The healthy donor effect impacts self-reported physical and mental health - results from the Danish Blood Donor Study (DBDS).

AIMS: This study aimed at quantifying the healthy donor effect by comparing self-perceived mental and physical health between blood donors and non-donors. BACKGROUND: In theory, the selection process known as the healthy donor effect should result in better self-perceived, health-related quality of life in donors than in non-donors. METHODS: The Short Form-12 data from the Danish Twin Registry (DTR) was compared with the data from the Danish Blood Donor Study (DBDS). Data on age, sex and smoking status were included in the analyses. The multivariable linear regression analysis was stratified by sex and age group intervals. Outcome variables were the mental component score (MCS) and the physical component score (PCS). RESULTS: A total of 28 982 and 36 913 participants from the DTR and the DBDS, respectively, were included in this study. Younger donors had higher MCS than non-donors, whereas MCS was only marginally high in older donors compared with non-donors. In contrast, PCS was almost similar for both young donors and non-donors. With the increase in age, non-donors had lower PCS than donors. CONCLUSIONS: Two selection patterns were revealed. Among young individuals, better self-perceived mental health was associated with a blood donor. With the increase in age, better self-perceived physical health was associated with blood donation.

Heritability of the Number of Teeth in Middle-Aged and Older Danish Twins.

Tooth loss is a common health concern in older adults. We aimed to estimate the relative contributions of genetic and environmental factors to the variation in the number of teeth in middle-aged and older populations using a population-based cohort of Danish twins. The study included 5,269 Danish middle-aged or older twins who provided data on the number of teeth at baseline by structured interviews. The data were analyzed using univariate liability threshold modeling, stratified by sex and age, to estimate familial risk of tooth loss as well as estimates of heritability. In the whole cohorts, 23% of participants were edentate and 53% had retained 20 or more teeth. A statistical model including additive genetic factors and environmental factors partly shared by co-twins and partly unique to each individual twin gave the best statistical fit for the number of teeth in both age categories as well as in men and women. Overall, additive genetic factors explained 36% (95% confidence interval [CI]: 23% to 49%), common environmental factors 20% (95% CI: 9% to 31%), and unique environmental factors 44% (95% CI: 40% to 48%) of the total variation of the number of teeth. This study indicates that a substantial part of the variation in tooth loss is explained by genetic as well as environmental factors shared by co-twins. Our results implied that family background importantly affects tooth loss in both the middle-aged and the older populations. Family history is thus an important factor to take into account in dental health care.

Genetic and environmental influences in Dupuytren's disease: a study of 30,330 Danish twin pairs.

We aimed to assess the relative contribution of genes and environment in the aetiology of Dupuytren's disease by studying Danish twins born between 1870 and 2000. Twins with a diagnosis (n = 365) and the subgroup who also had an operation (n = 259) after 1977 were identified through linkage with a nationwide hospital registry among 30,330 monozygotic and same-sexed dizygotic twin pairs. Since monozygotic twins share all their genes and dizygotic twins share on average half of their genetic material, greater phenotypic similarity is expected in monozygotic than in dizygotic twins if a genetic component is involved. The number of concordant male twin pairs with Dupuytren's disease was 17 and 7 (monozygotic and dizygotic pairs, respectively), compared with 60 and 174 discordant monozygotic and dizygotic pairs, yielding probandwise concordance rates of 0.37 (95% confidence interval (CI): 0.26 to 0.50) and 0.07 (95% CI: 0.04 to 0.14), respectively. The heritability of Dupuytren's disease was approximately 80%. We conclude that genetic factors play a major role in the development of Dupuytren's disease.

Metabolic effects of lifestyle intervention in obese pregnant women. Results from the randomized controlled trial 'Lifestyle in Pregnancy' (LiP).

AIMS: The Lifestyle in Pregnancy intervention in obese pregnant women resulted in significantly lower gestational weight gain compared with the control group, but without improvement in rates of clinical pregnancy complications. The impact of the lifestyle intervention on metabolic measurements in the study participants is now reported. METHODS: The Lifestyle in Pregnancy study was a randomized controlled trial among 360 obese women (BMI 30-45 kg/m²) who were allocated in early pregnancy to lifestyle interventions with diet counselling and physical activities or to the control group. Fasting blood samples, including plasma glucose, insulin, lipid profile and capillary blood glucose during a 2-h oral glucose tolerance test were carried out three times throughout pregnancy. Insulin resistance was estimated with the homeostasis model assessment of insulin resistance. RESULTS: Three hundred and four women (84%) were followed until delivery. Women in the intervention group had a significantly lower change in insulin resistance (HOMA-IR) from randomization to 28-30 weeks' gestation compared with control subjects (mean ± SD: 0.7 ± 1.3 vs. 1.0 ± 1.3, P = 0.02). Despite a significantly lower gestational weight gain in the intervention group, there was no difference between the groups with respect to total cholesterol, HDL, LDL or triglycerides. CONCLUSIONS: Lifestyle intervention in obese pregnant women resulted in attenuation of the physiologic pregnancy-induced insulin resistance. Despite restricted gestational weight gain, there were no changes in glucose or lipid metabolism between the groups.

