant, four different neuroticism scores were available to calculate a neuroticism composite score that was used in the statistical analyses. Blood samples for inflammatory marker determination were taken after an overnight fast. Heritabilities, phenotypic and genetic correlations were estimated using bivariate structural equation modeling., Results: Heritabilities are fair for neuroticism (0.55), CRP (0.52) and fibrinogen (0.67) and moderate for IgG (0.43). No significant phenotypic or genetic correlations were found between neuroticism and the inflammatory markers. Interaction models yielded no moderation of the genetic and environmental pathways in the regulation of inflammatory markers by neuroticism., Conclusion: Substantial heritabilities were observed for all variables. No evidence was found for significant shared (or moderation of) genetic or environmental pathways underlying neuroticism and inflammatory status.

Objective: The purpose of this study was to evaluate the predictiveness of circulating interleukin (IL)-8 for 60-day mortality in premature infants with necrotizing enterocolitis (NEC)., Background: NEC affects up to 5% of premature infants and remains a leading cause of mortality among neonates., Methods: A total of 113 infants with surgically (n=50) or medically (n=63) treated NEC were retrospectively analyzed. Laboratory parameters including serum IL-8 were assessed at the diagnosis of NEC and during the preoperative workup., Results: The 60-day mortality was 19% (22/113), 10% (6/63) in medical and 33% (16/50) in surgical NEC. IL-8 levels significantly correlated with 60-day mortality (odds ratio: 1.38; CI 1.14-1.67; p=0.001). Median IL-8 levels at diagnosis were significantly higher in neonates who were later treated surgically (median=2625 pg/ml; range: 27-7500) compared with those treated medically (median=156 pg/ml; range: 5-7500; p<0.001). The AUC to discriminate between medical and surgical NEC was 0.82 (CI, 0.74-0.90), and an exploratory IL-8 cutoff point could be established at 1783 pg/ml (sensitivity of 90.5%; specificity of 59.2%)., Conclusions: Our findings that serum IL-8 (i) correlates directly with 60-day mortality and (ii) differs significantly between medically and surgically treated infants may change the process of therapeutic decision making in NEC., (© 2013.)

Objective: To compare serum N-terminal pro-brain natriuretic peptide levels at birth between monochorionic diamniotic twins with and without selective intrauterine growth restriction., Study Design: Blood samples were collected from 73 monochorionic diamniotic twins without twin-to-twin transfusion syndrome. Two groups were studied on the basis of fetal ultrasonographic findings: 16 twins with and 57 twins without selective intrauterine growth restriction. Selective intrauterine growth restriction was defined as an estimated fetal weight below the 10th percentile in one twin at 18 to 26 weeks of gestation. Serum N-terminal pro-brain natriuretic peptide levels were measured., Result: Serum N-terminal pro-brain natriuretic peptide levels in monochorionic diamniotic twins with selective intrauterine growth restriction were significantly higher than in those without selective intrauterine growth restriction. Selective intrauterine growth restriction was independently associated with increased N-terminal pro-brain natriuretic peptide levels., Conclusion: N-terminal pro-brain natriuretic peptide levels at birth are elevated in monochorionic diamniotic twins with selective intrauterine growth restriction.

Brain Derived Neurotrophic Factor (BDNF) is a potential biomarker of affective disorder. However, longitudinal studies evaluating a potential predictive role of BDNF on subsequent psychopathology are lacking. The aim of this study was to investigate whether BDNF alone or in interaction with the BDNF Val66Met polymorphism predict onset of affective disorder in healthy individuals at heritable risk for affective disorder. In a high-risk study, we assessed whole blood levels of BDNF in 234 healthy monozygotic and dizygotic twins with or without a co-twin history of affective disorder (high and low risk twins, respectively). Participants were followed up longitudinally with questionnaires at 6-month intervals for mean seven years and then reassessed with a personal interview to obtain information about whether they had developed psychiatric illness. At follow-up 36 participants (15.4%) had developed psychiatric disorder. Cox regression analysis revealed that BDNF levels at baseline were not associated with onset of illness in this explorative study. Further, two-way interactions between BDNF levels and the Val66Met polymorphism or between familial risk and the Val66Met polymorphism did not predict illness onset., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Using a nontargeted metabolomics approach of 447 fasting plasma metabolites, we searched for novel molecular markers that arise before and after hyperglycemia in a large population-based cohort of 2,204 females (115 type 2 diabetic [T2D] case subjects, 192 individuals with impaired fasting glucose [IFG], and 1,897 control subjects) from TwinsUK. Forty-two metabolites from three major fuel sources (carbohydrates, lipids, and proteins) were found to significantly correlate with T2D after adjusting for multiple testing; of these, 22 were previously reported as associated with T2D or insulin resistance. Fourteen metabolites were found to be associated with IFG. Among the metabolites identified, the branched-chain keto-acid metabolite 3-methyl-2-oxovalerate was the strongest predictive biomarker for IFG after glucose (odds ratio [OR] 1.65 [95% CI 1.39-1.95], P = 8.46 × 10(-9)) and was moderately heritable (h(2) = 0.20). The association was replicated in an independent population (n = 720, OR 1.68 [ 1.34-2.11], P = 6.52 × 10(-6)) and validated in 189 twins with urine metabolomics taken at the same time as plasma (OR 1.87 [1.27-2.75], P = 1 × 10(-3)). Results confirm an important role for catabolism of branched-chain amino acids in T2D and IFG. In conclusion, this T2D-IFG biomarker study has surveyed the broadest panel of nontargeted metabolites to date, revealing both novel and known associated metabolites and providing potential novel targets for clinical prediction and a deeper understanding of causal mechanisms.

