Niels V. Holm

Environmental and Heritable Factors in the Causation of Cancer — Analyses of Cohorts of Twins from Sweden, Denmark, and Finland

BACKGROUND The contribution of hereditary factors to the causation of sporadic cancer is unclear. Studies of twins make it possible to estimate the overall contribution of inherited genes to the development of malignant diseases. METHODS We combined data on 44,788 pairs of twins listed in the Swedish, Danish, and Finnish twin registries in order to assess the risks of cancer at 28 anatomical sites for the twins of persons with cancer. Statistical modeling was used to estimate the relative importance of heritable and environmental factors in causing cancer at 11 of those sites. RESULTS At least one cancer occurred in 10,803 persons among 9512 pairs of twins. An increased risk was found among the twins of affected persons for stomach, colorectal, lung, breast, and prostate cancer. Statistically significant effects of heritable factors were observed for prostate cancer (42 percent; 95 percent confidence interval, 29 to 50 percent), colorectal cancer (35 percent; 95 percent confidence interval, 10 to 48 percent), and breast cancer (27 percent; 95 percent confidence interval, 4 to 41 percent). CONCLUSIONS Inherited genetic factors make a minor contribution to susceptibility to most types of neoplasms. This finding indicates that the environment has the principal role in causing sporadic cancer. The relatively large effect of heritability in cancer at a few sites suggests major gaps in our knowledge of the genetics of cancer.

Mortality among twins after age 6: fetal origins hypothesis versus twin method.

Abstract Objective: To test the validity of the fetal origins hypothesis and the classic twin method. Design: Follow up study of pairs of same sex twins in which both twins survived to age 6. Setting: Denmark. Subjects: 8495 twin individuals born 1870-1900, followed through to 31 December 1991. Main outcome measures: Mortality calculated on a cohort basis. Results: Mortality among twins and the general population was not significantly different except among females aged 60-89, in whom mortality among twins was 1.14 times (SE 0.03) higher than in the general population. Mortality among female dizygotic twins was 1.77 times (0.18) higher than among monozygotic twins at age 30.59. Otherwise, mortality for monozygotic and dizygotic twins did not consistently differ after age 6. Conclusion: According to the fetal origins hypothesis the risk of adult morbidity and mortality is heightened by retardation in intrauterine growth. Twins, and in particular monozygotic twins, experience growth retardation in utero. The findings in the present study suggest that the fetal origins hypothesis is not true for the retardation in intrauterine growth experienced by twins. Furthermore, the data are inconsistent with the underlying assumption of a recent claim that the classic twin method is invalid for studies of adult diseases. The present study is, however, based on the one third of all pairs of twins in which both twins survived to age 6. The possible impact of this selection can be evaluated in future studies of cohorts of younger twins with lower perinatal and infant mortality. Key messages Key messages It has been claimed that twin studies of adult diseases are invalid owing to the link between intrauterine development and adult diseases Contrary to the prediction from the fetal origins hypothesis this study found that mortality among twins and in the general population was similar after age 6 Contrary to the underlying assumption of the claim that the twin method is invalid, this study found that mortality in monozygotic and dizygotic twins was similar after age 6 This study suggests that the fetal origins hypothesis is not true for the retardation in intrauterine growth in these twin cohorts and that the hypothesis is no threat to the validity of the twin method

The Danish Twin Registry: 127 birth cohorts of twins.

The Danish Twin Registry is the oldest national twin register in the world, initiated in 1954 by ascertainment of twins born from 1870 to 1910. During a number of studies birth cohorts have been added to the register, and by the recent addition of birth cohorts from 1931 to 1952 the Registry now comprizes 127 birth cohorts of twins from 1870 to 1996, with a total of more than 65,000 twin pairs included. In all cohorts the ascertainment has been population-based and independent of the traits studied, although different procedures of ascertainment have been employed. In the oldest cohorts only twin pairs with both twins surviving to age 6 have been included while from 1931 all ascertained twins are included. The completeness of the ascertainment after adjustment for infant mortality is high, with approximately 90% ascertained up to 1968, and complete ascertainment of all liveborn twin pairs since 1968. The Danish Twin Registry is used as a source for large studies on genetic influence on aging and age-related health problems, normal variation in clinical parameters associated with the metabolic syndrome and cardiovascular diseases, and clinical studies of specific diseases. The combination of survey data with data obtained by linkage to national health related registers enables follow-up studies both of the general twin population and of twins from clinical studies.

