Socioeconomic disparities in survival from childhood leukemia in the United States and globally: a meta-analysis.

BACKGROUND: Despite advancements in the treatment of childhood leukemia, socioeconomic status (SES) may potentially affect disease prognosis. This study aims to evaluate whether SES is associated with survival from childhood leukemia. METHODS: The US National Cancer Institute Surveillance, Epidemiology and End Results Program (SEER) 1973-2010 data were analyzed; thereafter, results were meta-analyzed along with those from survival (cohort) studies examining the association between SES indices and survival from childhood leukemia (end-of-search date: 31 March 2014). Random-effects models were used to calculate pooled effect estimates (relative risks, RRs); meta-regression was also used. RESULTS: We included 29 studies yielding 28 804 acute lymphoblastic leukemia (ALL), 3208 acute myeloblastic leukemia (AML) and 27 650 'any' leukemia (denoting joint reporting of all subtypes) cases. According to individual-level composite SES indices, children from low SES suffered from nearly twofold higher death rates from ALL (pooled RR: 1.83, 95% confidence interval 1.00-3.34, based on four study arms); likewise, death RRs derived from an array of lower area-level SES indices ranged between 1.17 and 1.33 (based on 11 study arms). Importantly, the survival gap between higher and lower SES seemed wider in the United States, with considerably (by 20%-82%) increased RRs for death from ALL in lower SES. Regarding AML, poorer survival was evident only when area-level SES indices were used. Lastly, remoteness indices were not associated with survival from childhood leukemia. CONCLUSION: Children with lower SES suffering childhood leukemia do not seem to equally enjoy the impressive recent survival gains. Special health policy strategies and increased awareness of health providers might minimize the effects of socioeconomic disparities.

Birthweight discordant female twins and their offspring: is the intergenerational influence on birthweight due to genes or environment?

STUDY QUESTION: Does the intergenerational influence on birthweight and birth length remain within female dizygotic and monozygotic twin pairs? SUMMARY ANSWER: The intergenerational influence on birthweight and birth length remained within dizygotic but not within monozygotic twin pairs. WHAT IS KNOWN ALREADY: Low birthweight is associated with increased morbidity and mortality in both the short and long term; therefore it is important to understand determinants of fetal growth. There is a known intergenerational association between parents' and offspring's size at birth. STUDY DESIGN, SIZE, DURATION: This is a register-based cohort study with a nested within-twin-pair comparison. The study is retrospective, but based on prospectively collected information. The study population included 8685 monozygotic and like-sexed dizygotic female twins born in Sweden from 1926 to 1985, who had given birth to their first infant between 1973 and 2009. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study is set in Sweden and used data from the Swedish Twin Register and the Swedish Medical Birth Register. We used generalized estimating equations to obtain regression coefficients with 95% confidence intervals (CI) for the outcomes: offspring birthweight and birth length. To control for genetic and shared environmental factors, we performed within-twin-pair analyses in 1479 dizygotic and 1526 monozygotic twin pairs. MAIN RESULTS AND THE ROLE OF CHANCE: In the cohort of both dizygotic and monozygotic twins, there was an association between mother's and offspring's size at birth. Within-dizygotic twin pairs, a 500-g increase from the twin pair's mean birthweight was associated with increased offspring birthweight [70 g (95% CI: 35-106)] and birth length [0.22 cm (95% CI: 0.07-0.38)]. The corresponding increase in birth length of 1 cm was estimated to increase offspring's birthweight by 26 g (95% CI: 12-40) and birth length by 0.11 cm (95% CI: 0.04-0.17). Within-monozygotic twin pairs there were no such associations. LIMITATIONS, REASONS FOR CAUTION: This study is limited to twins who themselves or whose co-twin voluntarily responded to questionnaires. WIDER IMPLICATIONS OF THE FINDINGS: The intergenerational influence on size at birth is suggested to be due to direct or indirect genetic factors.

Association between gestational diabetes mellitus and subsequent overactive bladder among premenopausal female twins.

