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Thyroid peroxidase antibodies (TPOAbs) in patients with Hashimoto's thyroiditis (HT) predominantly react with two immunodominant regions (IDR-A, IDR-B). Theoretically, as shown for the level of TPOAbs, the autoantibody epitopic recognition of the IDRs could be under genetic control. To examine this, we compared the distribution of TPOAb epitopic fingerprints between healthy monozygotic (MZ) co-twins and siblings to patients with clinically overt HT with a control group of euthyroid subjects, matched for sex and age, but without autoimmune thyroid disease (AITD) among their first-degree relatives. Two ELISAs based on competition with rabbit antisera were used to determine the IDR specificities in 23 patients with HT, 6 MZ co-twins, 8 siblings to patients with HT, and 11 healthy euthyroid subjects without predisposition to AITD. The fraction of TPOAbs recognizing IDR-A was 19, 18, and 9% in HT patients, MZ-co-twins, and siblings, respectively, which was higher than the 0% found in the group of healthy subjects without predisposition to AITD (p = 0.007 vs. HT; p = 0.1078 vs. MZ co-twin and p = 0.069 vs. siblings). Moreover, the IDR-A fraction differed between healthy MZ-co-twins and ordinary siblings (18% vs. 9%, p = 0.0127). In conclusion, our data indicate that the propensity to produce autoantibodies directed against the IDR-A epitope of TPO is genetically determined. This finding may have implications with respect to inheritance of autoantibody specificities in other autoimmune diseases.

Although postmenopausal hormone-replacement therapy (HRT) is known to prevent fractures, knowledge on the influence of long-term HRT on bone strength and its determinants other than areal bone mineral density is scarce. This study used a genetically controlled design with 24 monozygotic female twin pairs aged 54 to 72 years in which one cotwin was using HRT (mean duration 8 years) and the other had never used HRT. Estimated bone strength, cross-sectional area, volumetric bone mineral density, bone mineral mass, and cross-sectional density and mass distributions were assessed in the tibial shaft, distal tibia, and distal radius with peripheral computed tomography (pQCT). In the tibial shaft, HRT users had 9% [95% confidence interval (CI) 3%-15%] higher estimated bending strength than their nonusing cotwins. Larger cortical area and higher cortical bone mineral density accounted for this difference. The cortex was larger in the HRT users in the endocortical region. In the distal tibia, estimated compressive strength was 24% (95% CI 9%-40%) higher and in the distal radius 26% (95% CI 11%-41%) higher in the HRT users than in their nonusing cotwins owing to higher volumetric bone mineral density. No difference between users and nonusers was observed in total bone cross-sectional area in any measured bone site. The added mineral mass in the HRT users was distributed evenly within and between bone sites. In postmenopausal women, long-term HRT preserves estimated bone strength systemically by preventing bone mineral loss similarly in body weight-loaded and non-weight-loaded bone., (Copyright © 2011 American Society for Bone and Mineral Research.)

In 2004 the Netherlands Twin Register (NTR) started a large scale biological sample collection in twin families to create a resource for genetic studies on health, lifestyle and personality. Between January 2004 and July 2008, adult participants from NTR research projects were invited into the study. During a home visit between 7:00 and 10:00 am, fasting blood and morning urine samples were collected. Fertile women were bled on day 2-4 of the menstrual cycle, or in their pill-free week. Biological samples were collected for DNA isolation, gene expression studies, creation of cell lines and for biomarker assessment. At the time of blood sampling, additional phenotypic information concerning health, medication use, body composition and smoking was collected. Of the participants contacted, 69% participated. Blood and urine samples were collected in 9,530 participants (63% female, average age 44.4 (SD 15.5) years) from 3,477 families. Lipid profile, glucose, insulin, HbA1c, haematology, CRP, fibrinogen, liver enzymes and creatinine have been assessed. Longitudinal survey data on health, personality and lifestyle are currently available for 90% of all participants. Genome-wide SNP data are available for 3,524 participants, with additional genotyping ongoing. The NTR biobank, combined with the extensive phenotypic information available within the NTR, provides a valuable resource for the study of genetic determinants of individual differences in mental and physical health. It offers opportunities for DNA-based and gene expression studies as well as for future metabolomic and proteomic projects.

