Recently, two G-->A polymorphisms at positions -308 and -238, in the promoter of the tumor necrosis factor alpha (TNF-alpha) gene, have been identified. These variants have, in different ethnic groups, been linked to estimates of insulin resistance and obesity. The objective of the present study was to investigate whether these genetic variants of TNF-alpha were associated with features of the insulin resistance syndrome or alterations in birth weight in two Danish study populations comprising 380 unrelated young healthy subjects and 249 glucose-tolerant relatives of type 2 diabetic patients, respectively. All study participants underwent an iv glucose tolerance test with the addition of tolbutamide after 20 min. In addition, a number of biochemical and anthropometric measures were performed on each subject. The subjects were genotyped for the polymorphisms by applying PCR restriction fragment length polymorphism. Neither of the variants was related to altered insulin sensitivity index or other features of the insulin resistance syndrome (body mass index, waist to hip ratio, fat mass, fasting serum lipids or fasting serum insulin or C-peptide). Birth weight and the ponderal index were also not associated with the polymorphisms. In conclusion, although the study was carried out on sufficiently large study samples, the study does not support a major role of the -308 or -238 substitutions of the TNF-alpha gene in the pathogenesis of insulin resistance or altered birth weight among Danish Caucasian subjects.
Longitudinal cohort studies have implicated an association between both low and high birth weight and schizophrenia. It has been suggested that schizophrenia associated genes could augment an individual's susceptibility to adverse prenatal and perinatal environmental events. We investigated the association between birth weight and schizophrenia in a large Finnish schizophrenia family study sample. We utilized the birth weight data of 1051 offspring from 315 Finnish families with at least one offspring with a diagnosis of schizophrenia. We used a multivariate COX frailty model to analyze the effect of birth weight on the risk of developing schizophrenia within the families. Using information from the Medication Reimbursement Register and patient interviews, we further investigated the association of maternal type 2 diabetes and schizophrenia risk among offspring. High birth weight (>4000g) was associated with a 1.68-fold increase in schizophrenia susceptibility. Maternal diabetes at the time of data collection, a proxy for gestational diabetes, was associated with a 1.66-fold increase in the risk of developing schizophrenia among offspring. Our results corroborate recent findings showing an association between high birth weight and schizophrenia. Our results also point to a potential birth-weight independent association between maternal type 2 diabetes and schizophrenia among offspring.
Pre- and perinatal environmental factors have been shown to increase schizophrenia risk particularly when combined with genetic liability. The investigation of specific gene environment interactions in the etiology of psychiatric disorders has gained momentum. We used multivariate GEE regression modeling to investigate the interaction between genes of the DISC1 pathway and birth weight, in relation to schizophrenia susceptibility in a Finnish schizophrenia family cohort. The study sample consisted of 457 subjects with both genotype and birth weight information. Gender and place of birth were adjusted for in the models. We found a significant interaction between birth weight and two NDE1 markers in relation to increased schizophrenia risk: a four SNP haplotype spanning NDE1 (b=1.26, SE=0.5, p=0.012) and one of its constituent SNPs rs4781678 (b=1.33, SE=0.51, p=0.010). Specifically, high birth weight (>4000g) was associated with increased schizophrenia risk among subjects homozygous for the previously identified risk alleles. The study was based on a family study sample with high genetic loading for schizophrenia and thus our findings cannot directly be generalized as representing the general population. Our results suggest that the functions mediated by NDE1 during the early stages of neurodevelopment are susceptible to the additional disruptive effects of pre- and perinatal environmental factors associated with high birth weight, augmenting schizophrenia susceptibility.
The field of traditional biometrical genetics uses mixed-effects models to quantify the influence of genetic and environmental factors on a biological trait, based essentially on estimating within-family trait correlations. Such analyses provide a useful preview of what may be discovered with the emerging full-scale genotyping strategies. However, biometrical analyses require unrealistically large sample sizes to obtain a reasonable precision, particularly for dichotomous traits. In addition, it may be very difficult to separate genetic and environmental effects because environmental correlations are poorly understood. We illustrate these and other difficulties using population-based cousins and nuclear family data for birth weight, collected from the Medical Birth Registry of Norway.
Prostate cancer has a strong hereditary component, but it has been proposed that hormonal influences in utero may contribute to offspring risk. We investigated the associations between birth characteristics and the risk of prostate cancer in twins, and whether possible associations could be confounded by familial factors, such as shared environment and common genes.
All like-sexed male twins in the Swedish Twin Registry, born from 1926 to 1958 and alive in 1973, were eligible. Data were obtained from birth records, and 11,420 male twins with reliable birth weight data were included in the final study population. Hazard ratios with 95% confidence intervals (CI) from Cox regression models were used to estimate associations between birth characteristics and risk of prostate cancer. Paired analysis was done to account for potential confounding by familial factors.
