Health research improves healthcare: now we have the evidence and the chance to help the WHO spread such benefits globally

There has been a dramatic increase in the body of evidence demonstrating the benefits that come from health research. In 2014, the funding bodies for higher education in the UK conducted an assessment of research using an approach termed the Research Excellence Framework (REF). As one element of the REF, universities and medical schools in the UK submitted 1,621 case studies claiming to show the impact of their health and other life sciences research conducted over the last 20 years. The recently published results show many case studies were judged positively as providing examples of the wide range and extensive nature of the benefits from such research, including the development of new treatments and screening programmes that resulted in considerable reductions in mortality and morbidity. Analysis of specific case studies yet again illustrates the international dimension of progress in health research; however, as has also long been argued, not all populations fully share the benefits. In recognition of this, in May 2013 the World Health Assembly requested the World Health Organization (WHO) to establish a Global Observatory on Health Research and Development (R&D) as part of a strategic work-plan to promote innovation, build capacity, improve access, and mobilise resources to address diseases that disproportionately affect the world’s poorest countries. As editors of Health Research Policy and Systems (HARPS), we are delighted that our journal has been invited to help inform the establishment of the WHO Global Observatory through a Call for Papers covering a range of topics relevant to the Observatory, including topics on which HARPS has published articles over the last few months, such as approaches to assessing research results, measuring expenditure data with a focus on R&D, and landscape analyses of platforms for implementing R&D. Topics related to research capacity building may also be considered. The task of establishing a Global Observatory on Health R&D to achieve the specified objectives will not be easy; nevertheless, this Call for Papers is well timed – it comes just at the point where the evidence of the benefits from health research has been considerably strengthened

GAD2 on chromosome 10p12 is a candidate gene for human obesity

The gene GAD2 encoding the glutamic acid decarboxylase enzyme (GAD65) is a positional candidate gene for obesity on Chromosome 10p11&ndash;12, a susceptibility locus for morbid obesity in four independent ethnic populations. GAD65 catalyzes the formation of &gamma;-aminobutyric acid (GABA), which interacts with neuropeptide Y in the paraventricular nucleus to contribute to stimulate food intake. A case-control study (575 morbidly obese and 646 control subjects) analyzing GAD2 variants identified both a protective haplotype, including the most frequent alleles of single nucleotide polymorphisms (SNPs) +61450 C&gt;A and +83897 T&gt;A (OR = 0.81, 95% CI [0.681&ndash;0.972], p = 0.0049) and an at-risk SNP (&minus;243 A&gt;G) for morbid obesity (OR = 1.3, 95% CI [1.053&ndash;1.585], p = 0.014). Furthermore, familial-based analyses confirmed the association with the obesity of SNP +61450 C&gt;A and +83897 T&gt;A haplotype (&chi;2 = 7.637, p = 0.02). In the murine insulinoma cell line &beta;TC3, the G at-risk allele of SNP &minus;243 A&gt;G increased six times GAD2 promoter activity (p &lt; 0.0001) and induced a 6-fold higher affinity for nuclear extracts. The &minus;243 A&gt;G SNP was associated with higher hunger scores (p = 0.007) and disinhibition scores (p = 0.028), as assessed by the Stunkard Three-Factor Eating Questionnaire. As GAD2 is highly expressed in pancreatic &beta; cells, we analyzed GAD65 antibody level as a marker of &beta;-cell activity and of insulin secretion. In the control group, &minus;243 A&gt;G, +61450 C&gt;A, and +83897 T&gt;A SNPs were associated with lower GAD65 autoantibody levels (p values of 0.003, 0.047, and 0.006, respectively). SNP +83897 T&gt;A was associated with lower fasting insulin and insulin secretion, as assessed by the HOMA-B% homeostasis model of &beta;-cell function (p = 0.009 and 0.01, respectively). These data support the hypothesis of the orexigenic effect of GABA in humans and of a contribution of genes involved in GABA metabolism in the modulation of food intake and in the development of morbid obesity.<br /

Ln GAD65Ab Levels Adjusted for Age and BMI According to the Genotypes at SNPs −243 A>G, +61450 C>A, and +83897 T>A

<p>Mean level values ± SD are displayed for each genotype. Wild-type are AA, CC, TT; heterozygous are AG, CA, TA; and homozygous are GG, AA, AA, respectively, for each SNP. (A) Nonobese normoglycemic subjects. (B) Morbidly obese patients.</p

EMSA of the the −243 A>G Polymorphism with βTC3 Nuclear Proteins

<p>Specific complex formation is indicated by an arrow. Lanes (−) are radiolabeled probes without nuclear extract. βTC3 nuclear proteins have an higher affinity for the G allele variant than for the A allele at SNP −243 A>G.</p

Mapping of Chromosome 10p and the <i>GAD2</i> Gene

<div><p>(A) Fine mapping of the Chromosome 10p locus between markers D10S548 and D10S220 in 188 nuclear families (620 individuals). Multipoint analysis for obesity phenotype.</p> <p>(B) SNP map of the <i>GAD2</i> gene. Positions were assigned according the location to the A of the ATG. The 15 SNPs selected for association studies are indicated in red. See also <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0000068#pbio.0000068-t001" target="_blank">Table 1</a>.</p></div

Pairwise LD between SNPs of <i>GAD2</i> and <i>MYO3</i> Genes in the French Obese Population

<p>Pairwise LD between SNPs is measured by triangles (color scale). Regions of high and low LD are represented by red and blue shading, respectively. The graph is not to scale; indeed, the SNPs are equidistant to highlight the detailed pattern of LD.</p

Effect of the −243 A>G , −1600 G>A, and −2004 A>T SNPs on Transcriptional Activity

<p>G, A, and T alleles at −243 A>G, −1600 G>A, and −2004 A>T SNPs were generated into the wild-type construct (wt). βTC3 cells were transfected with equivalent amounts of pGL3, wild-type, Gad-2004T, Gad-1600A, and Gad-243G constructs. pRLTK was cotransfected with each construct. Luciferase and <i>Renilla</i> activities were assayed and normalized. Each experiment was performed in duplicate and replicated five times. A 6-fold increase of transcriptional activity was observed for the Gad-243 as compared to the wild-type construct.</p