Intrapair Differences Research Articles

Obesity‐Related Derangements of Coagulation and Fibrinolysis: A Study of Obesity‐Discordant Monozygotic Twin Pairs

Coagulation and fibrinolytic activities are under strong genetic control. We studied the effects of acquired obesity, independent of genetic factors on coagulation and fibrinolysis activities in obesity-discordant healthy monozygotic (MZ) twin pairs. Fourteen obesity-discordant (BMI within-pair difference >3 kg/m(2)) and 10 concordant (BMI difference <2 kg/m(2)) MZ twin pairs were identified from the nationwide FinnTwin16 study. Body composition (dual-energy x-ray absorptiometry), abdominal fat distribution (magnetic resonance imaging), liver fat (magnetic resonance spectroscopy), high sensitivity C-reactive protein, insulin sensitivity (euglycemic hyperinsulinemic clamp), and a panel of different markers of blood coagulation and fibrinolysis in the fasting state were measured. Strong resemblance was observed in most coagulation factors within all twin pairs, with the intraclass correlations ranging from 0.73 to 0.97, P < 0.03. However, the activities of fibrinogen and FIX, FXI, and FXII, and plasminogen activator inhibitor-1 (PAI-1) activities were increased in the obese co-twins (P < 0.05) and strongly correlated with the measures of adiposity, inflammation, and insulin resistance (r = 0.32-0.73, P < 0.05) among the twin individuals. Intrapair differences in fibrinogen and PAI-1 correlated with those in BMI, adiposity, and fasting insulin levels (r = 0.40-0.58, P < 0.05) indicating the independent effect of obesity. Derangements of blood coagulation and fibrinolysis are present already in early adulthood in obese subjects. Acquired obesity, independent of genetic factors, increases the activities of fibrinogen and activities of FIX, FXI, FXII, and PAI-1. This study confirms the mechanisms of simultaneous activities of intrinsic coagulation factors and impaired fibrinolysis predisposing obese subjects to thrombosis.

Skewed X inactivation and survival: a 13-year follow-up study of elderly twins and singletons

In mammalian females, one of the two X chromosomes is inactivated in early embryonic life. Females are therefore mosaics for two cell populations, one with the maternal and one with the paternal X as the active X chromosome. A skewed X inactivation is a marked deviation from a 50:50 ratio. In populations of women past 55-60 years of age, an increased degree of skewing (DS) is found. Here the association between age-related skewing and mortality is analyzed in a 13-year follow-up study of 500 women from three cohorts (73-100 years of age at intake). Women with low DS had significantly higher mortality than the majority of women who had a more skewed DS (hazard ratio: 1.30; 95% CI: 1.04-1.64). The association between X inactivation and mortality was replicated in dizygotic twin pairs for which the co-twin with the lowest DS also had a statistically significant tendency to die first in the twin pairs with the highest intra-pair differences in DS (proportion: 0.71; 95% CI: 0.52-0.86). Both results suggest that lower DS is associated with higher mortality. We therefore propose that age-related skewing may be partly due to a population selection with lower mortality among those with higher DS.

Electrically detected crystal orientation dependent spin-Rabi beat oscillation of c-Si(111)/SiO2interface states

Electrically detected spin-Rabi beat oscillation of pairs of paramagnetic near interface states at the phosphorous doped (${10}^{16}$ cm${}^{\ensuremath{-}3}$) Si(111)/SiO${}_{2}$ interface is reported. Due to the $g$-factor anisotropy of the P${}_{b}$ center (a silicon surface dangling bond), one can tune intrapair Larmor frequency differences (Larmor separations) by orientation of the crystal with regard to an external magnetic field. Since Larmor separation governs the number of beating spin pairs, crystal orientation can control the beat current. This is used to identify spin states that are paired by mutual electronic transitions. The experiments confirm the presence of the previously reported ${}^{31}$P-P${}_{b}$ transition and provide direct experimental evidence of the previously hypothesized P${}_{b}$-${E}^{\ensuremath{'}}$ center (a near interface SiO${}_{2}$ bulk state) transition.

