Evaluation of genetic markers as instruments for Mendelian randomization studies on vitamin D

Combining SNPs into allele scores provides a more powerful instrument for MR analysis than a single SNP in isolation. Population stratification and the potential for pleiotropic effects need to be considered in MR studies on vitamin D.

A genome-wide association meta-analysis identifies new childhood obesity loci

Multiple genetic variants have been associated with adult obesity and a few with severe obesity in childhood; however, less progress has been made in establishing genetic influences on common early-onset obesity. We performed a North American, Australian and European collaborative meta-analysis of 14 studies consisting of 5,530 cases (≥95th percentile of body mass index (BMI)) and 8,318 controls (<50th percentile of BMI) of European ancestry. Taking forward the eight newly discovered signals yielding association with P < 5 × 10(-6) in nine independent data sets (2,818 cases and 4,083 controls), we observed two loci that yielded genome-wide significant combined P values near OLFM4 at 13q14 (rs9568856; P = 1.82 × 10(-9); odds ratio (OR) = 1.22) and within HOXB5 at 17q21 (rs9299; P = 3.54 × 10(-9); OR = 1.14). Both loci continued to show association when two extreme childhood obesity cohorts were included (2,214 cases and 2,674 controls). These two loci also yielded directionally consistent associations in a previous meta-analysis of adult BMI(1).

Interaction between allelic variations in vitamin D receptor and retinoid X receptor genes on metabolic traits

BACKGROUND: Low vitamin D status has been shown to be a risk factor for several metabolic traits such as obesity, diabetes and cardiovascular disease. The biological actions of 1, 25-dihydroxyvitamin D, are mediated through the vitamin D receptor (VDR), which heterodimerizes with retinoid X receptor, gamma (RXRG). Hence, we examined the potential interactions between the tagging polymorphisms in the VDR (22 tag SNPs) and RXRG (23 tag SNPs) genes on metabolic outcomes such as body mass index, waist circumference, waist-hip ratio (WHR), high- and low-density lipoprotein (LDL) cholesterols, serum triglycerides, systolic and diastolic blood pressures and glycated haemoglobin in the 1958 British Birth Cohort (1958BC, up to n = 5,231). We used Multifactor- dimensionality reduction (MDR) program as a non-parametric test to examine for potential interactions between the VDR and RXRG gene polymorphisms in the 1958BC. We used the data from Northern Finland Birth Cohort 1966 (NFBC66, up to n = 5,316) and Twins UK (up to n = 3,943) to replicate our initial findings from 1958BC. RESULTS: After Bonferroni correction, the joint-likelihood ratio test suggested interactions on serum triglycerides (4 SNP - SNP pairs), LDL cholesterol (2 SNP - SNP pairs) and WHR (1 SNP - SNP pair) in the 1958BC. MDR permutation model testing analysis showed one two-way and one three-way interaction to be statistically significant on serum triglycerides in the 1958BC. In meta-analysis of results from two replication cohorts (NFBC66 and Twins UK, total n = 8,183), none of the interactions remained after correction for multiple testing (Pinteraction >0.17). CONCLUSIONS: Our results did not provide strong evidence for interactions between allelic variations in VDR and RXRG genes on metabolic outcomes; however, further replication studies on large samples are needed to confirm our findings.

Analysis of DNA polymorphism in ancient barley herbarium material: validation of the KASP SNP genotyping platform

