Publications

What are the respective roles of polycystic ovary syndrome (PCOS), long-term weight gain and obesity for the development of prediabetes or Type 2 diabetes mellitus (T2DM) by age 46 years?The risk of T2DM in women with PCOS is mainly due to overweight and obesity, although these two factors have a synergistic effect on the development of T2DM.PCOS is associated with an increased risk of prediabetes and T2DM. However, the respective roles of PCOS per se and BMI for the development of T2DM have remained unclear.In a prospective, general population-based follow-up birth cohort 1966 (n = 5889), postal questionnaires were sent at ages 14 (95% answered), 31 (80% answered) and 46 years (72% answered). Questions about oligoamenorrhoea and hirsutism were asked at age 31 years, and a question about PCOS diagnosis at 46 years. Clinical examination and blood sampling were performed at 31 years in 3127 women, and at 46 years in 3280 women. A 2-h oral glucose tolerance test (OGTT) was performed at 46 years of age in 2780 women.Women reporting both oligoamenorrhoea and hirsutism at age 31 years and/or diagnosis of PCOS by 46 years were considered as women with PCOS (n = 279). Women without any symptoms at 31 years and without PCOS diagnosis by 46 years were considered as controls (n = 1577). The level of glucose metabolism was classified according to the results of the OGTT and previous information of glucose metabolism status from the national drug and hospital discharge registers.PCOS per se significantly increased the risk of T2DM in overweight/obese (BMI ≥ 25.0 kg/m2) women with PCOS when compared to overweight/obese controls (odds ratio: 2.45, 95% CI: 1.28-4.67). Normal weight women with PCOS did not present with an increased risk of prediabetes or T2DM. The increase in weight between ages 14, 31 and 46 years was significantly greater in women with PCOS developing T2DM than in women with PCOS and normal glucose tolerance, with the most significant increase occurring in early adulthood (between 14 and 31 years: median with [25%; 75% quartiles]: 27.25 kg [20.43; 34.78] versus 13.80 kg [8.55; 20.20], P < 0.001).The diagnosis of PCOS was based on self-reporting, and the questionnaire at 46 years did not distinguish between polycystic ovaries only in ultrasonography and the syndrome. Ovarian ultrasonography was not available to aid the diagnosis of PCOS.These results emphasize weight management already during adolescence and early adulthood to prevent the development of T2DM in women with PCOS, as the period between 14 and 31 years seems to be a crucial time-window during which the women with PCOS who are destined to develop T2DM by 46 years of age experience a dramatic weight gain. Furthermore, our results support the view that, particularly in times of limited sources of healthcare systems, OGTT screening should be targeted to overweight/obese women with PCOS rather than to all women with PCOS.Finnish Medical Foundation; North Ostrobothnia Regional Fund; Academy of Finland (project grants 104781, 120315, 129269, 1114194, 24300796, Center of Excellence in Complex Disease Genetics and SALVE); Sigrid Juselius Foundation; Biocenter Oulu; University Hospital Oulu and University of Oulu (75617); Medical Research Center Oulu; National Institute for Health Research (UK); National Heart, Lung, and Blood Institute (grant 5R01HL087679-02) through the STAMPEED program (1RL1MH083268-01); National Institute of Health/National Institute of Mental Health (5R01MH63706:02); ENGAGE project and grant agreement HEALTH-F4-2007-201413; EU FP7 EurHEALTHAgeing-277849 European Commission and Medical Research Council, UK (G0500539, G0600705, G1002319, PrevMetSyn/SALVE) and Medical Research Center, Centenary Early Career Award. The authors have no conflicts of interests.N/A.

