Metabolic profiles of socioeconomic position: a multi-cohort analysis

Background Low socioeconomic position (SEP) is a risk factor for multiple health outcomes, but its molecular imprints in the body remain unclear. Methods We examined SEP as a determinant of serum nuclear magnetic resonance metabolic profiles, in approximately 30,000 adults and 4,000 children across ten UK and Finnish cohort studies. Results In risk factor-adjusted analysis of 233 metabolic measures, low educational attainment was associated with 37 measures including higher levels of triglycerides in small high-density lipoproteins (HDL) and lower levels of docosahexaenoic acid (DHA), omega-3 fatty acids, apolipoprotein A1, large and very large HDL particles (including levels of their respective lipid constituents), and cholesterol measures across different density lipoproteins. Among adults whose father worked in manual occupations, associations with apolipoprotein A1, large and very large HDL particles and HDL-2 cholesterol remained after adjustment for SEP in later life. Among manual workers, levels of glutamine were higher compared to non-manual workers. All three indicators of low SEP were associated with lower DHA, omega-3 fatty acids and HDL diameter. At all ages, children of manual workers had lower levels of DHA as a proportion of total fatty acids. Conclusions Our work indicates that social and economic factors have a measurable impact on human physiology. Lower SEP was independently associated with a generally unfavorable metabolic profile, consistent across ages and cohorts. The metabolites we found associated with SEP, including DHA, are known to predict cardiovascular disease and cognitive decline in later life and may contribute to health inequalities

Metabolic profiles of socio-economic position: a multi-cohort analysis

Background: Low socio-economic position (SEP) is a risk factor for multiple health outcomes, but its molecular imprints in the body remain unclear. Methods: We examined SEP as a determinant of serum nuclear magnetic resonance metabolic profiles in 30 000 adults and 4000 children across 10 UK and Finnish cohort studies. Results: In risk-factor-adjusted analysis of 233 metabolic measures, low educational attainment was associated with 37 measures including higher levels of triglycerides in small high-density lipoproteins (HDL) and lower levels of docosahexaenoic acid (DHA), omega-3 fatty acids, apolipoprotein A1, large and very large HDL particles (including levels of their respective lipid constituents) and cholesterol measures across different density lipoproteins. Among adults whose father worked in manual occupations, associations with apolipoprotein A1, large and very large HDL particles and HDL-2 cholesterol remained after adjustment for SEP in later life. Among manual workers, levels of glutamine were higher compared with non-manual workers. All three indicators of low SEP were associated with lower DHA, omega-3 fatty acids and HDL diameter. At all ages, children of manual workers had lower levels of DHA as a proportion of total fatty acids. Conclusions: Our work indicates that social and economic factors have a measurable impact on human physiology. Lower SEP was independently associated with a generally unfavourable metabolic profile, consistent across ages and cohorts. The metabolites we found to be associated with SEP, including DHA, are known to predict cardiovascular disease and cognitive decline in later life and may contribute to health inequalities

A trans-ancestral meta-analysis of Genome-wide Association Studies reveals loci associated with childhood obesity

Although hundreds of GWAS-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity, and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of thirty studies consisting of up to 13,005 cases (≥95th percentile of BMI achieved 2-18 years old) and 15,599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1,888 cases and 4,689 controls from seven cohorts of European and North/South American ancestry. In addition to observing eighteen previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene: METTL15). The variant was nominally associated in only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than ten SNPs (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci

The Human Sweet Tooth

Humans love the taste of sugar and the word "sweet" is used to describe not only this basic taste quality but also something that is desirable or pleasurable, e.g., la dolce vita. Although sugar or sweetened foods are generally among the most preferred choices, not everyone likes sugar, especially at high concentrations. The focus of my group's research is to understand why some people have a sweet tooth and others do not. We have used genetic and molecular techniques in humans, rats, mice, cats and primates to understand the origins of sweet taste perception. Our studies demonstrate that there are two sweet receptor genes (TAS1R2 and TAS1R3), and alleles of one of the two genes predict the avidity with which some mammals drink sweet solutions. We also find a relationship between sweet and bitter perception. Children who are genetically more sensitive to bitter compounds report that very sweet solutions are more pleasant and they prefer sweet carbonated beverages more than milk, relative to less bitter-sensitive peers. Overall, people differ in their ability to perceive the basic tastes, and particular constellations of genes and experience may drive some people, but not others, toward a caries-inducing sweet diet. Future studies will be designed to understand how a genetic preference for sweet food and drink might contribute to the development of dental caries

Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis.