OBJECTIVE: To investigate the association between a history of gestational diabetes mellitus (GDM) and overactive bladder (OAB) in women of premenopausal age. DESIGN: Population-based study. SETTING: The Swedish Twin Register. POPULATION: In 2005, a total of 14 094 female twins born between 1959 and 1985 in the Swedish Twin Registry participated in a comprehensive survey on common exposures and complex diseases. Structured questions provided information on GDM and OAB. The present study was designed as a cross-sectional analysis including all women in the cohort having given birth before 2005 (n = 7855). METHODS: A logistic regression model based on generalised estimating equations was used to derive odds ratios (ORs). MAIN OUTCOME MEASURE: The association between a history of GDM and OAB was estimated using ORs with 95% confidence intervals (CIs). RESULTS: The prevalence of OAB in women with a history of GDM was 19.1% compared with 10.7% in women without GDM. This corresponded to a two-fold increased odds of OAB in women with a history of gestational diabetes (OR 2.13, 95% CI 1.48-3.05). After adjusting the analysis for age, body mass index, parity, smoking, and diabetes mellitus, having had GDM was associated with doubled odds of OAB (OR 1.88, 95% CI 1.26-2.80). CONCLUSIONS: A history of GDM was positively associated with OAB among women of premenopausal age. The association does not seem to be mediated by body mass index or type-I or type-II diabetes mellitus.

Epigenetics and assisted reproductive technology.

During gametogenesis, the female and male germ cells undergo a process whereby imprinting marks are erased from the genome. During the later stages of germ-cell development, the methylation marks of the female and male germ lines are re-established. A second phase of demethylation of the genome occurs at the time of fertilization, and during development of the early embryo. Assisted reproductive technology involves several steps that subject the gametes and early developing embryos to environmental stress, and this is the primary reason for an increased interest in the putative link between these techniques and imprinting disorders. Although animal studies support a link between assisted reproductive techniques (ARTs) and imprinting disorders, via altered methylation patterns, data in humans are inconsistent. Here we provide an overview of the field of epigenetics in relation to ARTs.

Effects of coffee and tea consumption on urinary incontinence in female twins.

OBJECTIVES: To assess the effect of coffee and tea consumption on symptoms of urinary incontinence. DESIGN: Population-based study. SETTING: The Swedish Twin Register. POPULATION: In 2005, all twins born between 1959 and 1985 in Sweden (n = 42,852) were invited to participate in a web-based survey to screen for common complex diseases and common exposures. The present study was limited to female twins with information about at least one urinary symptoms and coffee and tea consumption (n = 14,031). MAIN OUTCOME MEASURE: The association between coffee and tea consumption and urinary incontinence, as well as nocturia, was estimated as odds ratios (ORs) with 95% confidence intervals. RESULTS: Women with a high coffee intake were at lower risk of any urinary incontinence (OR 0.78, 95% CI 0.64-0.98) compared with women not drinking coffee. Coffee intake and incontinence subtypes showed no significant associations whereas high tea consumption was specifically associated with a risk for overactive bladder (OR 1.34, 95% CI 11.07-1.67) and nocturia (OR 1.18, 95% CI 1.01-1.38). Results from co-twin control analysis suggested that the associations observed in logistic regression were mainly the result of familial effects. CONCLUSIONS: This study suggests that coffee and tea consumption has a limited effect on urinary incontinence symptoms. Familial and genetic effects may have confounded the associations observed in previous studies.

Heritability of insulin sensitivity and lipid profile depend on BMI: evidence for gene-obesity interaction.

AIMS/HYPOTHESIS: Evidence from candidate gene studies suggests that obesity may modify genetic susceptibility to type 2 diabetes and dyslipidaemia. On an aggregate level, gene-obesity interactions are expected to result in different heritability estimates at different obesity levels. However, this hypothesis has never been tested. METHOD: The present study included 2,180 British female twins. BMI was used as an index of general obesity. Outcome measures were insulin sensitivity (indexed by quantitative insulin-sensitivity check index [QUICKI]) and fasting plasma lipid profile. Structural equation modelling was used to test whether BMI interacted with latent genetic and environmental effects to impact on the outcome measures. RESULTS: Genetic influences on triacylglycerol increased with BMI (p < 0.001) whereas the unique environmental influence on QUICKI decreased with BMI (p < 0.001), resulting in a higher heritability estimate for both measures at higher BMI levels. This was further illustrated by stratified analysis in twin pairs concordant for normal weight and twin pairs concordant for overweight. Heritability was 19 percentage points higher for triacylglycerol (p < 0.001) and 31 percentage points higher for QUICKI (p < 0.01) among twins concordant for overweight than among twins concordant for normal weight. BMI had no moderator effect on the latent genetic and environmental factors for total cholesterol and HDL-cholesterol. CONCLUSIONS/INTERPRETATION: Our results suggest that the expression of genes influencing triacylglycerol and insulin sensitivity can vary as a function of obesity status. The substantial increases in the genetic contribution to the total variance in insulin sensitivity and triacylglycerols at higher BMIs may prove extremely valuable in the search for candidate genes.