Effects of body size and change in body size from infancy through childhood on body mass index in adulthood.

BACKGROUND: Weight and weight gain throughout infancy are related to later obesity, but whether the strength of the associations varies during the infancy period is uncertain. AIMS: Our aims were to identify the period of infancy when change in body weight has the strongest association with adult body mass index (BMI) and also the extent to which these associations during infancy are mediated through childhood BMI. METHODS: The Copenhagen Perinatal Cohort, in which participants were followed from birth through 42 years of age, provided information on weight at 12 months and BMI at 42 years for 1633 individuals. Information on weight at birth, 2 weeks, 1, 2, 3, 4 and 6 months was retrieved from health visitors' records and information on BMI at ages 7 and 13 years from school health records. The associations of infant weight and weight gain standard deviation scores (SDS) with adult BMI-SDS were analyzed using multiple linear regression and path analysis. RESULTS: Higher-weight-SDS at all ages from birth to an age 12 months were associated with higher-BMI-SDS at 42 years (regression coefficients 0.08-0.12). Infant weight gain-SDS was associated with greater BMI-SDS at 42 years only between birth and 3 months (0.09, 95% confidence intervals (CI) 0.04, 0.15) driven by an association between 2 and 3 months (0.12, 95% CI: 0.04, 0.20). The latter was partly mediated through later BMI in the path analysis. Infant weight gain-SDS between 3 and 12 months was not associated with greater BMI-SDS at 42 years. CONCLUSIONS: Faster weight gain during only the first 3 months of infancy was associated with increased adult BMI, although not in a consistent monthly pattern. Adult BMI is more sensitive to high weight gain during early infancy than late infancy, but not specifically to the first month of life.

Heritability of psoriasis in a large twin sample.

BACKGROUND: Previous twin studies have shown greater concordance rates for psoriasis in MZ than in DZ twins, and heritability estimates between 66% and 90%. This supports a genetic influence on psoriasis, but also highlights the fact that genes are not the only explanation for the disease. OBJECTIVES: To study the concordance of psoriasis in a population-based twin sample. METHODS: Data on psoriasis in 10 725 twin pairs, aged 20-71 years, from the Danish Twin Registry was collected via a questionnaire survey. The concordance and heritability of psoriasis were estimated. RESULTS: In total, 4·1% of the men and 4·2% of the women had a lifetime history of psoriasis. The proband-wise concordance for psoriasis was larger in monozygotic than in dizygotic twins, 0·33 vs. 0·17. Genetic factors explained 68% (60-75%) of the variation in the susceptibility to psoriasis, whereas the rest of the variation was explained by nonshared environmental factors. CONCLUSION: The results confirm that psoriasis is a complex multifactorial disease controlled by both exogenous and endogenous factors.

Design, recruitment, logistics, and data management of the GEHA (Genetics of Healthy Ageing) project.

In 2004, the integrated European project GEHA (Genetics of Healthy Ageing) was initiated with the aim of identifying genes involved in healthy ageing and longevity. The first step in the project was the recruitment of more than 2500 pairs of siblings aged 90 years or more together with one younger control person from 15 areas in 11 European countries through a coordinated and standardised effort. A biological sample, preferably a blood sample, was collected from each participant, and basic physical and cognitive measures were obtained together with information about health, life style, and family composition. From 2004 to 2008 a total of 2535 families comprising 5319 nonagenarian siblings were identified and included in the project. In addition, 2548 younger control persons aged 50-75 years were recruited. A total of 2249 complete trios with blood samples from at least two old siblings and the younger control were formed and are available for genetic analyses (e.g. linkage studies and genome-wide association studies). Mortality follow-up improves the possibility of identifying families with the most extreme longevity phenotypes. With a mean follow-up time of 3.7 years the number of families with all participating siblings aged 95 years or more has increased by a factor of 5 to 750 families compared to when interviews were conducted. Thus, the GEHA project represents a unique source in the search for genes related to healthy ageing and longevity.

