BACKGROUND: Low birth weight has been associated with an increased risk of type 2 diabetes in adulthood. Poor fetal nutrition has been suggested to explain this association. Our objective was to determine whether genetic factors contribute to the association between low birth weight and subsequent risk of type 2 diabetes. METHODS: We retrieved information from original birth records on same-sex Swedish twins with known zygosity, born from 1926 to 1958. We used regression models to investigate whether birth weight was associated with risk of type 2 diabetes in the cohort of twins overall, and in case-control analyses within disease-discordant dizygotic and monozygotic twin pairs. RESULTS: Of 18,230 twins, 592 (3.2%) had type 2 diabetes. The rate of type 2 diabetes consistently increased with decreasing birth weight, from 2.4% among twins with birth weights of 3500 g or more to 5.3% among those with birth weights less than 2000 g. In the cohort analysis, in which twins are analyzed as independent individuals, the adjusted odds ratio (95% confidence interval) of type 2 diabetes per 500-g decrease in birth weight was 1.44 (1.28-1.63). When we compared the diseased twin with the healthy cotwin, the corresponding odds ratios were 1.38 (1.02-1.85), among dizygotic twins, and 1.02 (0.63-1.64), among monozygotic twins. CONCLUSIONS: Low birth weight is associated with type 2 diabetes in adulthood. The difference in this association between monozygotic and dizygotic twin pairs suggests that genetic mechanisms play an important role in this association.
There is a controversy whether use of smokeless tobacco is associated with an increased risk of diabetes. A population-based cross-sectional study was undertaken of 1,859 men, aged 60 years, in Stockholm County. No significant association was found between risk of diabetes and any use of tobacco, even if an association between snuff and risk of diabetes could not be excluded.
Epidemiologic studies suggest positive associations between poor oral health and cardiovascular disease. The authors undertook a prospective study among 15,273 Swedish twins (1963-2000) to examine whether genetic factors underlying the 2 diseases could explain previous associations. They estimated hazard ratios and 95% confidence intervals controlling for individual factors and stratifying on twin pairs to control for familial effects. Quantitative genetic analyses estimated genetic correlations between oral diseases and cardiovascular disease outcomes. Tooth loss (hazard ratio (HR) = 1.2, 95% confidence interval (CI): 1.1, 1.4) and periodontal disease (HR = 1.3, 95% CI: 1.0, 1.4) were associated with small excess risks of cardiovascular disease; periodontal disease was also associated with coronary heart disease (HR = 1.4, 95% CI: 1.1, 1.6). Adjustment for genetic factors in co-twin analyses did not appreciably change estimates. In contrast, tooth loss was more strongly associated with coronary heart disease in twin models (HR = 2.1, 95% CI: 1.2, 3.8) compared with adjusting for individual factors alone (HR = 1.3, 95% CI: 1.1, 1.4). There was evidence of shared genetic factors between cardiovascular disease and tooth loss (r(G) = 0.18) and periodontal disease (r(G) = 0.29). Oral disease was associated with excess cardiovascular disease risk, independent of genetic factors. There appear to be common pathogenetic mechanisms between poor oral health and cardiovascular disease.
BACKGROUND: High body mass index (BMI) and lack of physical activity have been recognized as important risk factors for coronary heart disease. The aim of the present study was to evaluate whether leisure-time physical activity compensates for the increased risk of acute myocardial infarction associated with overweight and obesity. METHODS: Data from the SHEEP (Stockholm Heart Epidemiology Program) study were used. The SHEEP study is a large Swedish population-based case-control study, comprising 1204 male and 550 female cases, and 1538 male and 777 female controls, conducted in Stockholm County, Sweden, during the period 1992-1994. Odds ratios (OR), together with 95 % confidence intervals (95% CI), were calculated using unconditional logistic regression, as estimates of the relative risks. RESULTS: Regular leisure-time physical activity was associated with a decreased risk of myocardial infarction among lean, normal-weight and overweight subjects, but not among obese subjects. Obese (BMI > or = 30) and physically active persons had an almost twofold risk of myocardial infarction, compared with normal-weight and sedentary persons (OR 1.85, 95% CI 1.07-3.18). The results were similar for men and women. CONCLUSION: While regular leisure-time physical activity seems to provide protection against myocardial infarction among lean, normal-weight and overweight subjects, this does not appear to be the case in obese subjects.