Objective: Angiogenic factors play a role in human placentation and may be aberrant in severe twin-to-twin transfusion syndrome (TTTS). The aim of this study was to investigate the maternal plasma and amniotic fluid angiogenic factor and receptor concentrations in twin pregnancies complicated by TTTS and to evaluate the effects of fetoscopic laser ablation., Methods: A prospective cohort of monochorionic (MC) twins complicated by severe TTTS (n = 23) was studied between October 2006 and December 2007. A cohort of uncomplicated dichorionic (DC) (n = 12) and MC (n = 7) pregnancies were studied for comparison. Circulating angiogenic factors and their receptors were measured in the maternal plasma and the recipient twin's amniotic fluid by enzyme-linked immunosorbent assay and/or FAST Quant human angiogenesis array., Results: Plasma vascular endothelial growth factor (VEGF)-C concentrations were significantly lower in TTTS than in uncomplicated twin pregnancies (P < 0.0001). In contrast, plasma angiopoietin (Ang)-2 levels and the ratio of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) to placental growth factor (PlGF) levels were significantly increased in TTTS (P < 0.01). Plasma VEGF-D was significantly increased in advanced stage TTTS (Stage III/IV cohort; P < 0.01). This was independent of fetal size, amniotic fluid volumes or the number of apparent placental arteriovenous anastomoses. In TTTS pregnancies, amniotic fluid VEGF-C, VEGF-A, Ang-1 and the sVEGFR-1/PlGF ratio were increased compared to paired maternal plasma concentrations (P < 0.0001) while amniotic fluid concentrations of PlGF, Ang-2 and soluble tyrosine kinase with immunoglobulin-like/epidermal growth factor-like domains 2 (sTie-2) were significantly lower than plasma concentrations (P < 0.0001). No significant association between maternal plasma and amniotic fluid concentrations of angiogenic factors was noted. Plasma PlGF was transiently decreased after fetoscopic laser ablation, returning to baseline by 1 week (P = 0.0314). Fetoscopic laser ablation also affected plasma sVEGFR-1/PlGF ratio with a transient increase after therapy, followed by a significant reduction to below basal concentrations by 1 week (P = 0.0102). Only VEGF-D was significantly different (+8.3%; P = 0.0155) in amniotic fluid immediately after the completion of fetoscopic laser ablation., Conclusion: Maternal angiogenic activity is decreased in severe TTTS, with an increased sVEGFR-1/PlGF ratio and concentrations of Ang-2 and VEGF-D in the maternal plasma compared to uncomplicated MC twin pregnancies. Maternal circulating PlGF concentrations decrease and the sVEGFR-1/PlGF ratio increases transiently in response to fetoscopic laser ablation, but in general the angiogenic factor and receptor concentrations studied are altered little by this therapy., ((c) 2009 ISUOG. Published by John Wiley & Sons, Ltd.)

We report the case of a 13-year-old woman who was pregnant with phenotypically discordant monochorionic twins: one with cystic hygroma and hydrops, the other one normal. Fetal blood sampling was performed by intrahepatic blood collection for karyotyping of both fetuses, revealing the same genotype of 46,XY/47,XYY in 2:1 proportion. Phenotypic discordance in monozygotic twins can have various causes, such as placental vascular anatomy, differences in allocation of the number of blastomeres or genetic postzygotic events.

The Older Australian Twins Study (OATS) was recently initiated to investigate genetic and environmental factors and their associations and interactions in healthy brain ageing and ageing-related neurocognitive disorders. The study extends the classic MZ-DZ design to include one or two equivalently aged siblings for each twin pair and utilizes the rich resources of the Australian Twin Registry. The study has a number of distinguishing features including comprehensive psychiatric, neuropsychological, cardiovascular, metabolic, and neuroimaging assessments, a longitudinal design and links with a brain donor program. The study measures many behavioral and environmental factors, but in particular lifetime physical and mental activity, physical and psychological trauma, loss of parent early in life, later losses and life events, early-life socioeconomic environment, alcohol and drug use, occupational exposure, and nutrition. It also includes comprehensive cardiovascular assessment, blood biochemistry, genetics and proteomics. The socio-demographic and health data on the first 172 pairs of twins participating in this study are presented. Prevalence of mild cognitive impairment is 12.8% and of dementia 1.5% in the sample. The target sample size is 1000, with at least 400 pairs of twins aged 65-90 years. The cohort will be assessed every two years, with in-depth assessments being repeated. OATS offers an excellent opportunity for collaboration with other similar studies as well as researchers who share the same interests.

Background: Most studies linking obesity and metabolic syndrome (MS) have used body mass index (BMI) and waist circumference (WC) to measure obesity. While BMI is correlated with direct measures of total and central adiposity, it is influenced by lean body and bone mass. We hypothesize that direct measures of adiposity may help develop further insight into the link between obesity and MS, thus more accurately identifying individuals at high risk for MS., Aim of the Study: We examined how surrogate and direct measures of adiposity were associated with MS risk and if direct adiposity measures enhanced BMI and WC identification of MS risk., Methods: 3,734 Chinese female twins aged 20-39 years were studied. Percent body fat (%BF) and proportion of trunk fat to total BF (%TF) were assessed by DEXA. Graphic plots and generalized estimating equations were used to examine the associations of adiposity measures with MS and its components. Concordance of adiposity measures and MS abnormalities between monozygotic (MZ) and dizygotic (DZ) twin pairs were compared., Results: The prevalence of MS increased for high BMI (>or=23 kg/m(2)), %BF (>or=32), WC (>or=80 cm), and (to a lesser degree) %TF (>or=50). Below those thresholds, the prevalence of MS was low (0-5.3%). %TF was independently associated with higher risk of MS and its components even after adjusting for BMI and WC. As a result, among women with normal BMI and WC, high %TF was associated with 1.3-2.0-fold elevated risk of MS components. In contrast, women with high BMI but normal WC and %TF neither have significantly increased risk of MS, nor for any component other than high BP. MZ twins showed higher concordance for MS and its components than DZ twins., Conclusions: In this lean Chinese rural female sample, BMI >or= 23 and WC >or= 80 were associated with a markedly increased risk of MS, which was further enhanced by elevated %TF. Even in women with a normal BMI and WC, %TF was independently associated with MS and its components. Twin analysis findings suggest that adiposity measurements and MS risk are influenced by genetics.

Objective: To study the localization and size of residual anastomoses in twin-to-twin transfusion syndrome treated with fetoscopic laser surgery and correlate the findings with outcome., Study Design: Placental injection in twin-to-twin transfusion syndrome placentas treated with laser was performed by using colored dye., Results: A total of 77 twin-to-twin transfusion syndrome placentas were included in the study. Residual anastomoses (n = 48) were found in 32% (25/77) of lasered placentas. Most residual anastomoses were localized near the margin of the placenta. The majority of residual anastomoses (67%; 32/48) were very small (diameter, < 1 mm). Eleven of the 25 cases (44%) in the residual anastomoses group developed twin anemia-polycythemia sequence., Conclusion: Most residual anastomoses in twin-to-twin transfusion syndrome placentas treated with laser are very small and localized near the placental margin. Almost half of cases with residual anastomoses developed twin anemia-polycythemia sequence after laser surgery.