Risk of asthma in adult twins with type 2 diabetes and increased body mass index.

AIM: To examine the relationship between asthma, type 2 diabetes and increased body mass index (BMI) in adult twins. METHODS: We performed record linkage between questionnaire-defined asthma and BMI, and hospital discharge diagnoses of type 2 diabetes in 34,782 Danish twins, 20-71 years of age. RESULTS: The risk of asthma was increased in subjects with type 2 diabetes relative to nondiabetic subjects both in men (13.5%vs 7.5%), P = 0.001 and in women (16.6%vs 9.6%), P = 0.001. The result remained significant after adjustment for age, BMI, smoking, symptoms of chronic bronchitis, marital status and zygosity, men: OR = 1.70 (1.07-2.70), P = 0.026; women: OR = 1.88 (1.24-2.85), P = 0.003. In this analysis, BMI remained a highly significant predictor for asthma independently of diabetes status in women, P < 0.000 but not in men, P = 0.336. Significant positive genetic correlations were found between asthma and type 2 diabetes, 0.20 (0.01-0.40), P = 0.047; between asthma and BMI in women, 0.15 (0.07-0.22), P < 0.000; and between BMI and type 2 diabetes, 0.40 (0.29-0.43), P < 0.000. CONCLUSIONS: Asthma, type 2 diabetes and increased BMI are strongly associated in adults, particularly in women. These results suggest a common aetiology for asthma and metabolic syndrome.

Relationship between type 1 diabetes and atopic diseases in a twin population.

AIM: To study the association between type 1 diabetes and atopic diseases in a twin population. METHODS: We performed record linkage between questionnaire-defined atopic dermatitis, asthma and hay fever, and hospital discharge diagnoses of type 1 diabetes in 54,530 Danish twins, 3-71 years of age. RESULTS: The age- and sex-adjusted risk of atopic dermatitis was decreased in subjects with type 1 diabetes compared with nondiabetic subjects, (2.1%vs 9.9%), odds ratio (OR)= 0.23 (0.07-0.71), P = 0.011, whereas asthma and hay fever were not significantly associated with type 1 diabetes. Within twin pairs discordant for type 1 diabetes, the diabetic twin had a lower risk of atopic dermatitis relative to the nondiabetic co-twin. Genetic factors for atopic dermatitis and type 1 diabetes were negatively correlated (r = -0.30), P = 0.0009. CONCLUSIONS: These findings substantiate the Th1 vs Th2 cell dichotomy for type 1 diabetes and atopic dermatitis, and indicate an inverse association between genetic factors for these disorders.

Estimates of asthma heritability in a large twin sample.

BACKGROUND: Asthma is a complex disease characterized by symptoms of wheezing, shortness of breath, chest tightness, and cough. OBJECTIVE: To study the relative contribution of genetic and environmental factors in the liability to asthma in a large sample of twins. METHODS: Data on asthma in 21,135 twin pairs, 3-71 years of age, from the Danish Twin Registry were collected via a multidisciplinary questionnaire survey. Heritability estimates were calculated using variance components models. RESULTS: A monozygotic twin had an approximately sixfold increased risk of asthma whereas a dizygotic twin only had an approximately threefold increased risk relative to the general population if his or her co-twin was affected. The difference was more pronounced among males. Familial aggregation of asthma in children and adolescents was explained mainly by additive genetic factors, but common environment was also important. The heritability of asthma was also substantial in adults aged 20-49 years. In older adults (aged 50-71 years), additive genetic factors did not significantly influence the disease risk. CONCLUSION: Genetic influences on asthma are substantial throughout the life span but the proportion of the disease liability explained by genetic factors is decreased in older adults.

Ankylosing spondylitis in Danish and Norwegian twins: occurrence and the relative importance of genetic vs. environmental effectors in disease causation.

