Common polymorphism in H19 associated with birthweight and cord blood IGF-II levels in humans

Background: Common genetic variation at genes that are imprinted and exclusively maternally expressed could explain the apparent maternal-specific inheritance of low birthweight reported in large family pedigrees. We identified ten single nucleotide polymorphisms ( SNPs) in H19, and we genotyped three of these SNPs in families from the contemporary ALSPAC UK birth cohort ( 1,696 children, 822 mothers and 661 fathers) in order to explore associations with size at birth and cord blood IGF- II levels. Results: Both offspring's and mother's H19 2992C> T SNP genotypes showed associations with offspring birthweight ( P = 0.03 to P = 0.003) and mother's genotype was also associated with cord blood IGF-II levels ( P = 0.0003 to P = 0.0001). The offspring genotype association with birthweight was independent of mother's genotype ( P = 0.01 to P = 0.007). However, mother's untransmitted H19 2992T allele was also associated with larger birthweight ( P = 0.04) and higher cord blood IGF-II levels ( P = 0.002), suggesting a direct effect of mother's genotype on placental IGF-II expression and fetal growth. The association between mother's untransmitted allele and cord blood IGF-II levels was more apparent in offspring of first pregnancies than subsequent pregnancies ( P-interaction = 0.03). Study of the independent Cambridge birth cohort with available DNA in mothers (N = 646) provided additional support for mother's H19 2992 genotype associations with birthweight ( P = 0.04) and with mother's glucose levels ( P = 0.01) in first pregnancies. Conclusion: The common H19 2992T allele, in the mother or offspring or both, may confer reduced fetal growth restraint, as indicated by associations with larger offspring birth size, higher cord blood IGF-II levels, and lower compensatory early postnatal catch-up weight gain, that are more evident among mother's smaller first-born infants

Common polymorphism in H19 associated with birthweight and cord blood IGF-II levels in humans.

BACKGROUND: Common genetic variation at genes that are imprinted and exclusively maternally expressed could explain the apparent maternal-specific inheritance of low birthweight reported in large family pedigrees. We identified ten single nucleotide polymorphisms (SNPs) in H19, and we genotyped three of these SNPs in families from the contemporary ALSPAC UK birth cohort (1,696 children, 822 mothers and 661 fathers) in order to explore associations with size at birth and cord blood IGF-II levels. RESULTS: Both offspring's and mother's H19 2992C>T SNP genotypes showed associations with offspring birthweight (P = 0.03 to P = 0.003) and mother's genotype was also associated with cord blood IGF-II levels (P = 0.0003 to P = 0.0001). The offspring genotype association with birthweight was independent of mother's genotype (P = 0.01 to P = 0.007). However, mother's untransmitted H19 2992T allele was also associated with larger birthweight (P = 0.04) and higher cord blood IGF-II levels (P = 0.002), suggesting a direct effect of mother's genotype on placental IGF-II expression and fetal growth. The association between mother's untransmitted allele and cord blood IGF-II levels was more apparent in offspring of first pregnancies than subsequent pregnancies (P-interaction = 0.03). Study of the independent Cambridge birth cohort with available DNA in mothers (N = 646) provided additional support for mother's H19 2992 genotype associations with birthweight (P = 0.04) and with mother's glucose levels (P = 0.01) in first pregnancies. CONCLUSION: The common H19 2992T allele, in the mother or offspring or both, may confer reduced fetal growth restraint, as indicated by associations with larger offspring birth size, higher cord blood IGF-II levels, and lower compensatory early postnatal catch-up weight gain, that are more evident among mother's smaller first-born infants.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Process evaluation of the Bridging the Age Gap in Breast Cancer decision support intervention cluster randomised trial

Background The Bridging the Age Gap in Breast Cancer research programme sought to improve treatment decision-making for older women with breast cancer by developing and testing, in a cluster randomised trial (n = 1339 patients), two decision support interventions (DESIs). Both DESIs were used in the intervention arm and each comprised an online risk prediction model, brief decision aid and information booklet. One DESI supported the decision to have either primary endocrine therapy (PET) or surgery with adjuvant therapies and the second supported the decision to have adjuvant chemotherapy after surgery or not. Methods Sixteen sites were randomly selected to take part in the process evaluation. Multiple methods of data collection were used. Medical Research Council (MRC) guidelines for the evaluation of complex interventions were used. Results Eighty-two patients, mean age 75.5 (range 70–93), provided data for the process evaluation. Seventy-three interviews were completed with patients. Ten clinicians from six intervention sites took part in telephone interviews. Dose: Ninety-one members of staff in the intervention arm received intervention training. Reach: The online tool was accessed on 324 occasions by 27 clinicians. Reasons for non-use of the online tool were commonly that the patient had already made a decision or that there was no online access in the clinic. Of the 32 women for whom there were data available, fifteen from the intervention arm and six from the usual care arm were offered a choice of treatment. Fidelity: Clinicians used the online tool in different ways, with some using it during the consultation and others checking the online survival estimates before the consultation. Adaptation: There was evidence of adaptation when using the DESIs. A lack of infrastructure, e.g. internet access, was a barrier to the use of the online tool. The brief decision aid was rarely used. Mediators: Shared decision-making: Most patients felt able to contribute to decision-making and expressed high levels of satisfaction with the process. Participants’ responses to intervention: Six patients reported the DESIs to be very useful, one somewhat useful and two moderately useful. Conclusions Clinicians who participated were mainly supportive of the interventions and had attempted some adaptations to make the interventions applicable, but there were practical and engagement barriers that led to sub-optimal adoption in routine practice