The availability of crop specimens archived in herbaria and old seed collections represent valuable resources for the analysis of plant genetic diversity and crop domestication. The ability to extract ancient DNA (aDNA) from such samples has recently allowed molecular genetic investigations to be undertaken in ancient materials. While analyses of aDNA initially focused on the use of markers which occur in multiple copies such as the internal transcribed spacer region (ITS) within ribosomal DNA and those requiring amplification of short DNA regions of variable length such as simple sequence repeats (SSRs), emphasis is now moving towards the genotyping of single nucleotide polymorphisms (SNPs), traditionally undertaken in aDNA by Sanger sequencing. Here, using a panel of barley aDNA samples previously surveyed by Sanger sequencing for putative causative SNPs within the flowering-time gene PPD-H1, we assess the utility of the Kompetitive Allele Specific PCR (KASP) genotyping platform for aDNA analysis. We find KASP to out-perform Sanger sequencing in the genotyping of aDNA samples (78% versus 61% success, respectively), as well as being robust to contamination. The small template size (≥46 bp) and one-step, closed-tube amplification/genotyping process make this platform ideally suited to the genotypic analysis of aDNA, a process which is often hampered by template DNA degradation and sample cross-contamination. Such attributes, as well as its flexibility of use and relatively low cost, make KASP particularly relevant to the genetic analysis of aDNA samples. Furthermore, KASP provides a common platform for the genotyping and analysis of corresponding SNPs in ancient, landrace and modern plant materials. The extended haplotype analysis of PPD-H1 undertaken here (allelic variation at which is thought to be important for the spread of domestication and local adaptation) provides further resolution to the previously identified geographic cline of flowering-time allele distribution, illustrating how KASP can be used to aid genetic analyses of aDNA from plant species. We further demonstrate the utility of KASP by genotyping ten additional genetic markers diagnostic for morphological traits in barley, shedding light on the phenotypic traits, alleles and allele combinations present in these unviable ancient specimens, as well as their geographic distributions.

Addressing rural social exclusion through African social purpose ventures

Objectives. The overarching aim of this paper is to consider the relationship between social entrepreneurship and rural development, and as a mechanism to address social exclusion in the Global South, with specific reference to Sub-Saharan Africa. Drawing upon a number of case examples of social purpose ventures in Kenya, Mozambique and Zambia the objectives of this paper are: - To provide a synthesis of existing literature on the interaction between social purpose ventures and rural BoP communities in the developing world; - To explore extant social exclusion literature including economic, political and international development dimensions; and - To analyse the case study examples to consider the channels through which social purpose ventures contribute to tackling social exclusion amongst the rural BoP. Prior Work. There is growing interest in the role that social enterprises and wider social purpose ventures can play in sustainable development in the Global South. In many developing countries the majority of the population still reside in rural areas with these areas often particularly marginalised and underdeveloped. Previous studies have provided anecdotal examples where social purpose ventures have the potential to provide innovative solutions to the development challenges faced by rural households and communities. Yet research in this area remains relatively nascent and fragmented. In depth empirical studies examining social purpose ventures and rural development in the Global South are furthermore limited. Approach. Data was collected during in-depth case study research with social purpose ventures in Zambia, Kenya and Mozambique. Cases were selected through a purposive sample with access negotiated to rural BoP communities through gatekeeper partners. Qualitative research methods were primarily employed including interviews, stakeholder focus groups and observational research. Results Six channels through which social purpose ventures contribute to tackling social exclusion amongst rural BoP communities are identified. These include ventures with the BoP as employees, producers, consumers, entrepreneurs, service users and shareholders. A number of shared characteristics for successful social purpose ventures are also outlined. Finally implications for policy, practice and research are discussed. Implications. Despite the increasing attention being given to social purpose ventures as a mechanism for global sustainable development many questions remain unanswered. Limited empirical work has been undertaken on such ventures operating in rural settings in the developing world, particularly Africa. The paper will add to academic and practitioner knowledge in this area especially in relation to up-scaling impact, the long term sustainability and viability of social purpose enterprise ventures, and effective supporting interventions. This paper adds to knowledge in the field of social purpose venturing in the developing world. It identifies various channels through which such ventures help tackle rural social exclusion and also factors influencing their success. The paper provides insights for practitioners and policy makers, particularly in relation to facilitating successful social purpose venturing. Value This paper will provide insights relevant to both academic and practitioner audiences. It addresses a subject area and geographical region that has received limited research attention to date. The paper adds to knowledge on social purpose ventures and social entrepreneurship in Africa and wider developing world environments, and contributes to debates on its potential and present limitations as a vehicle for development and societal transformation

Institutional framing of CSR and social entrepreneurship interactions in South Africa