BACKGROUND: Studies have found associations between low birth weight and increased risks of cardiovascular diseases in adulthood. However, these associations could be due to confounding by genetic or socioeconomic factors. METHODS AND RESULTS: We performed a study on Swedish like-sexed twins with known zygosity who were born from 1926 to 1958. First, to obtain an overall effect of birth weight on risk of hypertension, we performed cohort analyses on all twins (n=16,265). Second, to address genetic and shared environmental confounding, we performed a nested co-twin control analysis within 594 dizygotic and 250 monozygotic twin pairs discordant for hypertension. Birth characteristics, including birth weight, were obtained from original birth records. Information from adulthood was collected from a postal questionnaire in 1973 (body mass index, height, smoking, and alcohol use) and from a telephone interview conducted from 1998 to 2002 (hypertension and socioeconomic status). Hypertension was defined as reporting both high blood pressure and treatment with antihypertensive medication. In the cohort analysis, the adjusted odds ratio for hypertension in relation to a 500-g decrease in birth weight was 1.42 (95% confidence interval, 1.25 to 1.61). In the co-twin control analyses, the corresponding odds ratios were 1.34 (95% confidence interval, 1.07 to 1.69) for dizygotic and 1.74 (95% confidence interval, 1.13 to 2.70) for monozygotic twins. CONCLUSIONS: In the largest twin study on the fetal origins of hypertension, we found that decreased birth weight is associated with increased risk of hypertension independently of genetic factors, shared familial environment, and risk factors for hypertension in adulthood, including body mass index.
The aim of this study was to determine the influence of genetic factors on the first episode of acute myocardial infarction. Probandwise concordances, tetrachoric correlations and quantitative genetic analyses of liability were applied to data drawn from the Swedish Twin Registry and the Swedish Acute Myocardial Infarction Register. All same-sexed twin pairs born between 1886 and 1958 who were alive in 1987 were included in the analyses. Our results show that concordance rates for acute myocardial infarction in monozygotic (MZ) twins were similar across sexes (among males .26 and females .27). For dizygotic (DZ) twins the concordances were .20 for males and .16 for females, yielding a greater MZ-DZ concordance differential for females than males. Tetrachoric correlations were greater for MZ than DZ twins for both sexes (.49 for male MZ and .34 for male DZ-twins and .56 and .35 for female MZ and DZ twins respectively). Quantitative genetic analyses of liability resulted in equal variance components for males and females (.36) but significantly different thresholds (prevalences). In conclusion, liability to first occurrence of acute myocardial infarction is moderately influenced by genetic variants in both sexes. The familial influence on phenotypic variance is exclusively explained by additive genetic factors.
The effect of genetic variants underlying atherosclerosis is thought to be mediated through intermediate phenotypes such as serum cholesterol levels. Localization of quantitative trait loci influencing levels of serum lipids and (apo)lipoproteins may aid in the search for determinants of susceptibility to atherosclerotic diseases. Since apolipoprotein A-I is the primary protein constituent of high-density lipoprotein, it is considered to be critical for the antiatherogenic effect of high-density lipoproteins. We describe here an effort to map loci influencing apolipoprotein A-I levels. Measurements of apolipoprotein A-I levels and genome scans with more than 1000 microsatellite markers were successfully performed in both members of 501 pairs of fraternal twins from Sweden. Variance component linkage analysis was undertaken to map quantitative trait loci. In the total study sample, two loci showed comparable suggestive evidence of linkage, 6p21-12 (LOD=2.4) and 12q23 (LOD=2.4). Sex-limited analyses revealed significant female-specific linkage at marker D15S156 on 15q11-13 (LOD=4.1). The loci on 12q and 15q in the present study confirm previously reported loci for apolipoprotein A-I, while the peak on chromosome 6p lends further support to a locus influencing several phenotypes related to atherosclerosis. Intriguingly, the presence of genes belonging to the phospholipase A2 superfamily under three out of four observed linkage peaks would lend some support to the view that this group of genes might collectively represent candidates as apolipoprotein A-I level regulators.