Birth characteristics and risk of colorectal cancer: a study among Swedish twins.

Type-2 diabetes increases the risk of colorectal cancer, and is also associated with low birth weight. However, we found no evidence of associations between birth characteristics and risk of colorectal cancer (m=248) among Swedish twins.

Physical workload, low back pain and neck-shoulder pain: a Swedish twin study.

OBJECTIVES: To investigate if high physical workload is associated with low back pain (LBP) and/or neck-shoulder pain (NSP) when taking into account the influence of genetic and shared environmental factors. Further, the study aims to explore the potential influence of genetic and shared environmental factors in the associations between high physical workload and the three disorder subgroups: solely LBP, solely NSP, and concurrent LBP and NSP. METHODS: Data on 16,107 monozygotic and dizygotic twins, born during 1959-1985, were obtained from a cross-sectional study, performed in 2005-2006 by the Swedish Twin Registry. Odds ratios (ORs) calculated in cohort analyses and co-twin control analyses were used to assess the associations between high physical workload and LBP and NSP when controlling for genetic and shared environmental factors. RESULTS: In the cohort analysis, the association between high physical workload and the group with any one symptom (LBP and/or NSP) was OR 1.47 (95% CI 1.37 to 1.57). The co-twin control analyses indicated that the association was not confounded by genetic and shared environmental factors with OR 1.34 (95% CI 1.02 to 1.75) for dizygotic twins and OR 1.44 (95% CI 1.06 to 1.95) for monozygotic twins. In the cohort analyses the association with high physical workload was higher for concurrent LBP and NSP (OR 1.80 (95% CI 1.62 to 1.99)) than for solely LBP (OR 1.41 (95% CI 1.27 to 1.57)) and solely NSP (OR 1.31 (95% CI 1.20 to 1.43)). Concurrent LBP and NSP was the only group that showed a stepwise decrease of the point estimates between the cohort analysis and the co-twin control analyses, OR 1.71 (95% CI 1.00 to 2.94) for dizygotic twins, and OR 1.29 (95% CI 0.64 to 2.59) for monozygotic twins indicating confounding by genetic and shared environmental factors. CONCLUSIONS: High physical workload was associated with LBP and/or NSP even after adjusting for genetic or shared environmental factors. Only for concurrent LBP and NSP, genetic and shared environmental factors seemed to have an influence on the association with high physical workload.

Genomewide scans of red cell indices suggest linkage on chromosome 6q23.

BACKGROUND: The red cell indices quantify the size, number and oxygen-carrying ability of erythrocytes. Although the genetic basis of many monogenic forms of anaemia is well understood, comparatively little is known about the genes responsible for variation in the red cell indices among healthy participants. OBJECTIVE: To identify quantitative trait loci (QTLs) responsible for normal variation in the red cell indices of 391 pairs of dizygotic twins who were measured longitudinally at 12, 14 and 16 years of age. RESULTS: Evidence suggesting linkage of red cell indices to haemoglobin concentration (LOD = 3.03) and haematocrit (LOD = 2.95) on chromosome 6q23, a region previously identified as possibly harbouring a QTL for haematocrit, was found. Evidence for linkage to several other regions of the genome, including chromosome 4q32 for red cell count and 7q for mean cell volume, was also found. In contrast, there was little evidence of linkage to the chromosomal regions containing the genes for erythropoietin (7q21) and its receptor (19p13.2), nor to the regions containing the genes for the haemoglobin alpha (16p13.3) and beta chains (11p15.5). CONCLUSION: Findings provide additional evidence for a QTL affecting haemoglobin and haematocrit on chromosome 6q23. In contrast, polymorphisms in the genes coding for erythropoietin, its receptor and the haemoglobin alpha and beta chains do not appear to contribute substantially to variation in the red cell indices between healthy persons.