Leukocyte telomere length and physical ability among Danish Twins age 70+

Leukocyte telomere length (LTL) shortens with age and is potentially a biomarker of human aging.We examined the relation of LTL with physical ability and cognitive function in 548 same-sex twins from the Longitudinal Study of Aging Danish Twins. LTL was measured by Southern blots of the terminal restriction fragments (TRF). Physical ability was evaluated using a self reported scale of 11 questions, while cognitive function was scored by MMSE and a cognitive composite score sensitive to age-related decline.A random intercept model revealed a positive, significant association between LTL and physical ability. For every unit increase in physical ability score, LTL increased by 0.066kb (p=0.01), equal to approximately three years of age-dependent LTL shortening. A matched case-co-twin design showed that the group consisting of the twins from each pair with the longer LTL also displayed better physical ability (p<0.01). Moreover, the intra-pair difference in LTL was associated with intra-pair difference in physical ability (p<0.01), confirming the association. However, we found no association between cognitive function and LTL.The LTL-physical ability association in the elderly provides further support to the premise that LTL is an index of somatic fitness in the narrow context of human physical health.

Is Growth-Discordance in Twins a Substantial Risk Factor in Adverse Neonatal Outcomes?

To evaluate whether growth discordance is an independent risk factor in the neonatal outcome of the smaller twin, all medical records of twin pregnancies delivered between 26 and 41 weeks during a 5-year period (January 2004-December 2008) were reviewed. Among the 49 selected twins, weight discordance was 15-20% in 7 infants, 21-30% in 16 infants, 31-40% in 16 infants and > 40% in 10 infants. No significant differences between the four groups were found with regards to obstetric complications and neonatal disease. Occurrence of birthweight below the 10th percentile and rate of admission to the neonatal intensive care unit significantly increased as intra-pair birthweight difference increased (p = .03). The > 40% discordant group had a significantly lower gestational age (p = .03), lower birthweight (p = .007) and a significantly higher mortality rate (4/10 versus 3/39 p = .04) in comparison with the other discordant groups. Multiple logistic regression analysis showed that birthweight was the single independent and consistent factor associated with elevated risks of mortality. For every 250 g increase in birthweight, the risk for mortality decreased by about 84% [RR 0.16(CI 0.00-0.70)]. Gestational age was the most reliable predictor for major neonatal complications. For every 1-week increase in gestational age a significant decreased risk for all outcomes was found. Discordance alone should not be considered as a predictor for adverse neonatal outcome. Neonatal outcome in discordant twins appears to be related to gestational age and birthweight rather than to the degree of discordance.

Extensive variation and low heritability of DNA methylation identified in a twin study

Disturbance of DNA methylation leading to aberrant gene expression has been implicated in the etiology of many diseases. Whereas variation at the genetic level has been studied extensively, less is known about the extent and function of epigenetic variation. To explore variation and heritability of DNA methylation, we performed bisulfite sequencing of 1760 CpG sites in 186 regions in the human major histocompatibility complex (MHC) in CD4+ lymphocytes from 49 monozygotic (MZ) and 40 dizygotic (DZ) twin pairs. Individuals show extensive variation in DNA methylation both between and within regions. In addition, many regions also have a complex pattern of variation. Globally, there appears to be a bimodal distribution of DNA methylation in the regions, but a significant fraction of the CpG sites are also heterogeneously methylated. Classification of regions into CpG islands (intragenic and intergenic), 5' end of genes not associated with a defined CpG island, conserved noncoding regions, and random CpG sites shows region-type differences in variation and heritability. Analyses revealed slightly lower intra-pair differences among MZ than among DZ pairs, suggesting some genetic influences on DNA methylation variation, with most of the variance attributed to nongenetic factors. Overall, heritability estimates of DNA methylation were low. Our heritability estimates are, however, somewhat deflated due to the presence of batch effects that artificially inflate the estimates of shared environment.

Serum angiopoietin-like 4 protein levels and expression in adipose tissue are inversely correlated with obesity in monozygotic twins

Animal studies have suggested that angiopoietin-like 4 (Angptl4) regulates adiposity through central and peripheral mechanisms. The aim of this study was to investigate whether serum concentration and adipose tissue expression of Angptl4 are associated with obesity-related parameters in humans. Altogether, 75 dizygotic (DZ) and 46 monozygotic (MZ) twin pairs were studied, from the FinnTwin12 and FinnTwin16 cohorts. Among the MZ pairs, 21 were discordant for body mass index (BMI) (intra-pair BMI-difference >2.5 kg/m², age 23-33 years). Serum Angptl4 (s-Angptl4) levels were measured by ELISA, and adipose tissue gene expression was analyzed by genome-wide transcript profiling. In MZ twin pairs discordant for BMI, s-Angptl4 and adipose tissue ANGPTL4 mRNA (at-ANGPTL4) levels were significantly decreased (P = 0.04 and P = 0.03, respectively) in obese twins as compared with their nonobese cotwins. In all twins, intra-pair differences in s-Angptl4 levels were inversely correlated with intra-pair differences in BMI (r = -0.27, P = 0.003). In individual MZ twins, at-ANGPTL4 expression was inversely correlated with BMI (r = -0.44, P = 0.001) and positively correlated with at-LIPE (r = 0.24, P = 0.01) and at-ABHD5 (r = 0.41, P = 0.005) expression. Our results demonstrated that variation in Angptl4 concentration was only modestly accounted for by genetic factors and suggest a role for Angptl4 in acquired obesity in humans.