In twin studies of cardiovascular disease biomarkers the dizygotic correlations are often estimated to be less than half of monozygotic correlations indicating a potential influence of nonadditive genetic factors. Using a large and homogenous sample, we estimated the additive and dominance genetic influences on levels of high density lipoprotein, low density lipoprotein, apolipoprotein A-I, apolipoprotein B, total cholesterol, triglycerides, glucose, hemoglobin Alc and c-reactive protein, all of which are biomarkers associated with cardiovascular disease. The blood biomarkers were measured on 12,000 Swedish twins born between 1911 and 1958. The large sample allowed us to obtain heritability estimates with considerable precision and provided adequate statistical power for estimation of dominance genetic components. Our study showed complete absence of the shared environment component for the investigated traits. Dominant genetic component was shown to be significant for low density lipoprotein (0.18), glucose (0.31), Hemoglobin Alc (0.55), and c-reactive protein (0.27). To our knowledge, this is the first statistically significant evidence for dominance genetic variance found for low density lipoprotein, glucose, hemoglobin Alc, and c-reactive protein in a population based twin sample. The study highlights the importance of acknowledging nonadditive genes underlying the risk of developing cardiovascular diseases.

Objective: Twin-to-twin transfusion syndrome (TTTS) is a morbid perinatal condition associated with abnormal placentation and is treated by fetoscopic laser ablation (FLA). We assessed basal maternal serum alphafetoprotein (MSAFP) and free beta-human chorionic gonadotrophin (f-betaHCG) in uncomplicated dichorionic (DC) and monochorionic (MC) twin pregnancies and a cohort of MC twin pregnancies complicated by severe TTTS. Changes in MSAFP and f-betaHCG post-FLA were measured as markers of placental coagulation., Study Design: In a prospective case-cohort study, MC twins complicated by TTTS (n=23) were studied. A cohort of uncomplicated DC (n=12) and MC (n=6) twin pregnancies, which were appropriately grown for gestation with normal liquor volumes were also studied. Using solid phase, two site fluoroimmunometric assays, both MSAFP and f-betaHCG from uncomplicated and complicated cohorts were measured. Samples were taken, prior to FLA then at intervals after the procedures (6h, 24h and 1 week)., Results: The median multiples of median (MoM) were not significantly different in uncomplicated DC twin pregnancies for MSAFP 1.85 (95% CI 1.62-2.34) or fbetaHCG 1.66 (95% CI 1.21-2.04) compared to uncomplicated MC twin pregnancies (MSAFP 1.40 (95% CI 1.16-2.58) and fbetaHCG 1.70 (95% CI 0.32-3.35)). However, the median MSAFP MoM in MC twin pregnancies complicated by severe TTTS was increased (MSAFP 3.10 (95% CI 2.67-4.43); p<0.05) with a more significant increase being noted in median fbetaHCG (MoM 5.75 (95% CI 5.22-9.12); p<0.0001) compared to uncomplicated twin pregnancies. Post-FLA, the median MSAFP increased significantly at 6h by 445% (636.65 U/ml (95% CI 616-1216.9 U/ml)) and remained elevated at 1 week (553.4 U/ml (95% CI 203.7-3020.8 U/ml; p=0.001)). No significant difference in median fbetaHCG was noted post-FLA (p=0.36). This rise in MSAFP appears unrelated to the number of placental anastomoses coagulated or the total energy used. Also, in the small cohort in which amniodrainage alone was performed no rise in MSAFP was noted., Conclusions: MSAFP and fbetaHCG are increased in TTTS indicating an association with abnormal placentation. Post-FLA, a significant rise in MSAFP was noted for up to a week post-coagulation. This was not noted after amniodrainage.

The association between abdominal obesity and atherogenic lipid profile emerges from complex interactions of genes and environment. We aimed to explore the heritability and effects of overweight on serum lipid profile (high-density lipoprotein-cholesterol (HDL-C), HDL mean particle size, percentages of HDL(2b, 2a, 3a, 3b, and 3c,) low-density lipoprotein-cholesterol (LDL-C), LDL peak particle size and triglycerides (TGs)) in healthy, young adults. HDL-C, LDL-C, and TG were measured in 52 monozygotic (MZ) and 89 dizygotic (DZ) twin pairs, aged 23-32 years, chosen to represent a wide range of BMIs (17.6-42.9 kg/m2). Of them, 24 MZ and 26 DZ pairs were chosen at random for measurements of HDL mean and LDL peak particle sizes and percentages of HDL subspecies. The heritabilities of the lipid parameters adjusted for BMI were HDL-C 73%, HDL mean particle size 56%, HDL subspecies 46-63%, LDL-C 79%, LDL peak particle size 49%, and TG 64%. Genetic and environmental correlations between BMI and HDL-C, LDL-C, and TG were modest (0.3-0.4). Abdominal overweight (waist circumference>or=94 cm for males and >or=80 cm for females) associated with decreased HDL-C, increased LDL-C, and TG concentrations, smaller HDL mean particle size, lower HDL2b, and higher HDL3c percentages in both genders. Within MZ twins, controlling for genetic influences, within-pair differences in HDL3c percentage were associated with those in waist (r=0.46, P=0.032) and BMI (r=0.51, P=0.013). In conclusion, serum lipid parameters, including LDL peak and HDL mean particle sizes and HDL subspecies distribution are under strong genetic control. Overweight associated with significant lipid profile changes, particularly, small HDL3c increased in overweight independent of genetic influences.

