Magnus Svartengren

The Swedish Twin Registry: a unique resource for clinical, epidemiological and genetic studies

Abstract.  Lichtenstein P, de Faire U, Floderus B, Svartengren M, Svedberg P, Pedersen NL (Karolinska Institutet; Karolinska Hospital; Institute of Environmental Medicine, Karolinska Institutet, National Institute for Working life, Stockholm, Sweden; and University of Southern California, CA, USA) The Swedish Twin Registry: a unique resource for clinical, epidemiological and genetic studies (Review). J Intern Med 2002; 252: 184–205.

The Swedish Twin Registry in the Third Millennium: An Update

The Swedish Twin Registry was first established in the late 1950s. Today it includes more than 170,000 twins--in principle, all twins born in Sweden since 1886. In this article we describe some ongoing and recently completed projects based on the registry. In particular, we describe recent efforts to screen all twins born between 1959 and 1985, and young twin pairs when they turn 9 and 12 years of age. For these studies, we present initial frequencies of common conditions and exposures.

Residential Radon Exposure and Lung Cancer in Sweden

BACKGROUND Residential radon is the principal source of exposure to ionizing radiation in most countries. To determine the implications for the risk of lung cancer, we performed a nationwide case-control study in Sweden. METHODS The study included 586 women and 774 men 35 to 74 years of age with lung cancer that was diagnosed between 1980 and 1984. For comparison, 1380 female and 1467 male controls were studied. Radon was measured in 8992 dwellings occupied by the study subjects at some time since 1947. Information on smoking habits and other risk factors for lung cancer was obtained from questionnaires. RESULTS Radon levels followed a log-normal distribution, with geometric and arithmetic means of 1.6 and 2.9 pCi per liter (60.5 and 106.5 Bq per cubic meter), respectively. The risk of lung cancer increased in relation to both estimated cumulative and time-weighted exposure to radon. In comparison with time-weighted average radon concentrations up to 1.4 pCi per liter (50 Bq per cubic meter), the relative risk was 1.3 (95 percent confidence interval, 1.1 to 1.6) for average radon concentrations of 3.8 to 10.8 pCi per liter (140 to 400 Bq per cubic meter), and it was 1.8 (95 percent confidence interval, 1.1 to 2.9) at concentrations exceeding 10.8 pCi per liter. The estimates of risk were in the same range as those projected from data in miners. The interaction between radon exposure and smoking with regard to lung cancer exceeded additivity and was closer to a multiplicative effect. CONCLUSIONS Residential exposure to radon is an important cause of lung cancer in the general population. The risks appear consistent with earlier estimates based on data in miners.

Dietary prevention of allergic diseases in infants and small children.

Because of scientific fraud four trials have been excluded from the original Cochrane meta‐analysis on formulas containing hydrolyzed protein for prevention of allergy and food intolerance in infants. Unlike the conclusions of the revised Cochrane review the export group set up by the Section on Paediatrics, European Academy of Allergology and Clinical Immunology (SP‐EAACI) do not find that the exclusion of the four trials demands a change of the previous recommendations regarding primary dietary prevention of allergic diseases. Ideally, recommendations on primary dietary prevention should be based only on the results of randomized and quasi‐randomized trials (selection criteria in the Cochrane review). However, regarding breastfeeding randomization is unethical, Therefore, in the development of recommendations on dietary primary prevention, high‐quality systematic reviews of high‐quality cohort studies should be included in the evidence base. The study type combined with assessment of the methodological quality determines the level of evidence. In view of some methodological concerns in the Cochrane meta‐analysis, particularly regarding definitions and diagnostic criteria for outcome measures and inclusion of non peer‐reviewed studies/reports, a revision of the Cochrane analysis may seem warranted. Based on analysis of published peer‐reviewed observational and interventional studies the results still indicate that breastfeeding is highly recommended for all infants irrespective of atopic heredity. A dietary regimen is effective in the prevention of allergic diseases in high‐risk infants, particularly in early infancy regarding food allergy and eczema. The most effective dietary regimen is exclusively breastfeeding for at least 4–6 months or, in absence of breast milk, formulas with documented reduced allergenicity for at least the first 4 months, combined with avoidance of solid food and cows milk for the first 4 months.The role of primary prevention of allergic diseases has been a matter of debate for the last 40 years. In order to shed some light on this issue, a group of experts of the Section of Pediatrics EAACI reviewed critically the existing literature on the subject. An analysis of published peer-reviewed observational and interventional studies was performed following the statements of evidence as defined by WHO. The results of the analysis indicate that breastfeeding is highly recommended for all infants irrespective of atopic heredity. A dietary regimen is unequivocally effective in the prevention of allergic diseases in high-risk children. In these patients breastfeeding combined with avoidance of solid food and cows milk for at least 4-6 months is the most effective preventive regimen. In the absence of breast milk, formulas with documented reduced allergenicity for at least 4-6 months should be used.