Background: An understanding of the normal behavior of biochemical markers in twin pregnancies is necessary in order to offer prenatal screening to this subgroup. This study investigates the levels of first trimester maternal serum placental growth factor (PlGF) in twin and singleton pregnancies., Methods: The PlGF concentrations were measured by an automated assay in the first trimester maternal serum of 440 dichorionic twin, 116 monochorionic twin, and 607 singleton pregnancy samples thawed from frozen storage., Results: The PlGF concentrations in singleton levels were predicted by gestational age, maternal ethnicity, and smoking status. Following the correction for these variables, PlGF levels were, on average, 41% higher in dichorionics, but only 16% higher in monochorionics, compared to singleton pregnancies., Conclusions: First trimester maternal serum PlGF levels are increased in twin pregnancies compared with singleton pregnancies, but to less of an extent than is common with other screening markers, especially in monochorionic twins., (© 2013 John Wiley & Sons, Ltd.)

Heritability estimates of metabolic syndrome traits vary widely across studies. Some studies have suggested that the contribution of genes may vary with age or sex. We estimated the heritability of 11 metabolic syndrome-related traits and height as a function of age and sex in a large population-based sample of twin families (N = 2,792-27,021, for different traits). A moderate-to-high heritability was found for all traits [from H(2) = 0.47 (insulin) to H(2) = 0.78 (BMI)]. The broad-sense heritability (H(2)) showed little variation between age groups in women; it differed somewhat more in men (e.g., for glucose, H(2) = 0.61 in young females, H(2) = 0.56 in older females, H(2) = 0.64 in young males, and H(2)= 0.27 in older males). While nonadditive genetic effects explained little variation in the younger subjects, nonadditive genetic effects became more important at a greater age. Our findings show that in an unselected sample (age range, ~18-98 years), the genetic contribution to individual differences in metabolic syndrome traits is moderate to large in both sexes and across age. Although the prevalence of the metabolic syndrome has greatly increased in the past decades due to lifestyle changes, our study indicates that most of the variation in metabolic syndrome traits between individuals is due to genetic differences.

Objectives: A twin-based comparative study on the genetic influences in metabolic endophenotypes in two populations of substantial ethnic, environmental, and cultural differences was performed., Design and Methods: Data on 11 metabolic phenotypes including anthropometric measures, blood glucose, and lipids levels as well as blood pressure were available from 756 pairs of Danish twins (309 monozygotic and 447 dizygotic twin pairs) with a mean age of 38 years (range: 18-67) and from 325 pairs of Chinese twins (183 monozygotic and 142 dizygotic twin pairs) with a mean age of 40.5 years (range: 18-69). Twin modeling was performed on full and nested models with the best fitting models selected., Results: Heritability estimates were compared between Danish and Chinese samples to identify differential genetic influences on each of the phenotypes. Except for hip circumference, all other body measures exhibited similar heritability patterns in the two samples with body weight showing only a slight difference. Higher genetic influences were estimated for fasting blood glucose level in Chinese twins, whereas the Danish twins showed more genetic regulation over most lipids phenotypes. Systolic blood pressure was more genetically controlled in Danish than in Chinese twins., Conclusions: Metabolic endophenotypes show disparity in their genetic determinants in populations under distinct environmental conditions., (Copyright © 2012 The Obesity Society.)

The aim of this study was to assess the aorta-intima thickness (aIT) and serum metabolomic profile in selective intrauterine growth-restricted (sIUGR) monochorionic diamniotic (MCDA) twin fetuses presenting Doppler velocimetry alterations. Fetal abdominal aIT was measured by ultrasound at 32 weeks of gestation, enrolling 24 MCDA twin fetuses (8 sIUGR and 16 controls). sIUGR twin fetuses were classified into two groups: Group 1 consisted of sIUGR with abnormal umbilical artery (UA) Doppler waveforms and Group 2 included sIUGR with normal UA Doppler. Group 3 were control fetuses appropriate for gestational age (AGA). Fetal blood samples were obtained from the umbilical vein immediately after fetal extraction. A non-targeted metabolomic profiling investigated fetal metabolism alterations by using liquid chromatography-high-resolution mass spectrometry (LC-HRMS). Median fetal aIT was significantly larger in Group 1 (median value = 0.9 mm; range = 0.8-1.0 mm; p < .002) and Group 2 (median value = 0.8 mm; range = 0.7-0.8 mm; p < .002) than in AGA Group 3 (median value = 0.5 mm; range = 0.4-0.6 mm; p < .002). Metabolomic analyses, performed on four sIUGR cases (Group 1) compared with four AGA co-twins, showed an upregulation of phenylalanine, sphingosine, glycerophosphocholine, and choline, and a downregulation of valine, tryptophan, isoleucine, and proline sIUGR Group 1 compared with AGA. Although for metabolomics data only a statistical tendency (and not a statistical significance) was reached due to the small sample size, we believe that our results represent a valid starting point for further in-depth metabolomic and proteomic investigations of sIUGR in MCDA fetuses.