Kirsten Ohm Kyvik

Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts

Recent genome-wide association (GWA) studies of lipids have been conducted in samples ascertained for other phenotypes, particularly diabetes. Here we report the first GWA analysis of loci affecting total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides sampled randomly from 16 population-based cohorts and genotyped using mainly the Illumina HumanHap300-Duo platform. Our study included a total of 17,797–22,562 persons, aged 18–104 years and from geographic regions spanning from the Nordic countries to Southern Europe. We established 22 loci associated with serum lipid levels at a genome-wide significance level (P < 5 × 10−8), including 16 loci that were identified by previous GWA studies. The six newly identified loci in our cohort samples are ABCG5 (TC, P = 1.5 × 10−11; LDL, P = 2.6 × 10−10), TMEM57 (TC, P = 5.4 × 10−10), CTCF-PRMT8 region (HDL, P = 8.3 × 10−16), DNAH11 (LDL, P = 6.1 × 10−9), FADS3-FADS2 (TC, P = 1.5 × 10−10; LDL, P = 4.4 × 10−13) and MADD-FOLH1 region (HDL, P = 6 × 10−11). For three loci, effect sizes differed significantly by sex. Genetic risk scores based on lipid loci explain up to 4.8% of variation in lipids and were also associated with increased intima media thickness (P = 0.001) and coronary heart disease incidence (P = 0.04). The genetic risk score improves the screening of high-risk groups of dyslipidemia over classical risk factors.

Telomere Length Inversely Correlates With Pulse Pressure and Is Highly Familial

There is evidence that telomeres, the ends of chromosomes, serve as clocks that pace cellular aging in vitro and in vivo. In industrialized nations, pulse pressure rises with age, and it might serve as a phenotype of biological aging of the vasculature. We therefore conducted a twin study to investigate the relation between telomere length in white blood cells and pulse pressure while simultaneously assessing the role of genetic factors in determining telomere length. We measured by Southern blot analysis the mean length of the terminal restriction fragments (TRF) in white blood cells of 49 twin pairs from the Danish Twin Register and assessed the relations of blood pressure parameters with TRF. TRF length showed an inverse relation with pulse pressure. Both TRF length and pulse pressure were highly familial. We conclude that telomere length, which is under genetic control, might play a role in mechanisms that regulate pulse pressure, including vascular aging.

Low birth weight is associated with NIDDM in discordant monozygotic and dizygotic twin pairs.

Summary Previous studies have demonstrated an association between low weight at birth and risk of later development of non-insulin-dependent diabetes mellitus (NIDDM). It is not known whether this association is due to an impact of intrauterine malnutrition per se, or whether it is due to a coincidence between the putative “NIDDM susceptibility genotype” and a genetically determined low weight at birth. It is also unclear whether differences in gestational age, maternal height, birth order and/or sex could explain the association. Twins are born of the same mother and have similar gestational ages. Furthermore, monozygotic (MZ) twins have identical genotypes. Original midwife birth weight record determinations were traced in MZ and dizygotic (DZ) twins discordant for NIDDM. Birth weights were lower in the NIDDM twins (n = 2 × 14) compared with both their identical (MZ; n = 14) and non-identical (DZ; n = 14) non-diabetic co-twins, respectively (MZ: mean ± SEM 2634 ± 135 vs 2829 ± 131 g, p < 0.02; DZ: 2509 ± 135 vs 2854 ± 168 g, p < 0.02). Using a similar approach in 39 MZ and DZ twin pairs discordant for impaired glucose tolerance (IGT), no significantly lower birth weights were detected in the IGT twins compared with their normal glucose tolerant co-twins. However, when a larger group of twins with different glucose tolerance were considered, birth weights were lower in the twins with abnormal glucose tolerance (NIDDM + IGT; n = 106; 2622 ± 45 g) and IGT (n = 62: 2613 ± 55 g) compared with twins with normal glucose tolerance (n = 112: 2800 ± 51 g; p = 0.01 and p = 0.03, respectively). Furthermore, the twins with the lowest birth weights among the two co-twins had the highest plasma glucose concentrations 120 min after the 75-g oral glucose load (n = 86 pairs: 9.6 ± 0.6 vs 8.0 ± 0.4 mmol/l, p = 0.03). In conclusion, the association between low birth weight and NIDDM in twins is at least partly independent of genotype and may be due to intrauterine malnutrition. IGT was also associated with low birth weight in twins. However, the possibility cannot be excluded that the association between low birth weight and IGT could be due to a coincidence with a certain genotype causing both low birth weight and IGT in some subjects. [Diabetologia (1997) 40: 439–446]

Concordance rates of insulin dependent diabetes mellitus: a population based study of young Danish twins.