OBJECTIVE: To estimate the influence of genetic effects in the aetiology and pathogenesis of ankylosing spondylitis (AS). METHODS: The study comprised one Norwegian and two Danish nationwide twin surveys. In 1994 and 2002, respectively, 37,388 and 46,331 Danish twin individuals were asked by questionnaire if they had AS. Similarly, in 1998, 12,718 Norwegian twins were asked if they had AS using a questionnaire phrased according to the Danish survey. Twins reporting AS were categorized according to the modified New York criteria. RESULTS: A total of 113 twin individuals reported AS, of whom 81 (72.3%) participated in validation of the diagnosis. After validation, 39 probands were diagnosed with AS. Subsequent invitation of co-twins resulted in 27 complete pairs. The point prevalence and the annual incidence of AS was 0.1% and 3/100,000 person-years (pyr) among the Danish twins. The positive predictive value of self-reported AS was 49.3%. Probandwise concordance rates on AS were (2/5) 40% in monozygotic (MZ) and (1/23) 4% in dizygotic (DZ) twins [difference 35% (95% CI 2.9-72.8), p = 0.26]. Heredity analysis including previously published and the present HLA-B27-positive twin pairs indicated that additive genetic effects account for 94% (95% CI 0.56-0.99) of the variance in the causation of AS. CONCLUSION: Self-reported AS needs careful validation. The occurrence of AS in a Danish twin population was 0.1% and accords well with previous studies on singletons in hospital settings. The present study adds to previous evidence of a major genetic effect in the pathogenesis of AS.

The occurrence of psoriatic arthritis in Denmark.

OBJECTIVE: To apply and compare different classification criteria on a representative nationwide sample of psoriatic arthritis (PsA) twins and to estimate the prevalence and incidence of PsA. METHODS: The study comprised three Danish nationwide twin cohorts. In 1994 37 388 Danish twin individuals and in 2002 46 418 twin individuals received a questionnaire, including questions on rheumatic diseases. Twins reporting PsA and their co-twins were classified according to the Moll and Wright and CASPAR (ClASsification criteria for Psoriatic ARthritis) criteria based on interview, clinical examination and scrutiny of medical records. RESULTS: 228 twin individuals reported PsA and 164 (72%) participated in clinical validation. By using the Moll and Wright and CASPAR criteria, 54 and 50 cases were diagnosed with PsA respectively. The positive predictive value of self-reported PsA was 31%. According to the Moll and Wright and CASPAR criteria the prevalence was 0.15% (95% CI: 0.13%, 0.22%) and 0.14% (95% CI: 0.11%, 0.19%) respectively. The annual incidence rate based on new self-reported cases in 2002 was 6/100 000 person-years (95% CI: 3/100 000 person-years, 11/100 000 person-years). CONCLUSIONS: The positive predictive value of self-reported PsA was 31%. The prevalence and incidence figures of PsA were equivalent to the previously reported occurrence in population- and hospital-based studies.

On the heritability of psoriatic arthritis. Disease concordance among monozygotic and dizygotic twins.

OBJECTIVE: A nationwide unselected twin population to estimate the relative importance of genetic and environmental effectors in the aetiopathogenesis of psoriatic arthritis (PsA). METHODS: The study comprised three Danish nationwide twin cohorts. In 1994 and 2002 a total of 37 388 and 46 418 Danish twin individuals respectively were asked by questionnaire if they had PsA. Twins reporting PsA were invited to participate in a clinical examination. Patients were classified according to the Moll and Wright and the CASPAR (ClASsification criteria for Psoriatic ARthritis) criteria. Heritability was estimated by probandwise concordance rates and variance component analysis. RESULTS: 228 twin individuals reported PsA. Following diagnostic validation in 164 (70%), 50 probands were diagnosed with PsA according to the Moll and Wright criteria. Five of their co-twins were either dead, had emigrated, or did not participate in the twin study and nine did not respond, resulting in 36 complete pairs. A total of one of 10 monozygotic pairs and one of 26 dizygotic pairs were concordant for PsA, yielding a 6.2% difference in proportions (95% CI: -11%, 37%). Five of 10 monozygotic pairs and four of 26 dizygotic pairs were concordant for psoriatic skin disease implying a 35% difference (95% CI: 2%, 60%, p<0.05). CONCLUSIONS: This first twin study on PsA confirms that genes are important in the causation of psoriatic skin disease. Despite the limited statistical power, the almost identical concordance rates for PsA in monozygotic and dizygotic twins stresses the importance of the continued search for non-genetic effectors in PsA.

Early exposure to smoking and future fecundity among Danish twins.

Several studies have examined the effect of in utero exposure to smoking and fecundity among the offspring but the findings are contradictory. We therefore studied the waiting time to first pregnancy (TTP) and exposure to smoking in utero and childhood among Danish twins born between 1931 and 1952. Information about TTP, exposure to mothers smoking in pregnancy, exposure to smoking in childhood and current smoking among the male twins and smoking in their own pregnancy among female twins was collected by interview. Fecundability odds ratio (FOR) estimating the odds of conception in a cycle among exposed compared to the unexposed were calculated separately for female and male twins. A total of 1653 female and 1598 male twins reported a TTP. Female twins, exposed in utero, had reduced fecundability after control for confounders (FOR = 0.81; 95% CI 0.67-0.99). A nonsignificant increase in fecundity among male twins exposed to smoking in utero was found (FOR = 1.12; 95% CI 0.89-1.40). Among dizygotic twins of opposite sex sharing the same in utero exposures, the future fecundity of the male twin was unaffected by in utero exposure (FOR = 0.97; 95% CI 0.60-1.55) whereas the female twin had reduced fecundity (FOR = 0.65; 95% CI 0.47-0.91). This study supports that smoking is hazardous to the female fetus not only in the short term but also affects her future ability to conceive and makes it even more important to advise pregnant women to stop smoking.