OBJECTIVE: Phosphorylcholine (PC) is one important epitope on oxidized low-density lipoprotein that may play an important role by contributing to the atherogenicity of oxidized low-density lipoprotein. IgM antibodies against PC (anti-PC) are present ubiquitously in the population as natural antibodies. We here determine the association between anti-PC and incidence of myocardial infarction (MI). METHODS: We studied 462 incident cases of first events of MI and 888 age-matched and sex-matched controls identified through 13 years of follow-up (1987-1999) of participants in a population-based study from northern Sweden. Relative risks (RRs) with 95% confidence intervals (CIs) of incident MI with adjustments for age, sex, geographical region, hypertension, diabetes, BMI, smoking habits, s-cholesterol and high-sensitivity C-reactive protein were determined. Anti-PC levels were measured by enzyme-linked immunoassay. RESULTS: Low anti-PC values were associated with increased risk of MI. Significant associations were found for values below 26.8 U/ml, corresponding to the lowest 25th percentile, and the highest association was seen below 16.9 U/ml. These results remained almost the same after adjustment for confounding factors (RR crude: 1.56, CI: 1.07-2.28 and RR adjusted: 1.69, CI: 1.09-2.54). CONCLUSION: Low levels of natural IgM anti-PC could play an important role as risk markers for development of MI. Adjustment for common confounders only marginally affected the RR, suggesting that the addition of IgM anti-PC add independent information to the more traditional risk factors.
Markers of endothelial activity are related to components of the metabolic syndrome, but not to circulating concentrations of the advanced glycation end-product N epsilon-carboxymethyl-lysine in healthy Swedish men.
Endothelial function is considered important in the development of cardiovascular diseases and type 2 diabetes. Circulating advanced glycation end-products (AGEs) and dietary components have been shown to affect endothelial function in type 2 diabetics, but determinants of endothelial function in a non-diabetic population are more poorly investigated. Therefore, we investigated relationships between dietary habits, AGEs and endothelial activation in men with isolated metabolic disturbances. Circulating markers of endothelial activation (soluble forms of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-selectin and von Willebrand factor) and plasma N epsilon-carboxymethyl-lysine (CML, the predominant AGE in human plasma) were analyzed in a cross-sectional study of 294 healthy men. Individuals completed a 7-day dietary record, and metabolic and inflammatory parameters were determined. NCEP/ATPIII-criteria were used to define the metabolic syndrome. Endothelial activation was higher in individuals with the metabolic syndrome, and was positively related to certain features of the syndrome (insulin, glucose, inflammation and obesity), but not to others (triacylglycerol and blood pressure). Dietary factors were related to endothelial activation, but CML was not. Multivariate analysis revealed energy and alcohol intake, along with insulin and markers of oxidative stress and inflammation, to be positive predictors of endothelial activation. In this cohort of otherwise healthy men, endothelial activation was increased in individuals with the full metabolic syndrome, but not in those with only some of the components of the metabolic syndrome. Insulin resistance, inflammation, oxidative stress, the dietary intake of energy and alcohol, but not plasma CML, predicted endothelial activation in these men.
The practice of using discrete clinical diagnoses in genetic association studies has seldom led to a replicable genetic model. If, as the literature suggests, weak genotype-phenotype relationships are detected when clinical diagnoses are used, power might be increased by exploring more fundamental biological traits. Emerging solutions to this include directly modeling levels of the protein product of a gene (usually in plasma) and sequence variation specifically in/around that gene, as well as exploring multiple quantitative traits related to a disease of interest. Here, we attempt a strategy based upon these premises examining sequence variants near the TNF locus, a region widely studied in cardiovascular disease. Multilocus genotype models were used to perform a systematic screen of 18 metabolic and anthropometric traits for genetic association. While there was no evidence for an effect of TNF polymorphism on plasma TNF levels, a relatively strong effect on plasma PAI-1 levels did emerge (P=0.000019), but this was only evident in post-myocardial infarction patients. Modeled jointly with the common 4G/5G insertion/deletion polymorphism of SERPINE1 (formerly PAI), this effect appears large (10% of variance explained versus 2% for SERPINE1 4G/5G). We exhibit this finding cautiously, and use it to illustrate how transitioning the study of disease risk to quantitative traits might empower the identification of functionally variable genes. Further, a case is highlighted where association between sequence variation in a gene and its product is not readily apparent even in large samples, but where association with a down-stream pathway may be.