Differential Nongenetic Impact of Birth Weight Versus Third-Trimester Growth Velocity on Glucose Metabolism and Magnetic Resonance Imaging Abdominal Obesity in Young Healthy Twins

Low birth weight is associated with type 2 diabetes, which to some extent may be mediated via abdominal adiposity and insulin resistance. Fetal growth velocity is high during the third trimester, constituting a potential critical window for organ programming. Intra-pair differences among monozygotic twins are instrumental in determining nongenetic associations between early environment and adult metabolic phenotype. Our objective was to investigate the relationship between size at birth and third-trimester growth velocity on adult body composition and glucose metabolism using intra-pair differences in young healthy twins. Fifty-eight healthy twins (42 monozygotic/16 dizygotic) aged 18-24 yr participated. Insulin sensitivity was assessed using hyperinsulinemic-euglycemic clamps. Whole-body fat was assessed by dual-energy x-ray absorptiometry scan, whereas abdominal visceral and sc fat (L1-L4) were assessed by magnetic resonance imaging. Third-trimester growth velocity was determined by repeated ultrasound examinations. Size at birth was nongenetically inversely associated with adult visceral and sc fat accumulation but unrelated to adult insulin action. In contrast, fetal growth velocity during third trimester was not associated with adult visceral or sc fat accumulation. Interestingly, third-trimester growth was associated with insulin action in a paradoxical inverse manner. Abdominal adiposity including accumulation of both sc and visceral fat may constitute primary nongenetic factors associated with low birth weight and reduced fetal growth before the third trimester. Reduced fetal growth during vs. before the third trimester may define distinct adult trajectories of metabolic and anthropometric characteristics influencing risk of developing type 2 diabetes.

DNA Methylation Variability at Growth‐Related Imprints Does not Contribute to Overweight in Monozygotic Twins Discordant for BMI

Defective genomic imprinting is often associated with syndromes that include abnormal growth as a clinical phenotype. However, whether differential methylation at imprinted loci also contributes to nonsyndromic abnormal body weight regulation is yet unknown. In this study, we investigated a potential contribution of aberrant DNA methylation at nine differentially methylated regions (DMRs) to the development of nonsyndromic overweight. Sixteen monozygotic (MZ) twins discordant for BMI (BMI difference ranging from 2.9-9.5 kg/m(2)) were recruited from the East Flanders Prospective Twin Survey. DNA extracted from saliva samples was bisulfite-treated followed by PCR amplification of target regions in DMRs most representative for abnormal growth syndromes: KvDMR1, H19 CTCF4, H19 CTCF6, IGF2 DMR0, IGF2 DMR2, GRB10, MEST, SNRPN, GNAS XL-α-s and GNAS Exon1A. At the DMRs analyzed, methylation-dependent primer extension experiments revealed only small intrapair differences in methylation indexes (MI) between the heavy and lean co-twins. In addition, no significant correlations between intrapair BMI differences and intrapair differences in MI were observed. In conclusion, DNA methylation variability at the nine DMRs analyzed does not seem to contribute to the discordancy in BMI observed in these MZ twins.

Twin-twin transfusion syndrome: fetal MRI measurement of intrapair differences in brain biometry

BackgroundAntenatal ultrasound studies report similar transcerebellar diameter (TCD) measurements within monochorionic twin pairs regardless of growth concordance. Biparietal diameter (BPD) studies demonstrate less consistent results. The cerebellum is recognised as...