Safety and Efficacy of a Dapivirine Vaginal Ring for HIV Prevention in Women.

BACKGROUND: The incidence of human immunodeficiency virus (HIV) infection remains high among women in sub-Saharan Africa. We evaluated the safety and efficacy of extended use of a vaginal ring containing dapivirine for the prevention of HIV infection in 1959 healthy, sexually active women, 18 to 45 years of age, from seven communities in South Africa and Uganda. METHODS: In this randomized, double-blind, placebo-controlled, phase 3 trial, we randomly assigned participants in a 2:1 ratio to receive vaginal rings containing either 25 mg of dapivirine or placebo. Participants inserted the rings themselves every 4 weeks for up to 24 months. The primary efficacy end point was the rate of HIV type 1 (HIV-1) seroconversion. RESULTS: A total of 77 participants in the dapivirine group underwent HIV-1 seroconversion during 1888 person-years of follow-up (4.1 seroconversions per 100 person-years), as compared with 56 in the placebo group who underwent HIV-1 seroconversion during 917 person-years of follow-up (6.1 seroconversions per 100 person-years). The incidence of HIV-1 infection was 31% lower in the dapivirine group than in the placebo group (hazard ratio, 0.69; 95% confidence interval [CI], 0.49 to 0.99; P=0.04). There was no significant difference in efficacy of the dapivirine ring among women older than 21 years of age (hazard ratio for infection, 0.63; 95% CI, 0.41 to 0.97) and those 21 years of age or younger (hazard ratio, 0.85; 95% CI, 0.45 to 1.60; P=0.43 for treatment-by-age interaction). Among participants with HIV-1 infection, nonnucleoside reverse-transcriptase inhibitor resistance mutations were detected in 14 of 77 participants in the dapivirine group (18.2%) and in 9 of 56 (16.1%) in the placebo group. Serious adverse events occurred more often in the dapivirine group (in 38 participants [2.9%]) than in the placebo group (in 6 [0.9%]). However, no clear pattern was identified. CONCLUSIONS: Among women in sub-Saharan Africa, the dapivirine ring was not associated with any safety concerns and was associated with a rate of acquisition of HIV-1 infection that was lower than the rate with placebo. (Funded by the International Partnership for Microbicides; ClinicalTrials.gov number, NCT01539226 .)

Genomic analysis of diet composition finds novel loci and associations with health and lifestyle

We conducted genome-wide association studies (GWAS) of relative intake from the macronutrients fat, protein, carbohydrates, and sugar in over 235,000 individuals of European ancestries. We identified 21 unique, approximately independent lead SNPs. Fourteen lead SNPs are uniquely associated with one macronutrient at genome-wide significance (P < 5 x 10(-8)), while five of the 21 lead SNPs reach suggestive significance (P < 1 x 10(-5)) for at least one other macronutrient. While the phenotypes are genetically correlated, each phenotype carries a partially unique genetic architecture. Relative protein intake exhibits the strongest relationships with poor health, including positive genetic associations with obesity, type 2 diabetes, and heart disease (r(g) approximate to 0.15-0.5). In contrast, relative carbohydrate and sugar intake have negative genetic correlations with waist circumference, waist-hip ratio, and neighborhood deprivation (|r(g)| approximate to 0.1-0.3) and positive genetic correlations with physical activity (r(g) approximate to 0.1 and 0.2). Relative fat intake has no consistent pattern of genetic correlations with poor health but has a negative genetic correlation with educational attainment (r(g) approximate to-0.1). Although our analyses do not allow us to draw causal conclusions, we find no evidence of negative health consequences associated with relative carbohydrate, sugar, or fat intake. However, our results are consistent with the hypothesis that relative protein intake plays a role in the etiology of metabolic dysfunction.Public Health and primary carePrevention, Population and Disease management (PrePoD

A systematic review of the incidence of schizophrenia: the distribution of rates and the influence of sex, urbanicity, migrant status and methodology