Familial Risk and Heritability of Cancer Among Twins in Nordic Countries

IMPORTANCE Estimates of familial cancer risk from population-based studies are essential components of cancer risk prediction. OBJECTIVE To estimate familial risk and heritability of cancer types in a large twin cohort. DESIGN, SETTING, AND PARTICIPANTS Prospective study of 80,309 monozygotic and 123,382 same-sex dizygotic twin individuals (N = 203,691) within the population-based registers of Denmark, Finland, Norway, and Sweden. Twins were followed up a median of 32 years between 1943 and 2010. There were 50,990 individuals who died of any cause, and 3804 who emigrated and were lost to follow-up. EXPOSURES Shared environmental and heritable risk factors among pairs of twins. MAIN OUTCOMES AND MEASURES The main outcome was incident cancer. Time-to-event analyses were used to estimate familial risk (risk of cancer in an individual given a twins development of cancer) and heritability (proportion of variance in cancer risk due to interindividual genetic differences) with follow-up via cancer registries. Statistical models adjusted for age and follow-up time, and accounted for censoring and competing risk of death. RESULTS A total of 27,156 incident cancers were diagnosed in 23,980 individuals, translating to a cumulative incidence of 32%. Cancer was diagnosed in both twins among 1383 monozygotic (2766 individuals) and 1933 dizygotic (2866 individuals) pairs. Of these, 38% of monozygotic and 26% of dizygotic pairs were diagnosed with the same cancer type. There was an excess cancer risk in twins whose co-twin was diagnosed with cancer, with estimated cumulative risks that were an absolute 5% (95% CI, 4%-6%) higher in dizygotic (37%; 95% CI, 36%-38%) and an absolute 14% (95% CI, 12%-16%) higher in monozygotic twins (46%; 95% CI, 44%-48%) whose twin also developed cancer compared with the cumulative risk in the overall cohort (32%). For most cancer types, there were significant familial risks and the cumulative risks were higher in monozygotic than dizygotic twins. Heritability of cancer overall was 33% (95% CI, 30%-37%). Significant heritability was observed for the cancer types of skin melanoma (58%; 95% CI, 43%-73%), prostate (57%; 95% CI, 51%-63%), nonmelanoma skin (43%; 95% CI, 26%-59%), ovary (39%; 95% CI, 23%-55%), kidney (38%; 95% CI, 21%-55%), breast (31%; 95% CI, 11%-51%), and corpus uteri (27%; 95% CI, 11%-43%). CONCLUSIONS AND RELEVANCE In this long-term follow-up study among Nordic twins, there was significant excess familial risk for cancer overall and for specific types of cancer, including prostate, melanoma, breast, ovary, and uterus. This information about hereditary risks of cancers may be helpful in patient education and cancer risk counseling.

The Danish Twin Registry in the New Millennium

The Danish Twin Registry is the oldest national twin register in the world, initiated in 1954, and, by the end of 2005, contained more than 75,000 twin pairs born in the between 1870 and 2004. The Danish Twin Registry is used as a source for studies on the genetic influence on normal variation in clinical parameters associated with the metabolic syndrome and cardiovascular diseases, clinical studies of specific diseases, and aging and age-related health problems. The combination of survey data, clinical data and linkage to national health-related registers enables follow-up studies of both the general twin population and twins from clinical studies. This paper summarizes the newest extension of the register and gives examples of new developments and phenotypes studied.