MMP12, lung function, and COPD in high-risk populations.

BACKGROUND Genetic variants influencing lung function in children and adults may ultimately lead to the development of chronic obstructive pulmonary disease (COPD), particularly in high-risk groups. METHODS We tested for an association between single-nucleotide polymorphisms (SNPs) in the gene encoding matrix metalloproteinase 12 (MMP12) and a measure of lung function (prebronchodilator forced expiratory volume in 1 second [FEV(1)]) in more than 8300 subjects in seven cohorts that included children and adults. Within the Normative Aging Study (NAS), a cohort of initially healthy adult men, we tested for an association between SNPs that were associated with FEV(1) and the time to the onset of COPD. We then examined the relationship between MMP12 SNPs and COPD in two cohorts of adults with COPD or at risk for COPD. RESULTS The minor allele (G) of a functional variant in the promoter region of MMP12 (rs2276109 [-82A-->G]) was positively associated with FEV(1) in a combined analysis of children with asthma and adult former and current smokers in all cohorts (P=2x10(-6)). This allele was also associated with a reduced risk of the onset of COPD in the NAS cohort (hazard ratio, 0.65; 95% confidence interval [CI], 0.46 to 0.92; P=0.02) and with a reduced risk of COPD in a cohort of smokers (odds ratio, 0.63; 95% CI, 0.45 to 0.88; P=0.005) and among participants in a family-based study of early-onset COPD (P=0.006). CONCLUSIONS The minor allele of a SNP in MMP12 (rs2276109) is associated with a positive effect on lung function in children with asthma and in adults who smoke. This allele is also associated with a reduced risk of COPD in adult smokers.

Dietary prevention of allergic diseases in infants and small children. Part III: Critical review of published peer-reviewed observational and interventional studies and final recommendations

The role of primary prevention of allergic diseases has been a matter of debate for the last 40 years. In order to shed some light on this issue, a group of experts of the Section of Pediatrics EAACI reviewed critically the existing literature on the subject. An analysis of published peer‐reviewed observational and interventional studies was performed following the statements of evidence as defined by WHO. The results of the analysis indicate that breastfeeding is highly recommended for all infants irrespective of atopic heredity. A dietary regimen is unequivocally effective in the prevention of allergic diseases in high‐risk children. In these patients breastfeeding combined with avoidance of solid food and cows milk for at least 4–6 months is the most effective preventive regimen. In the absence of breast milk, formulas with documented reduced allergenicity for at least 4–6 months should be used.

Traffic-related air pollution and childhood respiratory symptoms, function and allergies.

Background: Urban air pollution can trigger asthma symptoms in children, but there is conflicting evidence on effects of long-term exposure on lung function, onset of airway disease and allergic sensitization. Methods: The spatial distribution of nitrogen oxides from traffic (traffic-NOx) and inhalable particulate matter from traffic (traffic-PM10) in the study area was assessed with emission databases and dispersion modeling. Estimated levels were used to assign first-year exposure levels for children in a prospective birth cohort (n = 4089), by linking to geocoded home addresses. Parents in 4 Swedish municipalities provided questionnaire data on symptoms and exposures when the children were 2 months and 1, 2, and 4-year-old. At 4 years, 73% of the children underwent clinical examination including peak expiratory flow and specific IgE measurements. Results: Exposure to air pollution from traffic during the first year of life was associated with an excess risk of persistent wheezing (odds ratio [OR] for 44 &mgr;g/m3 [5th–95th percentile] difference in traffic-NOx = 1.60; 95% confidence interval [CI] = 1.09–2.36). Similar results were found for sensitization (measured as specific IgE) to inhalant allergens, especially pollen (OR for traffic-NOx = 1.67; 95% CI = 1.10–2.53), at the age of 4 years. Traffic-related air pollution exposure during the first year of life was also associated with lower lung function at 4 years of age. Results were similar using traffic-NOx and traffic-PM10 as indicators. Conclusions: Exposure to moderate levels of locally emitted air pollution from traffic early in life appears to influence the development of airway disease and sensitization in preschool children.