A common hormone-sensitive lipase i6 gene polymorphism is associated with decreased human adipocyte lipolytic function.

Hereditary factors may be involved in the pathogenesis of type 2 diabetes. A polymorphism in the hormone-sensitive lipase (HSL) gene (HSLi6) is associated with obesity and diabetes, although it is unknown whether the polymorphism is functional and thereby influences lipolysis. We genotyped 355 apparently healthy nonobese male and female subjects for the HSLi6 polymorphism. Allele 5 was found to be the most common allele (allele frequency 0.57). In 117 of the subjects, we measured abdominal subcutaneous fat cell lipolysis induced by drugs acting at various steps in the lipolytic cascade. The lipolysis rate induced by norepinephrine isoprenaline (acting on beta-adrenoceptors), forskolin (acting on adenylyl cyclase), and dibutyryl cyclic AMP (acting on HSL) were all decreased by approximately 50% in allele 5 homozygotes, as compared with noncarriers. Heterozygotes showed an intermediate lipolytic rate. The difference in lipolysis rate between genotypes was more pronounced in men than in women. We conclude that allele 5 of the HSLi6 polymorphism is associated with a marked decrease in the lipolytic rate of abdominal fat cells. This may in turn contribute to the development of obesity.

The effect of the beta(2) adrenoceptor gene Thr164Ile polymorphism on human adipose tissue lipolytic function.

A rare beta(2)-adrenoceptor gene polymorphism, Thr164Ile, has been described that impairs receptor function when transfected into cell lines. We investigated whether the polymorphism influences native receptor function by studying lipolysis in freshly isolated subcutaneous fat cells from 236 apparently healthy subjects. Twelve subjects were heterozygous for the 164Ile variant. The fat cells of Ile carriers displayed a 6 fold increase (P=0.02) in the lipolytic EC(50) of terbutaline (a selective beta(2)-adrenoceptor agonist), but no change in the lipolytic action of dobutamine (a selective beta(1)-adrenoceptor agonist), compared with the Thr carriers. Maximum adrenoceptor agonist stimulated lipolysis did not differ between Thr and Ile carriers. The influence of two other polymorphisms (Arg16Gly and Gln27Glu) in the beta(2)-adrenoceptor gene was considered. Six 164Ile carriers also carried the 16Gly and 27Glu alleles. The latter combination occurred among 105 of the 164Thr carriers. For the 16Gly27Glu subgroup, the EC(50) of terbutaline was about 10 fold higher in 164Ile as than in 164Thr carriers (P=0.02) but there was no difference between genotypes in maximum terbutaline action. There was no difference between groups in dobutamine action. In conclusion, the 164Ile variant of the beta(2)-adrenoceptor is associated with a decreased native adipocyte receptor function, as evidenced by a marked increase in the half maximal effective concentration of the lipolytic action of a selective beta(2)-adrenoceptor agonist. This suggests that genetic variance in the beta(2)-adrenoceptor gene might be important for catecholamine function in humans, at least as far as adipocyte lipolysis is concerned.

Variation in genetic and environmental influences in serum lipid and apolipoprotein levels across the lifespan in Swedish male and female twins.

The contribution of genetic and environmental factors to variation in lipids and apolipoproteins has been estimated in previous twin and family studies. However, it is unclear whether there are sex and/or age differences in parameter estimates. We investigated a sample selected from the population-based Swedish Twin Registry of 725 like- and unlike-sex twin pairs, ages 17-85. Quantitative genetic methods were used to evaluate sex and age differences in genetic and environmental variation in lipid and apolipoprotein levels in three age groups, 17-49, 50-69, and 70-85. Heritabilities for lipids and apolipoproteins ranged from 35%-74%. Consistent sex differences were found in triglycerides. Females had higher heritabilities (56%) than males (35%) across the age groups. Total phenotypic variation increased across the age groups for cholesterol and apolipoprotein B due to an increase in unique environmental variance components. In contrast, in apolipoprotein A1 variance was highest in the middle age group and no differences were found in the phenotypic variance between age groups for triglycerides. We concluded that differences in phenotypic variation for cholesterol and apolipoprotein B were almost entirely due to the accumulation of environmental experiences throughout life, whereas there were no consistent patterns of differences in phenotypic variance for apolipoprotein A1 and triglycerides.