How heritable is individual susceptibility to death? The results of an analysis of survival data on Danish, Swedish and Finnish twins

Molecular epidemiological studies confirm a substantial contribution of individual genes to variability in susceptibility to disease and death for humans. To evaluate the contribution of all genes to susceptibility and to estimate individual survival characteristics, survival data on related individuals (eg twins or other relatives) are needed. Correlated gamma-frailty models of bivariate survival are used in a joint analysis of survival data on more than 31,000 pairs of Danish, Swedish and Finnish male and female twins using the maximum likelihood method. Additive decomposition of frailty into genetic and environmental components is used to estimate heritability in frailty. The estimate of the standard deviation of frailty from the pooled data is about 1.5. The hypothesis that variance in frailty and correlations of frailty for twins are similar in the data from all three countries is accepted. The estimate of narrow-sense heritability in frailty is about 0.5. The age trajectories of individual hazards are evaluated for all three populations of twins and both sexes. The results of our analysis confirm the presence of genetic influences on individual frailty and longevity. They also suggest that the mechanism of these genetic influences may be similar for the three Scandinavian countries. Furthermore, results indicate that the increase in individual hazard with age is more rapid than predicted by traditional demographic life tables.

Relative importance of genetic effects in rheumatoid arthritis: historical cohort study of Danish nationwide twin population

Abstract Objective: To determine the relative importance of environmental and genetic effects in the development of rheumatoid arthritis. Design: Historical cohort study with record linkage between a twin registry and the Danish discharge registry as well as the Danish national registry of deaths used to estimate completeness. Setting: Two population based nationwide twin birth cohorts. Participants: 37 338 twins were sent a questionnaire about rheumatic diseases. Self reported rheumatoid arthritis was verified by clinical examination and from medical records. Main outcome measures: The probandwise concordance rate of rheumatoid arthritis in monozygotic and dizygotic twins. Results: The response rate was 84.7%. Rheumatoid arthritis was verified in 13 monozygotic and 36 dizygotic twins. There were no concordant monozygotic twin pairs and two concordant dizygotic twin pairs. Based on capture-recapture methods the probability of ascertainment was 78.3%. The probandwise concordance rate was 0 (95% confidence interval 0 to 24.7) in monozygotic twins and 8.8 (1.9 to 23.7) in dizygotic twins. Conclusion: Genes are of minor importance in the development of rheumatoid arthritis. What is already known on this topic Rheumatoid arthritis is a multifactorial disease determined by both genetic and environmental factors Previous twin studies have shown a higher concordance for rheumatoid arthritis in monozygotic than in dizygotic twins, but the results have been biased in favour of genetic effects What this paper adds As concordance for rheumatoid arthritis in this study was no more common in monozygotic twins than in dizygotic twins environmental effects may be more important than genetic effects in the development of rheumatoid arthritis

The Danish Twin Registry.

Introduction: The Danish Twin Registry is a unique source for studies of genetic, familial and environmental factors on life events, health conditions and diseases. Content: More than 85,000 twin pairs born 1870—2008 in Denmark. Validity and coverage: Four main ascertainment methods have been employed. Completeness of ascertainment varies according to birth cohorts. For birth cohorts 1870—1930 both twins should survive to age 6 years. From 1931—1968 72% of all twin pairs has been ascertained, with complete ascertainment of all live born twins since 1968. Conclusion: Because twins have been identified independent of traits and on a population basis, the Danish Twin Registry is well suited for studies to understand the influence of genetic and environmental factors for a wide variety of diseases and traits.

Time-Dependent Association Measures for Bivariate Survival Distributions

Abstract We propose time-dependent association measures for application to bivariate survival analysis. Such association measures provide informative summaries for data on twins, ophthalmic and auditory studies, and for other matched-pair designs. We develop several desirable properties of time-dependent association measures and study three measures motivated by these properties. We examine the measures from a general bivariate survival perspective and for the proportional hazards frailty model. We use monozygotic (MZ) and dizygotic (DZ) twin data from the Danish Twin Registry to illustrate how these measures depend on the specification of the proportional hazards frailty model. This model consists of two components: a baseline hazard function and a frailty distribution. We produce gamma and nonparametric maximum likelihood estimates of the frailty distribution and estimate a Gompertz baseline hazard function. For two of the measures, a nonparametric estimate provides a comparison to the model-based estim...

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.