Concordance for multiple sclerosis in Danish twins: an update of a nationwide study.

The occurrence of multiple sclerosis (MS) in twins has not previously been studied in complete nationwide data sets. The existence of almost complete MS and twin registries in Denmark ensures that essentially unbiased samples of MS cases among twins can be obtained. In this population-based study, virtually all Danish MS cases among twins born before 1983 with onset of MS after 1948 and diagnosis before I January 1997 were identified. Of 13 286 MS cases, 178 were twins and, of these 164 twin pairs were discordant and seven were concordant. We found significantly higher proband-wise concordance among monozygotic twins than dizygotic twins, with estimated proband-wise concordances of 24% (95% confidence interval (CI): 5-39%) for monozygotic and 3% (95% CI: 0-8%) for dizygotic twins. Thus, a monozygotic twin whose co-twin has MS has a 24% risk of developing the disease, while the corresponding risk for a dizygotic twin is only 3%. Our results largely confirm previously published concordance estimates and indicate that genetic factors are of importance in susceptibility to MS.

The heritability of mortality due to heart diseases: a correlated frailty model applied to Danish twins.

Data of the Danish Twin Registry on monozygotic and dizygotic twins are used to analyse genetic and environmental influences on susceptibility to heart diseases for males and females, respectively. The sample includes 7955 like-sexed twin pairs born between 1870 and 1930. Follow-up was from 1 January 1943 to 31 December 1993 which results in truncation (twin pairs were included in the study if both individuals were still alive at the beginning of the follow-up) and censoring (nearly 40% of the study population was still alive at the end of the follow-up). We use the correlated gamma-frailty model for the genetic analysis of frailty to account for this censoring and truncation. During the follow-up 9370 deaths occurred, 3393 deaths were due to heart diseases in general, including 2476 deaths due to coronary heart disease (CHD). Proportions of variance of frailty attributable to genetic and environmental factors were analyzed using the structural equation model approach. Different standard biometric models are fitted to the data to evaluate the magnitude and nature of genetic and environmental factors on mortality. Using the best fitting model heritability of frailty (liability to death) was found to be 0.55 (0.07) and 0.53 (0.11) with respect to heart diseases and CHD, respectively, for males and 0.52 (0.10) and 0.58 (0.14) for females in a parametric analysis. A semi-parametric analysis shows very similar results. These analyses may indicate the existence of a strong genetic influence on individual frailty associated with mortality caused by heart diseases and CHD in both, males and females. The nature of genetic influences on frailty with respect to heart diseases and CHD is probably additive. No evidence for dominance and shared environment was found.

Cardiovascular mortality in twins and the fetal origins hypothesis.

The intrauterine growth patterns for twins are characterized by normal development during the first two trimesters and reduced growth during the third trimester. According to the fetal origins hypothesis this growth pattern is associated with risk factors for cardiovascular morbidity and mortality. We studied cause-specific mortality of 19,986 Danish twin individuals from the birth cohorts 1870-1930 followed from 1952 through 1993. Despite the large sample size and follow-up period we were not able to detect any difference between twins and the general population with regard to all-cause mortality or cardiovascular mortality. Hence, the intrauterine growth retardation experienced by twins does not result in any "fetal programming" of cardiovascular diseases. There is still an important role for twins (and other sibs) to play in the testing of the fetal origins hypothesis, namely in studies of intra-pair differences, which can assess the role of genetic confounding in the association between fetal growth and later health outcome.

Breast cancer risk in male twins: joint analyses of four twin cohorts in Denmark, Finland, Sweden and the United States.

To test the hypothesis that in utero exposure to high levels of oestrogen increases the risk of male breast cancer, we followed 115 235 male twins for more than 3.5 million person-years at risk. We observed 11 cases of male breast cancer versus 16.16 expected based on national rates (standardized rate ratio 0.68, 95% confidence interval 0.34-1.22) and conclude that any adverse influence of in utero oestrogen exposure is likely to be small.