Cardiovascular fitness is associated with cognition in young adulthood

During early adulthood, a phase in which the central nervous system displays considerable plasticity and in which important cognitive traits are shaped, the effects of exercise on cognition remain poorly understood. We performed a cohort study of all Swedish men born in 1950 through 1976 who were enlisted for military service at age 18 (N = 1,221,727). Of these, 268,496 were full-sibling pairs, 3,147 twin pairs, and 1,432 monozygotic twin pairs. Physical fitness and intelligence performance data were collected during conscription examinations and linked with other national databases for information on school achievement, socioeconomic status, and sibship. Relationships between cardiovascular fitness and intelligence at age 18 were evaluated by linear models in the total cohort and in subgroups of full-sibling pairs and twin pairs. Cardiovascular fitness, as measured by ergometer cycling, positively associated with intelligence after adjusting for relevant confounders (regression coefficient b = 0.172; 95% CI, 0.168–0.176). Similar results were obtained within monozygotic twin pairs. In contrast, muscle strength was not associated with cognitive performance. Cross-twin cross-trait analyses showed that the associations were primarily explained by individual specific, non-shared environmental influences (≥80%), whereas heritability explained <15% of covariation. Cardiovascular fitness changes between age 15 and 18 y predicted cognitive performance at 18 y. Cox proportional-hazards models showed that cardiovascular fitness at age 18 y predicted educational achievements later in life. These data substantiate that physical exercise could be an important instrument for public health initiatives to optimize educational achievements, cognitive performance, as well as disease prevention at the society level.

Breast-feeding in relation to asthma, lung function, and sensitization in young schoolchildren

BACKGROUND The evidence from previous studies on beneficial effects of breast-feeding in relation to development of asthma is conflicting. OBJECTIVE To investigate the relation between breast-feeding and asthma and/or sensitization during the first 8 years of life. METHOD In a birth cohort, children were followed up to 8 years by questionnaires at ages 2 months and 1, 2, 4, and 8 years to collect information on exposures and health effects. Determination of serum IgE antibodies to common inhalant and food allergens was performed at 4 and 8 years. Longitudinal analyses were applied by using general estimated equations. The study population consisted of 3825 children (93% of the original cohort), of whom 2370 gave blood and 2564 performed lung function measurements at 8 years. RESULTS Children exclusively breast-fed 4 months or more had a reduced risk of asthma during the first 8 years of life (adjusted odds ratio [OR], 0.63; 95% CI, 0.50-0.78) compared with children breast-fed less than 4 months. At 8 years, reduced risks of sensitization (adjusted OR, 0.79; 95% CI, 0.64-0.99) and asthma in combination with sensitization (adjusted OR, 0.59; 95% CI, 0.37-0.93) were seen among children exclusively breast-fed 4 months or more. This group also had a significantly better lung function measured with peak expiratory flow. CONCLUSION Breast-feeding for 4 months or more seems to reduce the risk of asthma up to 8 years. At this age, a reduced risk was observed particularly for asthma combined with sensitization. Furthermore, breast-feeding seems to have a beneficial effect on lung function.

Air Pollution Exposure and Lung Function in Children: The ESCAPE Project.

Background: There is evidence for adverse effects of outdoor air pollution on lung function of children. Quantitative summaries of the effects of air pollution on lung function, however, are lacking due to large differences among studies. Objectives: We aimed to study the association between residential exposure to air pollution and lung function in five European birth cohorts with a standardized exposure assessment following a common protocol. Methods: As part of the European Study of Cohorts for Air Pollution Effects (ESCAPE) we analyzed data from birth cohort studies situated in Germany, Sweden, the Netherlands, and the United Kingdom that measured lung function at 6–8 years of age (n = 5,921). Annual average exposure to air pollution [nitrogen oxides (NO2, NOx), mass concentrations of particulate matter with diameters < 2.5, < 10, and 2.5–10 μm (PM2.5, PM10, and PMcoarse), and PM2.5 absorbance] at the birth address and current address was estimated by land-use regression models. Associations of lung function with estimated air pollution levels and traffic indicators were estimated for each cohort using linear regression analysis, and then combined by random effects meta-analysis. Results: Estimated levels of NO2, NOx, PM2.5 absorbance, and PM2.5 at the current address, but not at the birth address, were associated with small decreases in lung function. For example, changes in forced expiratory volume in 1 sec (FEV1) ranged from –0.86% (95% CI: –1.48, –0.24%) for a 20-μg/m3 increase in NOx to –1.77% (95% CI: –3.34, –0.18%) for a 5-μg/m3 increase in PM2.5. Conclusions: Exposure to air pollution may result in reduced lung function in schoolchildren. Citation: Gehring U, Gruzieva O, Agius RM, Beelen R, Custovic A, Cyrys J, Eeftens M, Flexeder C, Fuertes E, Heinrich J, Hoffmann B, de Jongste JC, Kerkhof M, Klümper C, Korek M, Mölter A, Schultz ES, Simpson A, Sugiri D, Svartengren M, von Berg A, Wijga AH, Pershagen G, Brunekreef B. 2013. Air pollution exposure and lung function in children: the ESCAPE project. Environ Health Perspect 121:1357–1364; http://dx.doi.org/10.1289/ehp.1306770