Publications

Background Plasma levels of C-reactive protein (CRP) are independently associated with the risk of coronary heart disease (CHD). Whether the relationship of CRP with CHD is causal, or whether CRP is simply an “innocent bystander” of the inflammatory disease process, is unknown. Methods We first carried out a genome-wide association (n  =  17 967) and replication study (n  =  14 747) to identify genetic loci associated with plasma CRP concentrations. At each locus, we selected the most closely associated (“top-ranking”) single nucleotide polymorphism (SNP) for testing against CHD. For the CRP locus, we then carried out a Mendelian randomisation experiment and meta-analysis with published studies, providing data for 21 876 cases and 58 738 controls. Results Genetic variants in the CRP, LEPR, IL-6R, HNF1A and APOE-CI-CII loci were strongly associated with differences in CRP levels. Polymorphisms in LEPR (rs6700896), IL-6R (rs4537545) and APOE-CI-CII (rs4420638) were associated with the risk of CHD (p Interpretation The weak association between variants in the CRP locus and CHD risk suggests that any causal association of CRP with atherosclerosis is likely to be small. We identify LEPR and IL-6R as putative new susceptibility loci for CHD.

Haptoglobin is an acute phase inflammatory marker. Its main function is to bind hemoglobin released from erythrocytes to aid its elimination, and thereby haptoglobin prevents the generation of reactive oxygen species in the blood. Haptoglobin levels have been repeatedly associated with a variety of inflammation-linked infectious and non-infectious diseases, including malaria, tuberculosis, human immunodeficiency virus, hepatitis C, diabetes, carotid atherosclerosis, and acute myocardial infarction. However, a comprehensive genetic assessment of the inter-individual variability of circulating haptoglobin levels has not been conducted so far. We used a genome-wide association study initially conducted in 631 French children followed by a replication in three additional European sample sets and we identified a common single nucleotide polymorphism (SNP), rs2000999 located in the Haptoglobin gene (HP) as a strong genetic predictor of circulating Haptoglobin levels (Poverall = 8.1×10−59), explaining 45.4% of its genetic variability (11.8% of Hp global variance). The functional relevance of rs2000999 was further demonstrated by its specific association with HP mRNA levels (β = 0.23±0.08, P = 0.007). Finally, SNP rs2000999 was associated with decreased total and low-density lipoprotein cholesterol in 8,789 European children (Ptotal cholesterol = 0.002 and PLDL = 0.0008). Given the central position of haptoglobin in many inflammation-related metabolic pathways, the relevance of rs2000999 genotyping when evaluating haptoglobin concentration should be further investigated in order to improve its diagnostic/therapeutic and/or prevention impact.

It has been hypothesized that low frequency (1–5% minor allele frequency (MAF)) and rare (<1% MAF) variants with large effect sizes may contribute to the missing heritability in complex traits. Here, we report an association analysis of lipid traits (total cholesterol, LDL-cholesterol, HDL-cholesterol triglycerides) in up to 27 312 individuals with a comprehensive set of low frequency coding variants (ExomeChip), combined with conditional analysis in the known lipid loci. No new locus reached genome-wide significance. However, we found a new lead variant in 26 known lipid association regions of which 16 were >1000-fold more significant than the previous sentinel variant and not in close LD (six had MAF <5%). Furthermore, conditional analysis revealed multiple independent signals (ranging from 1 to 5) in a third of the 98 lipid loci tested, including rare variants. Addition of our novel associations resulted in between 1.5- and 2.5-fold increase in the proportion of heritability explained for the different lipid traits. Our findings suggest that rare coding variants contribute to the genetic architecture of lipid traits.

Lithographic techniques applied to a substrate prior to film deposition can create areas of low interface adhesion surrounded by regions of high adhesion. If the film is under compression and if buckle delamination is nucleated, conditions can be controlled such that delaminations are confined to the patterned areas of low adhesion. When the area of low adhesion is a strip, the width of the strip controls the buckle morphology: smooth Euler buckles for narrow strips, asymmetric telephone cord buckles for wider strips, and symmetric varicose buckles under a very limited range of conditions. Results for the elastic energy in the buckled state show that above a critical stress the telephone cord morphology is the preferred morphology. Energy release rates for propagating delaminations are determined for each of the three morphologies. Tapered strips provide an accurate means of measuring interface adhesion based on the width of the strip where the delamination arrests.