A Longitudinal Twin Study of Effects of Adolescent Alcohol Abuse on the Neurophysiology of Attention and Orienting

Long-term functional brain effects of adolescent alcohol abuse remain uncertain, partially because of difficulties in distinguishing inherited deficits from neuronal effects of ethanol and by confounds associated with alcohol abuse, especially nicotine exposure. We conducted a longitudinal twin study to determine neurocognitive effects of adolescent alcohol abuse, as measured with the auditory event-related potential (ERP) component P3, a putative marker of genetic vulnerability to alcoholism. Twin pairs (N=177; 150 selected for intrapair concordance/discordance for alcohol-related problems at age 18½) were recruited from ongoing studies of twins born 1975-1979 in Finland. Alcohol and tobacco use were assessed with questionnaires at ages 16, 17, 18½, and ~25, and by a structured psychiatric interview concurrent with the ERP testing at mean age 25.8. During ERP recordings, subjects were instructed to detect target tones within a train of frequent "standards" and to ignore occasional "novel" sounds. To distinguish familial factors from ethanol effects, ERP and self-reported alcohol use measures were incorporated into hierarchical multiple regression (HMR) analysis, and intrapair differences in ERP were associated with intra-pair differences in alcohol variables. Novel-sound P3 amplitude correlated negatively with self-reported alcohol use in both between- and within-family analyses. No similar effect was observed for target-tone P3. HMR results suggest that twins' similarity for novel-sound P3 amplitude is modulated by their alcohol use, and this effect of alcohol use is influenced by genetic factors. Our results, from a large sample of twins selected from a population-based registry for pairwise concordance/discordance for alcohol problems at 18½, demonstrate that adolescent alcohol abuse is associated with subtle neurophysiological changes in attention and orienting. The changes are reflected in decreased novel-sound P3 amplitude and may be modified by genetic factors.

Transcranial stimulation techniques: which genetics is the best for which purpose?

Transcranial stimulation techniques: which genetics is the best for which purpose?

Plasticity in human motor cortex is in part genetically determined

Brain plasticity refers to changes in the organization of the brain as a result of different environmental stimuli. The aim of this study was to assess the genetic variation of brain plasticity, by comparing intrapair differences between monozygotic (MZ) and dizygotic (DZ) twins. Plasticity was examined by a paired associative stimulation (PAS) in 32 healthy female twins (9 MZ and 7 DZ pairs, aged 22.6±2.7 and 23.8±3.6 years, respectively). Stimulation consisted of low frequency repetitive application of single afferent electric stimuli, delivered to the right median nerve, paired with a single pulse transcranial magnetic stimulation (TMS) for activation of the abductor pollicis brevis muscle (APB). Corticospinal excitability was monitored for 30 min following the intervention. PAS induced an increase in the amplitudes of the motor evoked potentials (MEP) in the resting APB, compared to baseline. Intrapair differences, after baseline normalization, in the MEP amplitudes measured at 25-30 min post-intervention, were almost double for DZ (1.25) in comparison to MZ (0.64) twins (P =0.036). The heritability estimate for brain plasticity was found to be 0.68. This finding implicates that genetic factors may contribute significantly to interindividual variability in plasticity paradigms. Genetic factors may be important in adaptive brain reorganization involved in motor learning and rehabilitation from brain injury.

An investigation into the relationship between soft tissue body composition and bone mineral density in a young adult twin sample

The purpose of this study was to investigate the relationship of fat mass (FM) and lean mass (LM) with bone mineral density (BMD) independent of genetic effects. We also assessed the extent to which genetic and environmental influences explain the associations between these phenotypes. Body composition and BMD were measured using dual-energy X-ray absorptiometry in 57 monozygotic and 92 same-sex dizygotic twin pairs, aged 23 to 31 years, chosen to represent a wide range of intrapair differences in body mass index (BMI; 0 to 15.2 kg/m2). Heritability estimates were adjusted for height and gender. In multiple linear regression analysis, intrapair differences in both FM and LM were independently associated with intrapair differences in BMD at most skeletal sites after adjustment for gender and differences in height. Within monozygotic and dizygotic pairs, LM was a significantly stronger predictor of whole-body BMD than FM (p < .01). Additive genetic factors explained 87% [95% confidence interval (CI) 80%–91%), 81% (95% CI 70%–88%), and 61% (95% CI 41%–75%) of the variation in whole-body BMD, LM, and FM, respectively. Additive genetic factors also accounted for 69% to 88% of the covariance between LM and BMD and for 42% to 72% of the covariance between FM and BMD depending on the skeletal site. The genetic correlation between LM and whole-body BMD (rg = 0.46, 95% CI 0.32–0.58) was greater than that of FM and whole-body BMD (rg = 0.25, 95% CI 0.05–0.42). In conclusion, our data indicate that peak BMD is influenced by acquired body weight as well as genetic factors. In young adulthood, LM and BMD may have more genes in common than do FM and BMD. © 2011 American Society for Bone and Mineral Research.