BACKGROUND: Understanding variations in the incidence of schizophrenia is a crucial step in unravelling the aetiology of this group of disorders. The aims of this review are to systematically identify studies related to the incidence of schizophrenia, to describe the key features of these studies, and to explore the distribution of rates derived from these studies. METHODS: Studies with original data related to the incidence of schizophrenia (published 1965–2001) were identified via searching electronic databases, reviewing citations and writing to authors. These studies were divided into core studies, migrant studies, cohort studies and studies based on Other Special Groups. Between- and within-study filters were applied in order to identify discrete rates. Cumulative plots of these rates were made and these distributions were compared when the underlying rates were sorted according to sex, urbanicity, migrant status and various methodological features. RESULTS: We identified 100 core studies, 24 migrant studies, 23 cohort studies and 14 studies based on Other Special Groups. These studies, which were drawn from 33 countries, generated a total of 1,458 rates. Based on discrete core data for persons (55 studies and 170 rates), the distribution of rates was asymmetric and had a median value (10%–90% quantile) of 15.2 (7.7–43.0) per 100,000. The distribution of rates was significantly higher in males compared to females; the male/female rate ratio median (10%–90% quantile) was 1.40 (0.9–2.4). Those studies conducted in urban versus mixed urban-rural catchment areas generated significantly higher rate distributions. The distribution of rates in migrants was significantly higher compared to native-born; the migrant/native-born rate ratio median (10%–90% quantile) was 4.6 (1.0–12.8). Apart from the finding that older studies reported higher rates, other study features were not associated with significantly different rate distributions (e.g. overall quality, methods related to case finding, diagnostic confirmation and criteria, the use of age-standardization and age range). CONCLUSIONS: There is a wealth of data available on the incidence of schizophrenia. The width and skew of the rate distribution, and the significant impact of sex, urbanicity and migrant status on these distributions, indicate substantial variations in the incidence of schizophrenia

Genomic analysis of diet composition finds novel loci and associations with health and lifestyle

Abstract: We conducted genome-wide association studies (GWAS) of relative intake from the macronutrients fat, protein, carbohydrates, and sugar in over 235,000 individuals of European ancestries. We identified 21 unique, approximately independent lead SNPs. Fourteen lead SNPs are uniquely associated with one macronutrient at genome-wide significance (P < 5 × 10−8), while five of the 21 lead SNPs reach suggestive significance (P < 1 × 10−5) for at least one other macronutrient. While the phenotypes are genetically correlated, each phenotype carries a partially unique genetic architecture. Relative protein intake exhibits the strongest relationships with poor health, including positive genetic associations with obesity, type 2 diabetes, and heart disease (rg ≈ 0.15–0.5). In contrast, relative carbohydrate and sugar intake have negative genetic correlations with waist circumference, waist-hip ratio, and neighborhood deprivation (|rg| ≈ 0.1–0.3) and positive genetic correlations with physical activity (rg ≈ 0.1 and 0.2). Relative fat intake has no consistent pattern of genetic correlations with poor health but has a negative genetic correlation with educational attainment (rg ≈−0.1). Although our analyses do not allow us to draw causal conclusions, we find no evidence of negative health consequences associated with relative carbohydrate, sugar, or fat intake. However, our results are consistent with the hypothesis that relative protein intake plays a role in the etiology of metabolic dysfunction

Common polymorphism in H19 associated with birthweight and cord blood IGF-II levels in humans.

BACKGROUND: Common genetic variation at genes that are imprinted and exclusively maternally expressed could explain the apparent maternal-specific inheritance of low birthweight reported in large family pedigrees. We identified ten single nucleotide polymorphisms (SNPs) in H19, and we genotyped three of these SNPs in families from the contemporary ALSPAC UK birth cohort (1,696 children, 822 mothers and 661 fathers) in order to explore associations with size at birth and cord blood IGF-II levels. RESULTS: Both offspring's and mother's H19 2992C>T SNP genotypes showed associations with offspring birthweight (P = 0.03 to P = 0.003) and mother's genotype was also associated with cord blood IGF-II levels (P = 0.0003 to P = 0.0001). The offspring genotype association with birthweight was independent of mother's genotype (P = 0.01 to P = 0.007). However, mother's untransmitted H19 2992T allele was also associated with larger birthweight (P = 0.04) and higher cord blood IGF-II levels (P = 0.002), suggesting a direct effect of mother's genotype on placental IGF-II expression and fetal growth. The association between mother's untransmitted allele and cord blood IGF-II levels was more apparent in offspring of first pregnancies than subsequent pregnancies (P-interaction = 0.03). Study of the independent Cambridge birth cohort with available DNA in mothers (N = 646) provided additional support for mother's H19 2992 genotype associations with birthweight (P = 0.04) and with mother's glucose levels (P = 0.01) in first pregnancies. CONCLUSION: The common H19 2992T allele, in the mother or offspring or both, may confer reduced fetal growth restraint, as indicated by associations with larger offspring birth size, higher cord blood IGF-II levels, and lower compensatory early postnatal catch-up weight gain, that are more evident among mother's smaller first-born infants.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are