Objectives. This paper considers the intersection of Corporate Social Responsibility (CSR) and social entrepreneurship in South Africa through the lens of institutional theories and draws upon a number of illustrative case study examples. In particular it: (1) charts the historically evolving relationship between CSR and social entrepreneurship in South Africa, and how this relationship has been informed by institutional changes since the end of apartheid, particularly over the last few years; (2) identifies different interactional relationship forms between social enterprises and corporates engaging in CSR, with an emphasis on new innovative multi-stakeholder partnerships; and (3) considers internal engagements with social responsibility by SME social enterprises in South Africa. Prior Work. Reflecting South Africa’s history of division, the controversial role of business during apartheid, and the ongoing legacies of that period, the South African government has been particularly pro-active in encouraging companies to contribute to development and societal transformation through CSR and Black Economic Empowerment (BEE). Accordingly a substantial body of work now exists examining and critically reflecting upon CSR and BEE across a range of sectors. In response to perceived problems with BEE, efforts have recently been made to foster broader-based economic empowerment. However the implications of these transitions for the relationship between CSR and social entrepreneurship in South Africa have received scant academic attention. Approach. Analysis is undertaken of legislative and policy changes in South Africa with a bearing on CSR and social entrepreneurship. Data collected during fieldwork in South Africa working with 6 social enterprise case studies is utilised including qualitative data from key informant interviews, focus groups with stakeholders and observational research. Results. The paper considers the historically evolving relationship between CSR and social entrepreneurship in South Africa informed by institutional change. Five different relationship forms are identified and illustrated with reference to case examples. Finally internal engagement with social responsibility concerns by small and medium social enterprises are critically discussed. Implications. This paper sheds light on some of the innovative partnerships emerging between corporates and social enterprises in South Africa. It reflects on some of the strengths and weaknesses of South Africa’s policy and legislative approaches. Value. The paper provides insights useful for academic and practitioner audiences. It also has policy relevance, in particularly for other African countries potentially looking to follow South Africa’s example, in the development of legislative and policy frameworks to promote corporate responsibility, empowerment and transformation.

Reaching the underbanked and unbanked in subsistence markets at the nexus of the formal and informal economy

It is estimated that globally over 2 billion people do not have a bank account, with many more in the developed and developing worlds ‘under-banked’, meaning they have limited access to financial services. Reaching the unbanked and underbanked with appropriate financial services is widely recognised as critical for future global economic growth and prosperity. Drawing upon multidimensional understandings of poverty, and framed by literature on poverty pools, traps and cycles, this paper explores the use of financial products and services in the developing world and critically reflects on their potential role in poverty alleviation and wider sustainable development. Discussions are illustrated with reference to qualitative empirical research undertaken in East and Southern Africa, and a sense-making of the lived financial experiences of low income individuals, households and communities.

Financial services for the poor within the formal/informal nexus in sub-Saharan Africa

This paper draws upon fieldwork undertaken across Kenya, Zambia, Mozambique and South Africa to present a reflective overview of the use of financial services amongst the poorest members of society. It considers the role that access to a portfolio of financial products and services may have as a contributory factor in poverty alleviation, but also how inappropriate use of these mechanisms may exacerbate a descent into poverty. This work draws upon the notions of poverty pools and the rise of fall of low income households in and out of poverty, alongside the contributory nature of vicious cycles of economic and political poverty. Drawing on fieldwork experiences it presents a synopsis of the types of financial mechanisms commonly in use on the African continent, as well as examples of public, private and civil society partnerships that are producing services specifically tailored for those in extreme and absolute poverty.

Paralog re-emergence: a novel, historically contingent mechanism in the evolution of antimicrobial resistance

Evolution of resistance to drugs and pesticides poses a serious threat to human health and agricultural production. CYP51 encodes the target site of azole fungicides, widely used clinically and in agriculture. Azole resistance can evolve due to point mutations or overexpression of CYP51, and previous studies have shown that fungicide-resistant alleles have arisen by de novo mutation. Paralogs CYP51A and CYP51B are found in filamentous ascomycetes, but CYP51A has been lost from multiple lineages. Here, we show that in the barley pathogen Rhynchosporium commune, re-emergence of CYP51A constitutes a novel mechanism for the evolution of resistance to azoles. Pyrosequencing analysis of historical barley leaf samples from a unique long-term experiment from 1892 to 2008 indicates that the majority of the R. commune population lacked CYP51A until 1985, after which the frequency of CYP51A rapidly increased. Functional analysis demonstrates that CYP51A retains the same substrate as CYP51B, but with different transcriptional regulation. Phylogenetic analyses show that the origin of CYP51A far predates azole use, and newly sequenced Rhynchosporium genomes show CYP51A persisting in the R. commune lineage rather than being regained by horizontal gene transfer; therefore, CYP51A re-emergence provides an example of adaptation to novel compounds by selection from standing genetic variation.

Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study

BACKGROUND: Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with blood pressure and hypertension risk. METHODS: In this mendelian randomisation study, we generated an allele score (25[OH]D synthesis score) based on variants of genes that affect 25(OH)D synthesis or substrate availability (CYP2R1 and DHCR7), which we used as a proxy for 25(OH)D concentration. We meta-analysed data for up to 108 173 individuals from 35 studies in the D-CarDia collaboration to investigate associations between the allele score and blood pressure measurements. We complemented these analyses with previously published summary statistics from the International Consortium on Blood Pressure (ICBP), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and the Global Blood Pressure Genetics (Global BPGen) consortium. FINDINGS: In phenotypic analyses (up to n=49 363), increased 25(OH)D concentration was associated with decreased systolic blood pressure (β per 10% increase, -0·12 mm Hg, 95% CI -0·20 to -0·04; p=0·003) and reduced odds of hypertension (odds ratio [OR] 0·98, 95% CI 0·97-0·99; p=0·0003), but not with decreased diastolic blood pressure (β per 10% increase, -0·02 mm Hg, -0·08 to 0·03; p=0·37). In meta-analyses in which we combined data from D-CarDia and the ICBP (n=146 581, after exclusion of overlapping studies), each 25(OH)D-increasing allele of the synthesis score was associated with a change of -0·10 mm Hg in systolic blood pressure (-0·21 to -0·0001; p=0·0498) and a change of -0·08 mm Hg in diastolic blood pressure (-0·15 to -0·02; p=0·01). When D-CarDia and consortia data for hypertension were meta-analysed together (n=142 255), the synthesis score was associated with a reduced odds of hypertension (OR per allele, 0·98, 0·96-0·99; p=0·001). In instrumental variable analysis, each 10% increase in genetically instrumented 25(OH)D concentration was associated with a change of -0·29 mm Hg in diastolic blood pressure (-0·52 to -0·07; p=0·01), a change of -0·37 mm Hg in systolic blood pressure (-0·73 to 0·003; p=0·052), and an 8·1% decreased odds of hypertension (OR 0·92, 0·87-0·97; p=0·002). INTERPRETATION: Increased plasma concentrations of 25(OH)D might reduce the risk of hypertension. This finding warrants further investigation in an independent, similarly powered study.

Exploring the role of Associate Dean in UK universities

This paper reports on a research project, funded by the Leadership Foundation for Higher Education, which explored the under-researched role of the Associate Dean in UK Universities. Specifically, the project aimed to explore how the role was defined, perceived and experienced across a range of post and pre 1992 Universities. Data was collected through 15 interviews and a follow up on-line survey completed by 172 Associate Deans across the UK.

The effect of polyoxyethylene polymers on the transport of ranitidine in Caco-2 cell monolayers.

Previous in vivo studies using PEG 400 showed an enhancement in the bioavailability of ranitidine. This study investigated the effect of PEG 200, 300 and 400 on ranitidine transport across Caco-2 cells. The effect of PEG polymers (20%, v/v) on the bi-directional flux of (3)H-ranitidine across Caco-2 cell monolayers was measured. The concentration dependence of PEG 400 effects on ranitidine transport was also studied. A specific screen for P-glycoprotein (P-gp) activity was used to test for an interaction between PEG and P-gp. In the absence of PEG, ranitidine transport showed over 5-fold greater flux across Caco-2 monolayers in the secretory than the absorptive direction; efflux ratio 5.38. PEG 300 and 400 significantly reduced this efflux ratio (p<0.05), whereas PEG 200 had no effect (p>0.05). In concordance, PEG 300 and 400 showed an interaction with the P-gp transporter, whereas PEG 200 did not. Interestingly, with PEG 400 a non-linear concentration dependence was seen for the inhibition of the efflux ratio of ranitidine, with a maxima at 1%, v/v (p<0.05). The inhibition of ranitidine efflux by PEG 300 and 400 which interact with P-gp provides a mechanism that may account for the observations of ranitidine absorption enhancement by PEG 400 in vivo.