A Genetically Informed Study of the Covariation Between the CBCL/6-18 DSM-Oriented Problem Scales and the Competence Scales

In 398 twin pairs belonging to the population-based Italian Registry, we investigated by the monozygotic twin intrapair differences model and bivariate designs whether the phenotypic correlations between CBCL/6-18 problem behaviours and competencies could better be accounted for by direct, causal effects, or by the presence of latent etiological factors, acting simultaneously as elements of risk/protection for psychopathology and competencies. All zero-order correlations between six CBCL DSM-oriented scales (DOS) and three competence scales (CS) were negative and small-to-moderate. After implementing multiple regressions we found robust enough prediction only for ADH DOS on school CS, and for anxiety DOS on social CS. Results from the intrapair differences model indicated shared elements of liability, rather than direct causation, as more likely explanations for the negative phenotypic correlations between these emotional/behavioural problem and competencies scores. Bivariate analyses indicated shared genetic factors that influence simultaneously the emotional/behavioural problems and the competencies domains as the best explanations for the phenotypic covariations between DOS and CS.

Leisure‐time physical activity and artery lumen diameters: A monozygotic co‐twin control study

Exercise is thought to increase the diameter of the conduit arteries supplying the muscles involved. We studied the effects of a physically active vs inactive lifestyle on artery diameters in monozygotic (MZ) twin pairs discordant over 30 years for leisure-time physical activity habits. In a population-based co-twin control study design, six middle-aged (50-65 years) same-sex MZ twin pairs with long-term discordance for physical activity were comprehensively identified from the Finnish Twin Cohort (TWINACTIVE study). Discordance was initially defined in 1975 and the same co-twin remained significantly more active during the 32-year follow-up. The main outcomes were arterial lumen diameters measured from maximal intensity projections of contrast-enhanced MR angiography images. Paired differences between active and inactive co-twins were studied. Compared with inactive members, active members of MZ twin pairs had larger diameters for the distal aorta and iliac and femoral arteries (P<0.05 for all comparisons). The mean intrapair differences in the diameters of the arteries in these locations were 19% or larger. No significant differences between active and inactive co-twins (P>0.2 for all comparisons) were found in the dimensions of the carotid arteries. Our genetically controlled study confirms that habitual physical activity during adulthood enlarges arteries in a site-specific manner.

Monozygotic Twins With Neurofibromatosis Type 1 (NF1) Display Differences in Methylation ofNF1Gene Promoter Elements, 5' Untranslated region, Exon and Intron 1

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder caused by heterozygotic inactivation of the NF1 tumor suppressor gene at 17q11.2. The associated phenotypes are highly variable, and modifying genes have been proposed to explain at least in part the intriguing expressivity. Given that haploinsufficiency of the NF1 gene product neurofibromin is responsible for some of the clinical manifestations, variations in expression of the wildtype NF1 allele might modify the phenotype. We therefore investigated epigenetic molecular modifications that could result in variable expression of the normal NF1 allele. To exclude confounding by DNA sequence variations, we analyzed monozygotic twin pairs with NF1 who presented with several discordant features. We fine-mapped the methylation pattern of a nearly 1 kb NF1 promoter region in lymphocytes of 8 twin pairs. All twin pairs showed significant intra-pair differences in methylation, especially of specific promoter subregions such as 5'UTR, exon 1 and intron 1 (+7 to +622), transcription factor binding sites and promoter elements like NF1HCS. Furthermore, we detected significant intra-pair differences in cytosine methylation for the region from -249 to -234 with regard to discordance for optic glioma with a higher grade of methylation in glioma cases. In conclusion, our findings of epigenetic differences of the NF1 promoter in leukocytes within mono zygotic twin pairs may serve as a proof of principle for other tissues. The results point towards a role of methylation patterns of the normal NF1 allele for expression differences and for modification of the NF1 phenotype.