Background/aims: This study aimed to determine the heritability of serum alanine aminotransferase (S-ALT) and fasting serum insulin (fS-insulin) concentration as well as determine the association of these measures with liver fat content in young adult monozygotic (MZ) and dizygotic (DZ) twins., Methods: Three hundred and thirteen individual twins were recruited from a population-based cohort (n = 4929). The study subjects represented a wide range of body mass indexes (BMI), were free of any diseases or regular medications and had an intake of less than two drinks of alcohol/day. To verify that S-ALT is a marker of liver fat, it was measured by proton magnetic resonance spectroscopy ((1)H MRS) in 66 subjects. Heritability estimations were performed using BMI- and gender-adjusted values., Results: Intra-pair correlations were significantly higher in the MZ twins than the DZ twins for both S-ALT (0.65 for MZ and 0.04 for DZ) and fS-insulin (0.58 and 0.34, respectively). Heritability of S-ALT was 55% and that of fS-insulin 61%. In the 66 subjects S-ALT (r = 0.70 for women and r = 0.50 for men, p < or = 0.01 for both) and fS-insulin (r = 0.58 and r = 0.59, respectively, p < or = 0.01 for both) concentrations correlated significantly with liver fat content., Conclusions: These twin data suggest that approximately 60% of the variation in S-ALT, a marker of liver fat content, is genetically determined.

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

Objective: The purpose of this study was to determine vascular endothelial growth factor (VEGF) concentrations in the donor and the recipient in monochorionic twin pregnancies with twin-twin transfusion syndrome (TTTS) and single pregnancies in order to investigate the involvement of VEGF in the pathophysiology of TTTS., Methods: Six twin pregnancies in 11 monochorionic twin pregnancies complicated with TTTS and 11 single control pregnancies were compared. Gestational age-matched fetal blood and placental samples were obtained at birth. Serum VEGF concentration in the umbilical vein was measured by an enzyme-linked immunoabsorbant assay. Tissue protein expression of VEGF was determined by using immunohistochemistry. Western blot analysis and scanning densitometry were used to quantify and compare the VEGF expression in the terminal villi., Results: Serum VEGF concentrations in the umbilical vein in both donors and recipients tended to be higher than those in the controls. Immunolocalization of VEGF in terminal villous placenta samples in both donors and recipients was mainly observed in the syncytiotrophoblastic layer and vascular endothelial cells with less intense staining in stromal cells. The expression of VEGF in the donor placenta increased significantly (p=0.006) compared to that in the control placenta, but the expression of VEGF in the recipients tended to be higher than in the controls., Conclusion: Intrauterine circulatory imbalance may induce changes in VEGF expression and these alterations may be involved in both donor and recipient in the pathogenesis of TTTS, due to the maintenance of hemodynamic stability between the circulation of the twins.

Differences in genetic background and/or environmental exposure among individuals are expected to give rise to differences in measurable characteristics, or phenotypes. Consequently, genetic resemblance and similarities in environment should manifest as similarities in phenotypes. The metabolome reflects many of the system properties, and is therefore an important part of the phenotype. Nevertheless, it has not yet been examined to what extent individuals sharing part of their genome and/or environment indeed have similar metabolomes. Here we present the results of hierarchical clustering of blood plasma lipid profile data obtained by liquid chromatography-mass spectrometry from 23 healthy, 18-year-old twin pairs, of which 21 pairs were monozygotic, and 8 of their siblings. For 13 monozygotic twin pairs, within-pair similarities in relative concentrations of the detected lipids were indeed larger than the similarities with any other study participant. We demonstrate such high coclustering to be unexpected on basis of chance. The similarities between dizygotic twins and between nontwin siblings, as well as between nonfamilial participants, were less pronounced. In a number of twin pairs, within-pair dissimilarity of lipid profiles positively correlated with increased blood plasma concentrations of C-reactive protein in one twin. In conclusion, this study demonstrates that in healthy individuals, the individual genetic background contributes to the blood plasma lipid profile. Furthermore, lipid profiling may prove useful in monitoring health status, for example, in the context of personalized medicine.

Context: Differentiation of testicular tissue in 46,XX individuals is seen either in XX males, the majority of them with SRY gene, or in individuals, usually SRY(-), with ovotesticular disorder of sex development (OT-DSD). Although they are sporadic cases, there are some reports on familial recurrence, including coexistence of XX maleness and OT-DSD in the same family., Objective: We report on a case of SRY(-) 46,XX monozygotic twins with genital ambiguity., Methods: Hormonal evaluation included testosterone, FSH, and LH measurements. SRY gene was investigated by PCR and two-step PCR in peripheral leukocytes and gonadal tissues, respectively. Direct DNA sequencing of the DAX-1 coding sequence was performed. Real-time PCR for SOX9 region on chromosome 17 was obtained., Results: Both twins had a 46,XX karyotype. Twin A had a 1-cm phallus with chordee, penoscrotal hypospadias, and palpable gonads. Serum levels of FSH (2.34 mIU/ml), LH (8.8 mIU/ml), and testosterone (1.6 ng/ml) were normal, and biopsies revealed bilateral testes. Twin B had a 0.5-cm phallus, perineal hypospadias, no palpable gonad on the right, and a left inguinal hernia. Hormonal evaluation revealed high FSH (8.2 mIU/ml) and LH (15 mIU/ml) and low testosterone (0.12 ng/ml). Upon herniotomy, a right testis (crossed ectopia) and a small left ovotestis were found. SRY gene was absent in both peripheral leukocytes and gonadal tissue samples. Neither DAX-1 mutations nor SOX9 duplication was identified., Conclusions: This case provides evidence that both XX maleness and XX OT-DSD are different manifestations of the same disorder of gonadal development.