Introduction: Circulating levels of gut microbial metabolites, trimethylamine N-oxide (TMAO) and its nutrient precursors of choline and L-carnitine, have been suggested as risk factors for coronary heart disease (CHD). Whether changes in gut microbial metabolites are associated with the CHD incidence remains unknown. Hypothesis: We assessed the hypothesis that long-term (over 10 years) changes in plasma levels of TMAO, choline, and L-carnitine would be associated with the risk of CHD. Methods: This prospective nested case-control study included a total of 768 women (385 incident cases of fatal CHD and nonfatal myocardial infarction and 383 controls) who had data on blood concentrations of TMAO, choline, and L-carnitine at 2 time points, 10 years apart (1989-90, and 2000-01). We identified incident cases of CHD from the date of the second blood collection through 2014. Results: Higher TMAO levels at the second collection were associated with higher risk of CHD (relative risk (RR) 1.22 [95% CI: 1.05, 1.42] per 1 SD increment in log-transformed TMAO) in multivariate analyses controlling for traditional risk factors. Compared with women with low TMAO levels (lower two tertiles) at both time points, the RR was 1.74 (95% CI: 1.05, 2.89) for those with elevated levels of TMAO (the highest tertile) at both time points. Regardless of metabolite levels at the first collection, increases in TMAO or L-carnitine from the first to second collections were significantly associated with an increased risk of CHD (Fig. panels A-B). Women who had increases in both TMAO and L-carnitine had a particularly elevated risk of CHD (RR 2.12, 95% CI: 1.25, 3.59), as compared to those with decreases in both metabolites. Adherence to healthy dietary habits attenuated the associations of TMAO with CHD risk (Fig. panel C). Conclusions: Long-term increases in TMAO were significantly predictive of subsequent risk for CHD among women. The associations may be modified by the nutrient metabolite precursor, L-carnitine, and adherence to healthy dietary habits.

Abstract Genetic effects on changes in human traits over time are understudied and may have important pathophysiological impact. We propose a framework that enables data quality control, implements mixed models to evaluate trajectories of change in traits, and estimates phenotypes to identify age-varying genetic effects in GWAS. Using childhood BMI as an example trait, we included 71,336 participants from six cohorts and estimated the slope and area under the BMI curve within four time periods (infancy, early childhood, late childhood and adolescence) for each participant, in addition to the age and BMI at the adiposity peak and the adiposity rebound. GWAS of the 12 estimated phenotypes identified 28 genome-wide significant variants at 13 loci, one of which (in DAOA) has not been previously associated with childhood or adult BMI. Genetic studies of changes in human traits over time could uncover unique biological mechanisms influencing quantitative traits.

Cigarette smoking is strongly associated with an increased risk of CHD among women with type 2 diabetes mellitus. Furthermore, quitting smoking seems to decrease this excess risk substantially; women with diabetes should be strongly advised against smoking.CK

Background and Study Purpose: The conversion of plant lignans to enterolignans for absorption is mediated through the gut microbiota. We explored the interconnections between the intake of dietary lignans, circulating concentrations of plasma enterolignans, the gut microbiome, and cardio-metabolic risk factors (LDL-cholesterol, HDL-cholesterol, &amp; triglycerides). Design and method: The study was a repeated cross-sectional survey of up to 4 stool samples. Dietary lignan intake was assessed by two 7 day weighed records administered to coincide with fecal sample collection. DNA was extracted from 916 samples provided by 301 participants, and RNA was extracted from 369 samples from a subgroup of 96 participants. P&lt;0.25 after false discovery rate correction was considered statistically significant. Results: A high ratio of plasma enterolactone to dietary lignan was significantly associated with the relative abundance of 35 species (24 enriched and 11 depleted species), including 8 Bacteroidetes and 13 Firmicutes species. Greater dietary lignan was only significantly associated with a lower plasma ratio of triglyceride to HDL when plasma enterolactone was high. The association between dietary lignans and ratio of TG to HDL was mainly mediated by plasma enterolactone level (mediation effect: 74.3%, P=0.002), which was partially captured by the weighted species score (mediation effect: 28.6%, P=0.02). We observed several significant interactions between dietary lignans and presence of species on ratio of TG to HDL, suggesting that the protective effect of dietary lignans on CVD risk factor depends on the presence/abundance of certain microbiota. The relative abundance of microbial pathways involved in I-isoleucine biosynthesis and glutaryl-coa degradation pathways were significantly greater in in participants with a higher level of plasma enterolactone. Conclusion: The health benefits of dietary lignans on lipid levels may be modified by the greater enrichment of biologically relevant microbiota species. FIGURE