Abstract Objective: To study the genetic contribution to the aetiology of insulin dependent diabetes mellitus. Design: Historical cohort study of twins, with information on diabetes being gathered by questionnaire, verification of the diagnosis by the subjects diabetologist or general practitioner, and clinical examination in available twins. Setting: Danish twin register and diabetic clinics and general practices throughout Denmark. Subjects: 20888 twin pairs born during 1953-82, included in a population based nationwide register. Main outcome measures: Crude and cumulative concordance rates and heritability in monozygotic and dizygotic twins. Results: The crude probandwise concordance rate was 0.53 (95% confidence interval 0.33 to 0.73) for monozygotic twin pairs and 0.11 (0.05 to 0.21) for dizygotic twin pairs. When adjusted for age at onset of diabetes and age at last observation among unaffected twin partners the cumulative probandwise risk from birth to age 35 was estimated as 0.70 (0.45 to 0.95) for monozygotic twins and 0.13 (0.05 to 0.20) for dizygotic twins. The correlations of liability for monozygotic and dizygotic twin pairs were estimated as 0.96 (SE 0.09) and 0.58 (0.07), with a heritability estimate of 0.72 (0.21). Conclusions: The risk of insulin dependent diabetes in monozygotic twins is higher than previously thought and for dizygotic twins is higher than in ordinary first degree relatives. Based on the findings of this study the genetic component to the disease seems more important than hitherto believed.

Sex Differences in Heritability of BMI: A Comparative Study of Results from Twin Studies in Eight Countries

Body mass index (BMI), a simple anthropometric measure, is the most frequently used measure of adiposity and has been instrumental in documenting the worldwide increase in the prevalence of obesity witnessed during the last decades. Although this increase in overweight and obesity is thought to be mainly due to environmental changes, i.e., sedentary lifestyles and high caloric diets, consistent evidence from twin studies demonstrates high heritability and the importance of genetic differences for normal variation in BMI. We analysed self-reported data on BMI from approximately 37,000 complete twin pairs (including opposite sex pairs) aged 20-29 and 30-39 from eight different twin registries participating in the GenomEUtwin project. Quantitative genetic analyses were conducted and sex differences were explored. Variation in BMI was greater for women than for men, and in both sexes was primarily explained by additive genetic variance in all countries. Sex differences in the variance components were consistently significant. Results from analyses of opposite sex pairs also showed evidence of sex-specific genetic effects suggesting there may be some differences between men and women in the genetic factors that influence variation in BMI. These results encourage the continued search for genes of importance to the body composition and the development of obesity. Furthermore, they suggest that strategies to identify predisposing genes may benefit from taking into account potential sex specific effects.

At what age does low back pain become a common problem? A study of 29,424 individuals aged 12-41 years.

Study Design. A cross‐sectional study was performed in a Danish population of individuals 12‐41 years of age. Objectives. To study the lifetime cumulative incidence, the 1‐year period prevalence, and point prevalence of low back pain in the general population and to investigate whether there were any differences in the occurrence of low back pain that were related to age and gender, especially in young individuals. Summary of Background Data. The epidemiologic literature fails to provide a credible estimate of the prevalence of low back pain in children and adolescents compared with that of adults. Methods. A postal questionnaire was sent to 34,076 twins who were born between 1953 and 1982 and listed in the population‐based Danish Twin register. The response rate was 86%. Results. The prevalence of the various definitions of low back pain increased greatly in the early teen years (earlier for girls than for boys), and by the ages of 18 years (girls) and 20 years (boys) more than 50% had experienced at least one low back pain episode. The pattern for the 1‐year period prevalence of low back pain was very similar to that for the lifetime prevalence; both started at 7% (95% confidence interval, 5‐9%) for the 12‐year‐old individuals and reached 56% (95% confidence interval, 53‐59%) and 67% (95% confidence interval, 62‐71%), respectively, for the 41‐year‐old individuals. The pattern for the point prevalence resembled that of the more than 30 days of low back pain reported in the preceding year; the rate increased steadily from 1% (95% confidence interval, 0‐2%) to 17% (95% confidence interval, 14‐20%). There was a general tendency for more women to report low back pain than men, but this difference generally was not statistically significant. Conclusions. The study of the causes and prevention of low back pain needs to be focused on childhood and adolescence.