Unlabelled: Low adiponectin levels have been associated with high body mass index, low insulin sensitivity, and diabetes., Objective: To assess the relationships between changes in serum adiponectin concentration and adiposity, glucose, and insulin in response to long-term overfeeding in identical twins and to calculate the twin resemblance in serum adiponectin concentrations., Subjects and Design: Twenty-four sedentary young men [mean (+/-SD) age, 21+/-2 yr] who constituted 12 pairs of healthy identical twins were studied for metabolic and adiponectin changes in response to overfeeding., Intervention: Subjects were overfed by 84,000 kcal over a 100-day period., Outcome Measures: The overfeeding study provides an opportunity to examine the relationships between adiponectin and changes in body weight, adiposity, plasma glucose and insulin., Results: Serum adiponectin concentration correlated positively with body weight (r= 0.41, p=0.05) at baseline but not with indicators of adiposity or with visceral fat. No relationship existed between baseline adiponectin concentration and body weight or adiposity gains with overfeeding. However, serum adiponectin decreased significantly by -2.35+/-0.48 microg/ml (p=0.001) in response to overfeeding. Baseline adiponectin levels correlated negatively with changes in plasma fasting glucose levels (r=-0.53, p=0.01) and homeostasis model assessment index (r=-0.41, p=0.05), independently of fat mass. The intrapair coefficient for twin resemblance (r=0.75, p=0.001) strongly suggests that baseline serum adiponectin concentration is a familial trait., Conclusions: These data provide evidence that adiponectin concentration is a familial trait in normal-weight individuals, that it decreases when challenged by positive energy balance, and that its overfeeding-induced variations are correlated with glucose and insulin levels.

Background: Various studies have demonstrated an increased risk for adult diseases in newborns born small-for-gestational-age (SGA). Adiponectin and resistin can be detected in cord blood and are suggested to affect insulin resistance (IR). This might represent a link between metabolic syndrome and SGA birth., Study Design: We investigated the relationship between the adipocytokines and inter-twin birth weight (BW) difference of 31 monozygotic twins with twin-twin transfusion syndrome; in 14 twin pairs BW difference was >15% (1 SGA twin, 1 appropriate-for-gestational-age, AGA, twin)., Results: BW and length of all patients were positively related to adiponectin (r = 0.57; p < 0.0001; r = 0.47; p < 0.0001) and to resistin (r = 0.31; p < 0.01; r = 0.35; p < 0.01). In 71% (10/14), the SGA twins showed lower adiponectin concentrations than their AGA co-twins (only 6/14 for resistin). To correct for gestational age we calculated the relationship between the intrapair differences (Delta) of BW and Delta of the hormones. We found Delta BW positively correlated with adiponectin (r = 0.55; p < 0.001) but not with resistin (r = 0.22; p = 0.2). Delta adiponectin was positively correlated with Delta resistin (r = 0.45; p < 0.01)., Conclusion: These data demonstrate that adiponectin and resistin levels are associated with BW with only adiponectin levels being reduced in SGA children independently of gestational age. Prenatally different metabolic status between the twins might predispose the SGA twin to develop IR later in life., ((c) 2007 S. Karger AG, Basel.)

Objective: To evaluate BMI and direct measures of body fat (BF) and lean body mass (LBM) in relation to fasting serum lipid profiles in a large Chinese population based twin sample using a monozygotic (MZ) co-twin analysis., Methods: Adiposity measures collected 1998-2000 on 987 MZ female 20-60 year old twin pairs (n=1974) included BMI, waist circumference (WC), waist/hip ratio (WHR), LBM, trunk fat (TF), %TF, total BF, and % total BF (measured by DEXA). Serum lipids included total cholesterol (TC), triglycerides (TG), LDL, and HDL. Co-twin analyses and conventional regression analyses were used to assess the association between individual adiposity and LBM measures, and serum lipids., Results: In this lean population with a mean BMI 21.8 (2.8), we observed considerable variability in adiposity measures and serum lipids. A positive linear association between all adiposity measures with LDL, TC, and TG, and a negative linear association with HDL was observed. A 1-unit z-score increase of adiposity measures, reflecting fat distribution, was associated with increases in (mmol/L) TC (0.063 to 0.164), LDL (0.064 to 0.131), TG (0.049 to 0.164), and a decrease in HDL (0.021 to 0.038) while controlling for matched factors within twin pairs (i.e., age and unmeasured confounders). However, similar associations were not observed for LBM., Conclusion: It is the BF (not LBM) that appears to be associated with serum lipid profiles. This study underscores that in populations where BMI is highly correlated with BF, BMI can be used as a surrogate for BF in evaluating risk of dyslipidemia. Otherwise, direct measures of BF are needed.