Uterine leiomyomata (UL) are the most common neoplasms of the female reproductive tract and primary cause for hysterectomy, leading to considerable morbidity and high economic burden. Here we conduct a GWAS meta-analysis in 35,474 cases and 267,505 female controls of European ancestry, identifying eight novel genome-wide significant (P < 5 × 10-8) loci, in addition to confirming 21 previously reported loci, including multiple independent signals at 10 loci. Phenotypic stratification of UL by heavy menstrual bleeding in 3409 cases and 199,171 female controls reveals genome-wide significant associations at three of the 29 UL loci: 5p15.33 (TERT), 5q35.2 (FGFR4) and 11q22.3 (ATM). Four loci identified in the meta-analysis are also associated with endometriosis risk; an epidemiological meta-analysis across 402,868 women suggests at least a doubling of risk for UL diagnosis among those with a history of endometriosis. These findings increase our understanding of genetic contribution and biology underlying UL development, and suggest overlapping genetic origins with endometriosis.This study was supported by the U.S. National Institutes of Health (NIH)/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) grant HD060530 to C.C.M. C.C.M. is also supported by the NIHR Manchester Biomedical Research Centre. N.M. acknowledges support from the Academy of Finland (295693) and Orion Research Foundation. H.R.H. is supported by NIH K22 CA193860. T.F. is supported by the NIHR Biomedical Research Centre, Oxford. S.E.M. is supported by the National Health and Medical Research Council (NHMRC) Fellowship Scheme (1103623)

Understanding the complexity of glycaemic health: systematic bio-psychosocial modelling of fasting glucose in middle-age adults; a DynaHEALTH study

© The Author(s) 2018. Background: The prevention of the risk of type 2 diabetes (T2D) is complicated by multidimensional interplays between biological and psychosocial factors acting at the individual level. To address the challenge we took a systematic approach, to explore the bio-psychosocial predictors of blood glucose in mid-age. Methods: Based on the 31-year and 46-year follow-ups (5,078 participants, 43% male) of Northern Finland Birth Cohort 1966, we used a systematic strategy to select bio-psychosocial variables at 31 years to enable a data-driven approach. As selection criteria, the variable must be (i) a component of the metabolic syndrome or an indicator of psychosocial health using WHO guidelines, (ii) easily obtainable in general health check-ups and (iii) associated with fasting blood glucose at 46 years (P < 0.10). Exploratory and confirmatory factor analysis were used to derive latent factors, and stepwise linear regression allowed exploration of relationships between factors and fasting glucose. Results: Of all 26 variables originally considered, 19 met the selection criteria and were included in an exploratory factor analysis. Two variables were further excluded due to low loading (<0.3). We derived four latent factors, which we named as socioeconomic, metabolic, psychosocial and blood pressure status. The combination of metabolic and psychosocial factors, adjusted for sex, provided best prediction of fasting glucose at 46 years (explaining 10.7% of variation in glucose; P < 0.001). Regarding different bio-psychosocial pathways and relationships, the importance of psychosocial factors in addition to established metabolic risk factors was highlighted. Conclusions: The present study supports evidence for the bio-psychosocial nature of adult glycemic health and exemplifies an evidence-based approach to model the bio-psychosocial relationships. The factorial model may help further research and public health practice in focusing also on psychosocial aspects in maintaining normoglycaemia in the prevention of cardio-metabolic diseases.European Union’s Horizon 2020 research and innovation programme, grant agreement No 633595

Changes in gut bacterial populations and their translocation into liver and ascites in alcoholic liver cirrhotics