The course of low back pain from adolescence to adulthood : Eight-year follow-up of 9600 twins

Study Design. Prospective study with 8-year follow-up. Objective. To describe the evolution of low back pain from adolescence into adulthood. Summary of Background Data. High prevalence rates of low back pain among children and adolescents have been demonstrated in several studies, and it has been theorized that low back pain in childhood may have important consequences for future low back pain. It is important to understand the nature of such a link if effective preventive programs are to be established. Methods. Almost 10,000 Danish twins born between 1972 and 1982 were surveyed by means of postal questionnaires in 1994 and again in 2002. The questionnaires dealt with various aspects of general health, including the prevalence of low back pain, classified according to number of days affected (0, 1–7, 8–30, >30). Results. Low back pain in adolescence was found to be a significant risk factor for low back pain in adulthood with odds ratios as high as four. We also demonstrated a dose-response association: the more days with low back pain at baseline, the higher the risk of future low back pain. Twenty-six percent of those with low back pain for more than 30 days during the baseline year also had more than 30 days with low back pain during the follow-up year. This was true for only 9% of the rest of the sample. Conclusions. Our study clearly demonstrates correlations between low back pain in childhood/adolescence and low back pain in adulthood. This should lead to a change in focus from the adult to the young population in relation to research, prevention, and treatment.

The importance of genes and environment for ocular refraction and its determiners: a population based study among 20–45 year old twins

AIMS To estimate the heritability for ocular refraction and its determiners in a population based cohort of 20–45 years old twins. METHODS 114 twin pairs (53 monozygotic and 61 dizygotic) participated. Refraction was determined in cycloplegia and eye dimensions were measured with ultrasound. Educational length was assessed. The heritability was estimated employing aetiological model fitting. Evidence of gene-environment interaction was analysed. Correlations between intrapairwise differences in educational length and in refraction were evaluated. RESULTS The heritability was between 0.89 and 0.94 (95% CI: 0.82, 0.96) for refraction, total refraction, axial length, and radius of corneal curvature. Phenotypic variation was mostly due to additive genetic effects. Refraction revealed evidence of gene-environment interaction (r = −0.29 to −0.32; p <0.05). The heritability for anterior chamber depth and lens thickness was between 0.88 and 0.94 (95% CI: 0.81, 0.96) and dominant genetic effects were the most likely explanation. There was no correlation between age and intrapairwise differences in refraction. The dizygotic twins had significant larger intrapairwise differences in educational length (p <0.05), but the differences were not correlated with differences in refraction. CONCLUSIONS The results indicate a high heritability for ocular refraction and its determiners and thus suggest that environmental impact on refraction is not significant. However, the epidemiological association between educational length (near work) and myopia, the evidence of increasing myopia prevalence within a few generations, and the theory of gene-environment interaction imply that some individuals might be genetically liable to develop myopia if exposed to certain environmental factors.

Age- and Sex-differences in the Validity of Questionnaire-based Zygosity in Twins.

Questionnaire-based zygosity assessment in twins has generally been found to be valid. In this report we evaluate sex- and age-differences in the validity of such questionnaire-based classification when using the four questions that have been the basis of zygosity assessment in The Danish Twin Registry for half a century. Three hundred and forty-two male and 531 female twin pairs were zygosity diagnosed using genetic markers and the results compared with the original questionnaire based classification. We found significant differences in the accuracy of questionnaire based zygosity diagnosis when stratifying the data for sex as well as age: males and monozygotic having the highest misclassification. However, even in the group with the highest misclassification rate the frequency was less than 8%. The overall misclassification rate was only 4%, with a clear tendency towards a higher proportion of misclassified monozygotic than dizygotic twins. The results demonstrate that questionnaire based zygosity diagnosis can still be regarded as a valid and valuable classification method for most purposes.

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.