Body-mass index (BMI), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels are known to be highly heritable. We evaluated the genetic and environmental relationships of these measures over time in an analysis of twin pairs. Monozygotic (235 pairs) and dizygotic (260 pairs) male twins were participants in the National Heart Lung and Blood Institute Veteran Twin Study, and were followed with three clinical exams from mean age 48 years to mean age 63 years. Structural equation modeling (SEM) with adjustment for APOE genotype (a significant contributor to TC and LDL-C) was used to assess longitudinal patterns of heritability. Results indicated a contribution of genetic factors to BMI, TC, LDL-C, HLD-C, and TG. Modest increases over time were observed in the heritability of BMI (from 0.48 to 0.61), TC (from 0.46 to 0.57), LDL-C (from 0.49 to 0.64), and HDL-C (from 0.50 to 0.62), but this trend was not present for TG. There was a corresponding decrease in shared environmental influences over time for these traits, although shared environment was a significant contributor only for HDL-C. Moreover, we observed that genetic influences for all measures were significantly correlated over time, and we found no evidence of age-specific genetic effects. In summary, longitudinal analyses of twin data indicate that genetic factors do not account for a significant proportion of the variation in age-related changes of BMI or lipid and lipoprotein levels.

In vivo measurements of blood flow through arterio-venous anastomoses in monochorionic twin placentas have recently been attempted with Doppler ultrasound, but the accuracy is questionable. We present a case of twin-to-twin transfusion syndrome treated with fetoscopic laser surgery. The ex-recipient subsequently became severely anaemic and was treated with an intrauterine blood transfusion at 29 weeks' gestation. After birth, a placental injection study identified residual unidirectional arterio-venous anastomoses from the ex-recipient to the ex-donor without arterio-venous anastomoses in the opposite direction. Prospective measurements of decreasing haemoglobin levels between the intrauterine transfusion and birth allowed us to assess the net blood flow through the anastomoses as 27.9mL/24h. This finding may also explain the inaccuracy of Doppler flow measurements, as such low flow velocities cannot possibly be detected with current Doppler techniques.

Fetoscopic laser coagulation of placental vascular anastomoses is considered to be the treatment of choice in severe twin-to-twin transfusion syndrome. The aim of fetoscopic laser surgery is to separate completely the inter-twin placental circulation. Incomplete laser coagulation may result in residual vascular anastomoses. The incidence and clinical implications of residual anastomoses in twin-to-twin transfusion syndrome treated with fetoscopic laser surgery has not yet been studied. We examined all placentas treated with fetoscopic laser surgery and delivered at our center between June 2002 and December 2005 with vascular injection using colored dyes. Presence of residual anastomoses was studied in association with adverse outcome and inter-twin hemoglobin difference at birth. Adverse outcome was defined as fetal demise, neonatal death or severe cerebral injury. The relation between residual anastomoses and placental localization (anterior or posterior uterine wall) was evaluated. A total of 52 laser-treated placentas were studied. Residual anastomoses were detected in 33% (17/52) of placentas. Adverse outcome was similar in the groups with and without residual anastomoses, 18% (6/34) and 29% (20/70), respectively (p=0.23). Large inter-twin hemoglobin differences (>5g/dL) were found in 65% (11/17) of cases with residual anastomoses and 20% (7/35) of cases without residual anastomoses (p<0.01). Anterior placental localization was not associated with a more frequent presence of residual anastomoses. In conclusion, residual anastomoses at our institution are seen in one-third of monochorionic placentas treated with fetoscopic laser surgery. Although residual anastomoses in our study were not associated with adverse outcome, they were often associated with neonatal hematological complications.

The super-sensitivity of the neurohormone melatonin to light in patients with bipolar disorder provides evidence of the circadian nature of the disorder. This response has been proposed as an endophenotype for identifying people at risk of the disorder and guiding investigations of molecular genetic targets. However, before this response is used as an endophenotypic marker, the heritable nature of melatonin sensitivity in the normal population must be established. The aim of this study was to investigate the heritability of nocturnal melatonin secretion and sensitivity to light in monozygotic and dizygotic twins with no psychiatric history. This study investigated overall melatonin levels (between 2000 and 2400 h) and suppression by 500 lx of light (between 2400 and 0100 h) in 20 pairs of twins (nine monozygotic, 11 dizygotic). The results indicate that melatonin secretion is highly heritable with secretion in one twin being a significant predictor of secretion in their twin in both monozygotic and dizygotic pairs. In relation to light sensitivity, genetic loading appears to play a significant role with the greatest concordance between monozygotic twins, followed by dizygotic twins and finally low concordance in unrelated individuals. This provides additional support for the usefulness of melatonin sensitivity to light as a potential endophenotypic marker of bipolar affective disorder.

Objective: Cartilage oligomeric matrix protein (COMP) is a cartilage matrix macromolecule. The protein is detectable in serum and has been investigated as a biomarker of osteoarthritis (OA). An association between COMP and OA has been shown, yet the precise factors governing serum levels of COMP remain unclear. The aim of this study was to determine whether genetic factors influence serum levels of COMP., Methods: A classic twin study was conducted using COMP levels in serum obtained from healthy female twin volunteers. COMP levels were determined by an inhibition enzyme-linked immunosorbent assay method. The heritability of COMP was determined by comparing correlation among 160 monozygotic and 349 dizygotic twin pairs. Data on potential confounding factors, including age, body mass index, and the presence of OA as assessed by hand, hip, and knee radiographs, were included in the analysis., Results: Serum levels of COMP showed a correlation of 0.72 (95% confidence interval [95% CI] 0.65-0.80) among monozygotic twin pairs and 0.47 (95% CI 0.39-0.55) in dizygotic pairs. This equated to an estimated heritability for COMP of 40% (95% CI 20-60%). Although age and body mass index were found to be significantly associated with COMP in regression analysis, taking the effects of these factors into account did not influence the estimate of heritability., Conclusion: This study showed that heritable factors influence serum levels of the cartilage matrix biomarker COMP. Together with other published data, the results suggest that genetic factors operate at an early stage in the etiologic pathways that influence the development of radiographically discernible OA.