Abstract Background Several metabolites are individually related to incident type 2 diabetes (T2D) risk. We prospectively evaluated a novel T2D‐metabolite pattern with a risk of progression to T2D among high‐risk women with a history of gestational diabetes mellitus (GDM). Methods The longitudinal Nurses' Health Study II cohort enroled 116,429 women in 1989 and collected blood samples from 1996 to 1999. We profiled plasma metabolites in 175 incident T2D cases and 175 age‐matched controls, all with a history of GDM before the blood draw. We derived a metabolomics score from 21 metabolites previously associated with incident T2D in the published literature by scoring according to the participants' quintile (1–5 points) of each metabolite. We modelled the T2D metabolomics score categorically in quartiles and continuously per 1 standard deviation (SD) with the risk of incident T2D using conditional logistic regression models adjusting for body mass index at the blood draw, and other established T2D risk factors. Results The percentage of women progressing to T2D ranged from 10% in the bottom T2D metabolomics score quartile to 78% in the highest score quartile. Adjusting for established T2D risk factors, women in the highest quartile had more than a 20‐fold greater diabetes risk than women in the lowest quartile (odds ratios [OR] = 23.1 [95% CI = 8.6, 62.1]; p for trend&lt;0.001). The continuous T2D metabolomics score was strongly and positively associated with incident T2D (adjusted OR = 2.7 per SD [95% CI = 1.9, 3.7], p &lt; 0.0001). Conclusions A pattern of plasma metabolites among high‐risk women is associated with a markedly elevated risk of progression to T2D later in life.

This work demonstrates the practicality of forming two self-assembled monolayers (SAMs), independently but simultaneously, by adsorption of two different adsorbates from a common solution onto a substrate exposing two different materials at its surface. The experimental procedure and the degree of independence achieved in the resulting SAMs are illustrated by examination of monolayers obtained by adsorption of alkanethiols on gold and alkane carboxylic acids on alumina. This procedure provides a method for modifying the surface characteristics of microlithographically generated patterns and offers a versatile technique for controlling solid-vapor and solid-liquid interfacial properties in systems having patterns with dimensions of the order of 1 micrometer.

ABSTRACT The Nurses’ Health Study (NHS), Nurses’ Health Study II (NHSII), Health Professionals Follow Up Study (HPFS) and the Physicians Health Study (PHS) have collected detailed longitudinal data on multiple exposures and traits for approximately 310,000 study participants over the last 35 years. Over 160,000 study participants across the cohorts have donated a DNA sample and to date, 20,691 subjects have been genotyped as part of genome-wide association studies (GWAS) of twelve primary outcomes. However, these studies utilized six different GWAS arrays making it difficult to conduct analyses of secondary phenotypes or share controls across studies. To allow for secondary analyses of these data, we have created three new datasets merged by platform family and performed imputation using a common reference panel, the 1,000 Genomes Phase I release. Here, we describe the methodology behind the data merging and imputation and present imputation quality statistics and association results from two GWAS of secondary phenotypes (body mass index (BMI) and venous thromboembolism (VTE)). We observed the strongest BMI association for the FTO SNP rs55872725 (β=0.45, p=3.48×10 −22 ), and using a significance level of p=0.05, we replicated 19 out of 32 known BMI SNPs. For VTE, we observed the strongest association for the rs2040445 SNP (OR=2.17, 95% CI: 1.79-2.63, p=2.70×10 −15 ), located downstream of F5 and also observed significant associations for the known ABO and F11 regions. This pooled resource can be used to maximize power in GWAS of phenotypes collected across the cohorts and for studying gene-environment interactions as well as rare phenotypes and genotypes.