Background The liver is the first line of defence against continuously occurring influx of microbial-derived products and bacteria from the gut. Intestinal bacteria have been implicated in the pathogenesis of alcoholic liver cirrhosis. Escape of intestinal bacteria into the ascites is involved in the pathogenesis of spontaneous bacterial peritonitis, which is a common complication of liver cirrhosis. The association between faecal bacterial populations and alcoholic liver cirrhosis has not been resolved. Methods Relative ratios of major commensal bacterial communities (Bacteroides spp., Bifidobacterium spp., Clostridium leptum group, Enterobactericaea and Lactobacillus spp.) were determined in faecal samples from post mortem examinations performed on 42 males, including cirrhotic alcoholics (n = 13), non-cirrhotic alcoholics (n = 15), non-alcoholic controls (n = 14) and in 7 healthy male volunteers using real-time quantitative PCR (RT-qPCR). Translocation of bacteria into liver in the autopsy cases and into the ascites of 12 volunteers with liver cirrhosis was also studied with RT-qPCR. CD14 immunostaining was performed for the autopsy liver samples. Results Relative ratios of faecal bacteria in autopsy controls were comparable to those of healthy volunteers. Cirrhotics had in median 27 times more bacterial DNA of Enterobactericaea in faeces compared to the healthy volunteers (p = 0.011). Enterobactericaea were also the most common bacteria translocated into cirrhotic liver, although there were no statistically significant differences between the study groups. Of the ascites samples from the volunteers with liver cirrhosis, 50% contained bacterial DNA from Enterobactericaea, Clostridium leptum group or Lactobacillus spp.. The total bacterial DNA in autopsy liver was associated with the percentage of CD14 expression (p = 0.045). CD14 expression percentage in cirrhotics was significantly higher than in the autopsy controls (p = 0.004). Conclusions Our results suggest that translocation of intestinal bacteria into liver may be involved as a one factor in the pathogenesis of alcoholic liver cirrhosis.BioMed Central open acces

Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis

Uterine leiomyomata (UL) are the most common neoplasms of the female reproductive tract and primary cause for hysterectomy, leading to considerable morbidity and high economic burden. Here we conduct a GWAS meta-analysis in 35,474 cases and 267,505 female controls of European ancestry, identifying eight novel genome-wide significant (P < 5 × 10−8) loci, in addition to confirming 21 previously reported loci, including multiple independent signals at 10 loci. Phenotypic stratification of UL by heavy menstrual bleeding in 3409 cases and 199,171 female controls reveals genome-wide significant associations at three of the 29 UL loci: 5p15.33 (TERT), 5q35.2 (FGFR4) and 11q22.3 (ATM). Four loci identified in the meta-analysis are also associated with endometriosis risk; an epidemiological meta-analysis across 402,868 women suggests at least a doubling of risk for UL diagnosis among those with a history of endometriosis. These findings increase our understanding of genetic contribution and biology underlying UL development, and suggest overlapping genetic origins with endometriosis

Genetics of early-life head circumference and genetic correlations with neurological, psychiatric and cognitive outcomes

This is the final version. Available from BMC via the DOI in this record. Availability of data and materials GWAS summary data will be deposited at the EGG website (https://egg-consortium.org/) at publication. Individual study data are available from the corresponding author on reasonable request.Abstract Background: Head circumference is associated with intelligence and tracks from childhood into adulthood. Methods: We performed a genome-wide association study meta-analysis and follow-up of head circumference in a total of 29,192 participants between 6 and 30 months of age. Results: Seven loci reached genome-wide signifcance in the combined discovery and replication analysis of which three loci near ARFGEF2, MYCL1, and TOP1, were novel. We observed positive genetic correlations for early-life head circumference with adult intracranial volume, years of schooling, childhood and adult intelligence, but not with adult psychiatric, neurological, or personality-related phenotypes. Conclusions: The results of this study indicate that the biological processes underlying early-life head circumference overlap largely with those of adult head circumference. The associations of early-life head circumference with cognitive outcomes across the life course are partly explained by genetics.Wellcome TrustSimons FoundationWellcome TrustMRC & WTUniversity of Southern DenmarkMax Planck core societ