Nitrite and nitrate are the stable end products of the L-arginine-NO pathway, and the sum of nitrite and nitrate (NOx) is a common way to measure nitric oxide (NO) production or secretion. To uncover any genetic influence on NO, we measured NOx in serum samples from monozygotic twin pairs after an overnight fast. Heritability was estimated as intraclass correlation coefficient. We arrived at a heritability estimate of .32 (95% confidence interval 0.17-0.45) for NOx. The numerical heritability estimate was higher for females than for males (0.38 vs. 0.21), and higher for nonsmokers than for smokers (0.36 vs. 0.22). The heritability estimate of NOx was lower than the heritability estimate for other cardiovascular risk factors. This study suggests a low degree of heredity for NOx levels.

This study reports on the determination of zygosity in Chinese adult twins by simple questionnaire and physical features comparison. The subjects were 511 twin pairs from two cities and their town areas, consisting of 371 monozygotic (MZ) and 140 same-sex dizygotic (DZ) pairs, identified by ABO blood group and multiplex polymerase chain reaction of several polymorphic short tandem repeat markers. The twins themselves responded to 8 questionnaire items, 4 items on twin similarity, and 4 items on the frequency of mistaking one twin for another by parents, relatives, teachers and strangers when they were 6 to 13 years old. Research assistants responded to 20 items regarding twins' physical features at the moment of interview. A parsimonious model established using stepwise logistic regression analysis of the 28 items showed that the total accuracy of zygosity diagnosis was 90.1%. The accuracy was 89.2% when using only the items dealing with the confusion of twins and 85.4% using only similarity. In the questionnaire, 'facial appearance', 'mistaken by teachers' and 'mistaken by strangers' had stronger discriminating power between MZ and DZ twins. Two physical features--'eyelid' and 'middigital hair'--were informative to some extent. There was no statistically significant sex and area difference in the validity of such questionnaire and physical features comparison-based classification. In conclusion, questionnaire-based zygosity assessment in this Chinese adult twin sample could still be regarded as a valid and valuable classification method. Physical features comparison, however, could only provide limited information for zygosity determination.

Twins can be used to investigate the biological basis for observed associations between birth weight and later disease risk, as they experience in utero growth restriction compared with singletons, which can differ in magnitude within twin pairs despite partial or total genetic identity. In the present study, sixty monozygotic and seventy-one dizygotic same-sex twin pairs aged 19-50 years and eighty-nine singleton controls matched for age, gestational age, sex, maternal age and parity were recruited from an obstetric database. Associations between fasting lipid levels and birth weight were assessed by linear regression with adjustment for possible confounding factors. Twins were significantly lighter at birth but were not significantly different in adult height, weight or lipid levels from the singleton controls. There was a significant inverse association between birth weight and both total and LDL-cholesterol levels among singleton controls (-0.53 mmol/l per kg (95 % CI -0.97, -0.09), P = 0.02 and -0.39 mmol/l per kg (95 % CI -0.76, -0.02), P = 0.04, respectively), but there was no significant association between birth weight and lipid levels in either unpaired or within-pair analysis of twins. The results suggest that the in utero growth restriction and early catch-up growth experienced by twins does not increase the risk of an atherogenic lipid profile in adult life.

Background: FSH hypersecretion occurs in mothers of dizygotic (DZ) twins. Twinning is inherited via both sexes and transmitted through the female. FSH hypersecretion may thus occur in male DZ twins., Methods: We assayed FSH and its counter-regulatory hormone, Inhibin B, in 108 adult male DZ and 100 monozygotic (MZ) twins (as controls) and compared our results to published norms., Results: Inhibin B was elevated and higher in DZ compared with MZ twins with similar FSH., Conclusion: The normal FSH: Inhibin B endocrine feedback axis is different in adult male DZ twins. This contributes to the theory that the answer to human DZ twinning lies in the actions of FSH and Inhibin, and in their mutual interaction.

Objectives: To investigate a potential role of leptin and insulin-like growth factor (IGF)-I on fetal growth and metabolic function we determined plasma leptin and IGF-I concentrations in twins in relation to discordant fetal growth., Study Design: In studying monochorionic twins with inter-twin birth weight difference, we investigated the relative contribution of genetic (fetus) versus environmental (maternal/placental) factors on growth. Thirty-six sets of twins (14 with discordant growth, birth weight difference >15%) who had been treated for severe twin-to-twin transfusion syndrome (TTTS) by laser coagulation were studied. Cord blood samples were collected at birth and analyzed for IGF-I and leptin. Inter-twin differences (delta) of birth weight and head circumference were correlated to delta hormone levels., Results: An inter-twin correlation for leptin (r = 0.69; p <0.0001) and delta IGF-I (r = 0.49; p <0.0001) was found. delta birth weight correlated significantly with delta IGF-I (r = 0.67; p <0.0001) but not with delta leptin (r = 0.23; p = 0.19). delta IGF-I concentrations did not correlate with delta leptin (r = 0.18). delta head circumference correlated significantly with delta leptin (r = 0.47; p <0.01) and with delta IGF-I (r = 0.46; p <0.01). Using a multiple regression model with head circumference as dependent variable, adjusted for gestational age, head circumference remained significantly associated with higher leptin concentrations in all patients (p = 0.03)., Conclusion: IGF-I is a good indicator for fetal growth and brain development. Leptin seems to be mainly genetically determined but may play a role in fetal brain development and is not only an index for fetal fat mass.