Low birthweight and Type 2 diabetes: a study on 11 162 Swedish twins.

BACKGROUND: To investigate the association between low birthweight and diabetes in a population-based Swedish twin sample. Method A cohort of 11 162 same-sexed Swedish twins born between 1906 and 1958 was used in order to investigate the risk of developing Type 2 diabetes between and within twin pairs by utilizing random effects linear models. RESULTS: Between pairs there was a significant increase in risk of developing Type 2 diabetes for a 1-kg increase in their mean birthweight (odds ratio [OR] = 2.13; P < 0.01), adjusted for age, sex, body mass index (BMI), and smoking status. The corresponding risk within pair was 2.03 (P = 0.07) for monozygotic twins and 1.15 (P = 0.71) for dizygotic twins. The test of the heterogeneity of the within and between effects showed no significant difference between the estimates. CONCLUSIONS: The study suggests that reduced fetal growth increase the risk of Type 2 diabetes due to an in utero programming effect possibly caused by intrauterine malnutrition. However, it does not exclude the possibility of a common genetic mechanism.

Two common functional polymorphisms in the promoter region of the coagulation factor VII gene determining plasma factor VII activity and mass concentration.

Recent studies have provided evidence for associations between common polymorphic markers in the coagulation factor VII (FVII) gene and plasma FVII levels. Here we describe two common, nonrelated, functional polymorphisms in the promoter region of the FVII gene, a G to T substitution at position -401 and a novel G to A substitution at position -402. Both polymorphisms strongly influence the binding properties of nuclear protein(s). The rare -401T allele is associated with a reduced basal rate of transcription of the FVII gene in human hepatoblastoma cells and with reduced plasma concentrations of total FVII (VIIag) and fully activated FVII molecules (VIIa). In contrast, the rare -402A allele confers increased transcriptional activity and is associated with increased plasma FVII levels. Together, the two polymorphisms explained 18% and 28% of the variation in VIIag and VIIa, respectively, in a group of 183 healthy, middle-aged men. It is concluded that these polymorphisms are important for the regulation of the plasma levels of FVII and that they are likely to be useful genetic markers to resolve the issue of whether a causal relationship exists between FVII levels and risk of coronary heart disease.

Two common, functional polymorphisms in the promoter region of the beta-fibrinogen gene contribute to regulation of plasma fibrinogen concentration.

Plasma fibrinogen is a major risk factor for coronary heart disease, stroke, and peripheral artery disease. There is evidence that genetic variation in the beta-fibrinogen gene contributes to the rate of synthesis of fibrinogen, but the molecular mechanism underlying the genetic heritability of the plasma fibrinogen concentration is largely unknown. We evaluated the physiological roles of 5 common nucleotide substitutions in the promoter region of the beta-fibrinogen gene at positions -148, -249, -455, -854, and -993 from the transcriptional start site. Electrophoretic mobility shift assays revealed distinct differences in the binding characteristics of nuclear proteins between wild-type and mutant fragments of both the -455G/A and -854G/A polymorphisms, whereas no clear differences were observed for the -148C/T, -249C/T, and -993C/T sites. Transfection studies in HepG2 cells showed increased basal rates of transcription for both the G-to-A substitution at position -455 (+50%, P<0.05) and the G-to-A substitution at -854 (+51%, P<0.05). Additional transfection studies using proximal promoter constructs confirmed that both the -455A and -854A alleles independently enhance the basal rate of transcription of the beta-fibrinogen gene. The rare alleles of the nonrelated -455G/A and -854G/A polymorphisms were also associated with significantly increased plasma fibrinogen levels in healthy middle-aged men. Overall, the 2 polymorphisms together explained approximately 11% of the variation in plasma fibrinogen concentration. It is concluded that the -455G/A and -854G/A polymorphisms of the beta-fibrinogen gene are physiologically relevant mutations with a significant impact on the plasma fibrinogen concentration.

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.