Grandmothers' smoking during pregnancy was associated with higher birth weight, higher risk of overweight, and higher BMI through adolescence and young adulthood.

The interface between nanosystems and biosystems is emerging as one of the broadest and most dynamic areas of science and technology, bringing together biology, chemistry, physics, biotechnology, medicine, and many areas of engineering. The combination of these diverse areas of research promises to yield revolutionary advances in healthcare, medicine, and the life sciences through the creation of new and powerful tools that enable direct, sensitive, and rapid analysis of biological and chemical species. Devices based on nanowires have emerged as one of the most powerful and general platforms for ultrasensitive, direct electrical detection of biological and chemical species and for building functional interfaces to biological systems, including neurons. Here, we discuss representative ex amples of nanowire nanosensors for ultrasensitive detection of proteins and individual virus par ticles as well as recording, stimulation, and inhibition of neuronal signals in nanowire–neuron hybrid structures.

Objectives To identify indolepropionate (IPA)-predicting gut microbiota species, investigate potential diet–microbiota interactions, and examine the prospective associations of circulating IPA concentrations with type 2 diabetes (T2D) and coronary heart disease (CHD) risk in free-living individuals. Design We included 287 men from the Men’s Lifestyle Validation Study, a substudy of the Health Professionals Follow-Up Study (HPFS), who provided up to two pairs of faecal samples and two blood samples. Diet was assessed using 7-day diet records. Associations between plasma concentrations of tryptophan metabolites and T2D CHD risk were examined in 13 032 participants from Nurses’ Health Study (NHS), NHSII and HPFS. Results We identified 17 microbial species whose abundance was significantly associated with plasma IPA concentrations. A significant association between higher tryptophan intake and higher IPA concentrations was only observed among men who had higher fibre intake and a higher microbial species score consisting of the 17 species (p-interaction&lt;0.01). Dietary and plasma concentrations of tryptophan and most kynurenine pathway metabolites were positively associated with T2D risk (HR Q5 vs Q1 ranged from 1.17 to 1.46) while a significant inverse association was found for IPA (HR Q5 vs Q1 (95% CI) 0.70 (0.56 to 0.88)). No associations were found in CHD for any plasma tryptophan metabolites. Conclusions Specific microbial species and dietary fibre jointly predicted significantly higher circulating IPA concentrations at higher tryptophan intake. Dietary and plasma tryptophan, as well as its kynurenine pathway metabolites, demonstrated divergent associations from those for IPA, which was significantly predictive of lower risk of T2D.

This paper describes the use of magnetic levitation (MagLev) to measure the association of proteins and ligands. The method starts with diamagnetic gel beads that are functionalized covalently with small molecules (putative ligands). Binding of protein to the ligands within the bead causes a change in the density of the bead. When these beads are suspended in a paramagnetic aqueous buffer and placed between the poles of two NbFeB magnets with like poles facing, the changes in the density of the bead on binding of protein result in changes in the levitation height of the bead that can be used to quantify the amount of protein bound. This paper uses a reaction–diffusion model to examine the physical principles that determine the values of rate and equilibrium constants measured by this system, using the well-defined model system of carbonic anhydrase and aryl sulfonamides. By tuning the experimental protocol, the method is capable of quantifying either the concentration of protein in a solution, or the binding affinities of a protein to several resin-bound small molecules simultaneously. Since this method requires no electricity and only a single piece of inexpensive equipment, it may find use in situations where portability and low cost are important, such as in bioanalysis in resource-limited settings, point-of-care diagnosis, veterinary medicine, and plant pathology. It still has several practical disadvantages. Most notably, the method requires relatively long assay times and cannot be applied to large proteins (>70 kDa), including antibodies. The design and synthesis of beads with improved characteristics (e.g., larger pore size) has the potential to resolve these problems.