We report on 23 years old discordant monozygotic (MZ) twins, one with minor anomalies and mental delay, the other one being normal. Both had 46,XX,dup(11)(p12p15)/46,XX mosaicism in blood, with a similar proportion of abnormal cells (respectively, 16% and 17%). However, interphase fluorescence in situ hybridization (FISH) analysis performed on buccal smear and urinary sediment using specific probes located at the duplicated region showed that mosaicism was only present in the abnormal twin, with 68% abnormal cells. We hypothesize that the postzygotic chromosomal rearrangement may have occurred early in one embryo after the twinning event, and the blood mosaicism observed in both twins would have resulted from blood exchanges via placental anastomoses. This hypothesis of chimerism is strongly supported by twin-to-twin transfusion syndrome observed during fetal life of our twins. This case and those previously reported lead us to suggest that blood is particularly unsuitable for cytogenetic investigations of twins., (Copyright (c) 2005 Wiley-Liss, Inc.)

Free and receptor-bound leptin may be regulated by different mechanisms. Genes that influence the concentration of these fractions may have an important functional bearing. We determined circulating leptin receptor concentrations, bound as well as free leptin concentrations, and body composition in 24 monozygotic (MZ) and in 22 dizygotic (DZ) twin pairs. Bound leptin and leptin receptor concentrations were inversely correlated with body fat content. Free leptin concentrations were directly correlated with body fat content. The correlations in age- and sex-adjusted free leptin, bound leptin, and leptin receptor concentrations were higher between MZ twins than between DZ twins. Adjusted heritability (h2) estimates were 0.28 for free leptin, 0.73 for bound leptin, and 0.55 for leptin receptor. The genetic correlation with body fat was -0.58 for the leptin receptor, -0.20 for bound leptin, and 0.93 for free leptin. Our data are consistent with a strong genetic influence on leptin receptor and bound leptin and a weaker genetic influence on free leptin concentrations. The same genes that lower bound leptin and leptin receptor concentrations may increase fat mass or vice versa.

Can autoantibodies (Ab's) and cytokines play a role in epilepsy?Monozygotic twins discordant for epilepsy (most probably Rasmussen's encephalitis (RE)), compared to 49 neurologically intact controls, were both found to contain in their serum (at the time of epilepsy diagnosis) significantly elevated levels of specific Ab's against peptide B (amino acids 372-395) of the ionotropic glutamate receptor of AMPA subtype 3 (i.e. GluR3B peptide). Interestingly, both twins also had clinically elevated levels of Ab's to double-stranded (ds) DNA, glutamic acid decarboxylase, nuclear antigens, beta2-glycoprotein I and cardiolipin, as in "classical" autoimmune diseases. Both twins also had significantly elevated levels of IFNgamma, TNFalpha, IL-4 and IL-10 in the serum, compared to the controls. Comparing the twins revealed that the epileptic twin had significantly higher levels of five of the above anti-self Ab's, but significantly lower levels of all four cytokines compared to her healthy sister. Importantly, the epileptic twin, alike three other RE patients tested herein, contained elevated levels of Ab's to GluR3B and dsDNA also in cerebrospinal fluid (CSF) (unavailable of the healthy twin). Our results suggest that the various autoimmune Ab's studied herein, all of which are known already to have a potential to be pathogenic in the nervous system and/or peripheral organs, may play a role in some types of epilepsy. The titer of such Ab's and of key cytokines may be crucial for either facilitating or arresting the development of epilepsy. Our findings also show that anti-GluR3B Ab's in serum are not necessarily detrimental (their presence in the CSF may be more dangerous), and that they are not a mere side effect of already existing epilepsy, as they were found herein in serum of a healthy individual. These findings and suggestions may be of clinical importance and call for further studies.

Objective: To evaluate the impact of chorionicity on inter-twin differences in acid-base status at birth., Methods: Records for twin pregnancies delivered at > or = 24 weeks' gestation from 1 January 1990 to 31 June 2000 were reviewed. Collected data included maternal demographics, gestational age, fetal presentation, anesthesia, delivery mode, inter-twin interval, umbilical artery (UA) and venous (UV) acid-base values, Apgar scores and birth weights. The influence of chorionicity on umbilical cord biochemistry was evaluated. (p < 0.05 was considered significant.), Results: Analysis was carried out in 87 twin pairs (29 monochorionic, MC; and 58 dichorionic, DC). MC and DC twins were similar in maternal age (25.5 vs. 28.2 years), estimated gestational age (33.7 vs. 33.6 weeks), Cesarean delivery (55.2 vs. 52.6%), delivery interval (10 vs. 5 min) and respective birth weights (twin A, 1882 vs. 1981; and twin B, 1828 vs. 1872 g). MC first twins had a higher UA pH (7.31 +/- 0.05 vs. 7.26 +/- 0.08; p = 0.0005) than DC first twins. MC first and second twins had higher UA and UV bicarbonate levels than their DC counterparts (DeltapH = 21.7 +/- 5.1 vs. 18.5 +/- 3.1 mmol/l and 22.0 +/- 3.5 vs. 19.6 +/- 2.5 mmol/l, respectively; p = 0.003). MC twins were more discordant in UA pH than DC twins (DeltapH = 0.043 +/- 0.09 vs. 0.003 +/- 0.07; p = 0.009). MC and DC twins had a similar venous pH (DeltapH = 0.01 +/- 0.06 vs. 0.02 +/- 0.06; p = 0.5)., Conclusions: There is a significant association between placental chorionicity and umbilical cord biochemistry in twins. Although it is possible that the mechanism of this finding is related to placental angioarchitecture, it is unlikely to be a result of simple mixing of blood volumes between twins. The physiology of underlying processes requires further study.