Compared with twins with a birth weight of 2,500 to 2,999 g, the hazard ratio (95% CI) for twins with a higher birth weight (>or=3,000 g) corresponded to 1.22 (0.94-1.57). In analyses within twin pairs, in which both twins had a birth weight of >or=2,500 g, a 500 g increase in birth weight was associated with an increased risk of prostate cancer within dizygotic twin pairs (odds ratio, 1.41; 95% CI, 1.02-1.57), but not within monozygotic twin pairs (odds ratio, 1.06; 95% CI, 0.61-1.84).
High birth weight is associated with an increased risk of prostate cancer. The difference in risk within dizygotic and monozygotic twin pairs may be due to genetic factors playing an important role in this association.
Adult height has been found to be inversely associated with mortality. Recently, it has been suggested that growth in utero is linked with adult risk of several chronic diseases. The authors examined possible associations between birth weight, birth length, and adult height in young Danish men. They conducted the study in the fifth conscription district of Denmark including all the men born after January 1, 1973 who were residents in the study area during the period August 1, 1993 to July 31, 1994. The Danish Medical Birth Register contains information on all births in Denmark since January 1, 1973. Data on height from the Conscription Register were linked to the Danish Medical Birth Register in 4,300 conscripts examined. Nearly all Danish men have to register with the draft board around age 18 years of age where they undergo a physical examination. There was a strong positive association between birth weight and adult height; for subjects with birth weight or = 4,501 g, mean height was 184.1 cm. A positive association was also found between birth length and adult height. For subjects with birth length 56 cm. The associations between birth length and adult height persisted after adjustment for birth weight, gestational age, and other confounders, while the associations between birth weight and adult height almost disappeared when adjusting for birth length and the same confounders. Genetic and/or environmental factors operating both during the pre- and postnatal period may be responsible for the association between birth length and adult height.
Does the intergenerational influence on birthweight and birth length remain within female dizygotic and monozygotic twin pairs?
The intergenerational influence on birthweight and birth length remained within dizygotic but not within monozygotic twin pairs.
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.
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.
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.
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.
This study is limited to twins who themselves or whose co-twin voluntarily responded to questionnaires.
The intergenerational influence on size at birth is suggested to be due to direct or indirect genetic factors.
Human leukocyte antigen (HLA) genotypes associated with increased risk for type 1 diabetes mellitus (T1D) have been reported to be associated with increased birth weight. We set out to investigate the association between HLA haplotypes conferring risk for T1D and birth weight and search for possible differences in the strength of these associations among populations with contrasting incidence of T1D.
As a part of the EU-funded DIABIMMUNE study, genotyping for the HLA haplotypes associated with T1D was performed in 8369 newborn infants from Estonia, Finland and Russian Karelia. Infants born before 35 gestational weeks, from mothers with diabetes, and multiple pregnancies were excluded. Relative birth weight, expressed in standard deviation scores, was estimated for each gestational week, sex and country. The standard deviation scores were calculated internally using the actual population studied. According to their HLA haplotypes, participants were divided into risk groups, and the distribution of birth weight between quartiles was analysed.
We did not find any direct association between various HLA risk-associated genotypes (HLA DR3-DQ2/DR4-DQ8, DR3-DQ2/X or DR4-DQ8/X) and birth weight. We observed a significant relationship between increased relative birth weight and the protective HLA-DR2-DQ6 and DR13-DQ6 haplotypes. This association was significant only when these haplotypes were found together with the DR4-DQ8 haplotype.
The previously reported association between HLA-risk haplotypes for T1D and an increased birth weight was not confirmed. This suggests that the mechanisms behind the association between high birth weight and risk for T1D may be not directly HLA related.
Texel sheep were imported from Finland and Denmark for evaluation as a terminal sire population relative to the Suffolk breed. The objective was to estimate effects of sire breed on fitness, growth, and compositional traits of crossbred progeny that were serially slaughtered at 63, 105, 147, and 189 d of age. A total of 325 lambs, sired by 19 Texel and 20 Suffolk rams, were born to mature, half-Finnsheep ewes during a 2-yr period. Carcass traits were recorded on 183 lambs. Texel-sired lambs had greater survival to weaning (P = .06) and similar birth and weaning weights compared with Suffolk progeny. Lambs by Texel sires grew 11% less rapidly from 63 to 189 d of age. Estimated accretion rates of carcass fat at 189 d of age were 96.1 and 78.5 g/d for Suffolk and Texel progeny, respectively. Corresponding values for carcass protein were 17.4 and 16.0 g/d. At fixed ages, area of the longissimus muscle did not differ between sire breeds. Texel progeny weighed less at 189 d of age, producing lighter, leaner carcasses of shorter length (P