Antenatal factors associated with birth weight of twins and risk factors for discordant twins

Objective To investigate the antenatal influencing factors associated with birth weight of twins and the risk factors for the occurrence of discordant twins. Methods Totally, 834 twins delivered at the Third Affiliated Hospital from January 2000 to December 2009 and the First Affiliated Hospital of SUN Yat sen University, from January 2000 to June 2009, were recruited in the study. The diagnosis criteria of discordant twins was intrapair birth weight difference more than 25%. Antenatal factors on birth weight were retrospectively investigated among twins and discordant twins respectively with Logistic analysis. Results （1） There were several factors associated with birth weight of twins, including maternal age, conceptive style, chorionicity, gestational diabetes mellitus and placental cord insertion （P = 0. 021, 0. 000, 0. 000, 0. 012 and 0. 017, respectively）. While hypertensive disorder in pregnancy, parity and fetal gender differences were not associated with the birth weight of twins （P〉0.05）. Hypertensive disorder in pregnancy （OR =2.600, 95% CI：1. 566 4. 316） and monochorionicity （OR=1.833, 95% CI：1.010-3.582） were risk factors of discordant twins. All 834 twin pregnancies were divided into 4 groups according to rnateral age, 〈25 yrs （n =69）, 25-30 yrs （n= 312）, 30-35 yrs （n=325） and ≥35 yrs （n=128）. The average birth weight of twins were （2205±483） g, （2347±406） g, （2381±439） g and （2352±455） g. Significant difference was found bewteen every two groups （P〈0.05） except that between the 30-35 yrs and ≥35 yrs group （P〉0.05）. Among twins of different gender （n=270）, the average birth weight of boys and girls were （2416±514） g and （2322±488） g, and that of female twins （n=272） and male twins （n 292） were （2301±418） g and （2381±428） g. Significant difference was shown between every two groups （P〈0.05） except that between the male twins and male fetus of twins of different gender （P〉0.05）. Conclusions The fetal birth weight of twins decreases remarkably when maternal age 〈 25, or monochorionicity twins, or complicated with marginal or velamentous placental cord insertion or female pairs. However, birth weight of twins would increase if the pregnancy conceived by assisted reproductive technology or complicated with gestational diabetes mellitus. Twin pregnancy complicated with hypertensive disorder in pregnancy or monoehorionicity should alert the clinicians of discordance twins. Key words: Twins; Birth weight; Risk factor

1214 Survival After Fetoscopic Guided Laser Occlusion (FLOC) of Twin-To-Twin Transfusion Syndrome

Background and aim: Untreated twin-to-twin transfusion syndrome (TTTS) carries a mortality rate of approximately 80%. To improve survival, fetoscopic laser occlusion (FLOC) treatment of placental anastomoses has been introduced during the last decade in Sweden. We aimed to determine survival after introduction of this intervention. Methods: Data from all TTTS pregnancies (n=67) treated with FLOC from 2001-09 was assessed. In Sweden, FLOC is carried out at one center i.e. at Karolinska University Hospital, Stockholm. Rates of survival and intra-pair differences were analyzed, as well as maternal risk factors. The severity of TTTS in the cohort was graded according to Quintero (stage I n=2, stage II n=30, stage III n=29, stage IV n=6). Laser treatment was offered at a gestational age of 21 (17-26) weeks and delivery occurred at 29 (19-41) weeks. Results: In 76%, at least one twin was live-born. The rate of fetal survival in donors was 60% and in recipients 66% (p< 0.001). 1 year-survival was 37% in donors and 44% in recipients (p=0.01) and in 57% at least one twin was alive. There was no significant difference in survival when adjusted for Quintero stages, parity, maternal BMI or smoking whereas higher maternal age was associated with higher survival of both twins (p< 0.05). Conclusions: Survival of at least one twin after FLOC was comparable to corresponding data of other international centra. Recipients are more likely to survive than donors. The finding of an increased survival rate with maternal age needs further investigation.

Quantification of the Relative Contribution of Environmental and Genetic Factors to Variation in Cystic Fibrosis Lung Function

To assess the relative contributions of environmental and genetic factors to variation in cystic fibrosis (CF) lung disease. Genetic and environmental contributions were quantified by use of intrapair correlations and differences in CF-specific forced expiratory volume in 1 second measures from 134 monozygous twins and 272 dizygous twins and siblings while in different living environments (ie, living with parents vs living alone), as well as by use of intraindividual differences in pulmonary function from a separate group of 80 siblings. Pulmonary function among monozygous twins was more similar than among dizygous twin and sibling pairs, regardless of living environment, affirming the role of genetic modifiers in CF pulmonary function. Regression modeling revealed that genetic factors account for 50% of pulmonary function variation, unique environmental or stochastic factors (36%), and shared environmental factors (14%; P < .0001). The intraindividual analysis produced similar estimates for the contributions of the unique and shared environment. The shared environment effects appeared primarily because of living with a sibling with CF (P = .003), rather than factors within the parental household (P = .310). Genetic and environmental factors contribute equally to pulmonary function variation in CF. Environmental effects are dominated by unique and stochastic effects rather than common exposures.