This paper describes the use of a nanoindenter, equipped with a diamond tip, to form patterns of indentations on planar substrates (epoxy, silicon, and SiO(2)). The process is called "Indentation Lithography" (IndL). The indentations have the form of pits and furrows, whose cross-sectional profiles are determined by the shapes of the diamond indenters, and whose dimensions are determined by the applied load and hardness of the substrate. IndL makes it possible to indent hard materials, to produce patterns with multiple levels of relief by changing the loading force, and to control the profiles of the indentations by using indenters with different shapes. This paper also demonstrates the transfer of indented patterns to elastomeric PDMS stamps for soft lithography, and to thin films of evaporated gold or silver. Stripping an evaporated film from an indented template produces patterns of gold or silver pyramids, whose tips concentrate electric fields. Patterns produced by IndL can thus be used as substrates for surface-enhanced Raman scattering (SERS) and for other plasmonic applications.

This article describes a point-of-care (POC) system—comprising a microfluidic, paper-based analytical device (μ-PAD) and a hand-held optical colorimeter—for quantifying the concentration of analytes in biological fluids. The μ-PAD runs colorimetric assays, and consists of paper that has been (i) patterned to expose isolated regions of hydrophilic zones and (ii) wet with an index-matching fluid (e.g., vegetable oil) that is applied using a disposable, plastic sleeve encasement. Measuring transmittance through paper represents a new method of quantitative detection that expands the potential functionality of μ-PADs. This prototype transmittance colorimeter is inexpensive, rugged, and fully self-contained, and thus potentially attractive for use in resource-limited environments and developing countries.

Children's biological age does not always correspond to their chronological age. In the case of BMI trajectories, this can appear as phase variation, which can be seen as shift, stretch, or shrinking between trajectories. With maturation thought of as a process moving towards the final state - adult BMI, we assessed whether children can be divided into latent groups reflecting similar maturational age of BMI. The groups were characterised by early factors and time-related features of the trajectories. We used data from two general population birth cohort studies, Northern Finland Birth Cohorts 1966 and 1986 (NFBC1966 and NFBC1986). Height (n = 6329) and weight (n = 6568) measurements were interpolated in 34 shared time points using B-splines, and BMI values were calculated between 3 months to 16 years. Pairwise phase distances of 2999 females and 3163 males were used as a similarity measure in k-medoids clustering. We identified three clusters of trajectories in females and males (Type 1: females, n = 1566, males, n = 1669; Type 2: females, n = 1028, males, n = 973; Type 3: females, n = 405, males, n = 521). Similar distinct timing patterns were identified in males and females. The clusters did not differ by sex, or early growth determinants studied. Trajectory cluster Type 1 reflected to the shape of what is typically illustrated as the childhood BMI trajectory in literature. However, the other two have not been identified previously. Type 2 pattern was more common in the NFBC1966 suggesting a generational shift in BMI maturational patterns.

Abstract Background Comparable evidence on adiposity inequalities in early life is lacking across a range of European countries. This study investigates whether low maternal education is associated with overweight and obesity risk in children from distinct European settings during early childhood. Methods Prospective data of 45 413 children from 11 European cohorts were used. Children's height and weight obtained at ages 4–7 years were used to assess prevalent overweight and obesity according to the International Obesity Task Force definition. The Relative/Slope Indices of Inequality ( RII / SII ) were estimated within each cohort and by gender to investigate adiposity risk among children born to mothers with low education as compared to counterparts born to mothers with high education. Individual‐data meta‐analyses were conducted to obtain aggregate estimates and to assess heterogeneity between cohorts. Results Low maternal education yielded a substantial risk of early childhood adiposity across 11 European countries. Low maternal education yielded a mean risk ratio of 1.58 (95% confidence interval ( CI ) 1.34, 1.85) and a mean risk difference of 7.78% (5.34, 10.22) in early childhood overweight, respectively, measured by the RII and SII . Early childhood obesity risk by low maternal education was as substantial for all cohorts combined ( RII = 2.61 (2.10, 3.23)) and ( SII = 4.01% (3.14, 4.88)). Inequalities in early childhood adiposity were consistent among boys, but varied among girls in a few cohorts. Conclusions Considerable inequalities in overweight and obesity are evident among European children in early life. Tackling early childhood adiposity is necessary to promote children's immediate health and well‐being and throughout the life course.