Emmanuel Peprah

Examination of FMR1 transcript and protein levels among 74 premutation carriers.

Fragile X-associated disorders are caused by a CGG trinucleotide repeat expansion in the 5′-untranslated region of the FMR1 gene. Expansion of the CGG trinucleotide repeats to >200 copies (that is, a full mutation) induces methylation of the FMR1 gene, with transcriptional silencing being the eventual outcome. Previous data have shown that FMR1 premutation carriers (individuals with 55–199 repeats) have increased FMR1 mRNA levels with decreased protein (fragile X mental retardation protein (FMRP)) levels. However, the point at which this translational inefficiency occurs, given the increased transcription mechanism, has not yet been explored and remains to be elucidated. We examined the repeat length group, FMR1 transcript and FMRP levels in 74 males with a wide range of repeat lengths using analysis of covariance to better characterize this association. Results showed that the mean FMRP level among carriers with 80–89 repeats was significantly higher than the mean levels among lower (54–79) and higher (90–120) premutation carriers, in spite of the increasing transcript level with repeat length. Taken together, these results suggest that the 80–89-repeat group may lead to different properties that increase the efficiency of translation compared with other premutation repeat size groups.

Fragile X Syndrome: The FMR1 CGG Repeat Distribution Among World Populations

Fragile X syndrome (FXS) is characterized by moderate to severe intellectual disability, which is accompanied by macroorchidism and distinct facial morphology. FXS is caused by the expansion of the CGG trinucleotide repeat in the 5′ untranslated region of the fragile X mental retardation 1 (FMR1) gene. The syndrome has been studied in ethnically diverse populations around the world and has been extensively characterized in several populations. Similar to other trinucleotide expansion disorders, the gene‐specific instability of FMR1 is not accompanied by genomic instability. Currently we do not have a comprehensive understanding of the molecular underpinnings of gene‐specific instability associated with tandem repeats. Molecular evidence from in vitro experiments and animal models supports several pathways for gene‐specific trinucleotide repeat expansion. However, whether the mechanisms reported from other systems contribute to trinucleotide repeat expansion in humans is not clear. To understand how repeat instability in humans could occur, the CGG repeat expansion is explored through molecular analysis and population studies which characterized CGG repeat alleles of FMR1. Finally, the review discusses the relevance of these studies in understanding the mechanism of trinucleotide repeat expansion in FXS.

Genome-Wide Association Studies in Africans and African Americans: Expanding the Framework of the Genomics of Human Traits and Disease

Genomic research is one of the tools for elucidating the pathogenesis of diseases of global health relevance and paving the research dimension to clinical and public health translation. Recent advances in genomic research and technologies have increased our understanding of human diseases, genes associated with these disorders, and the relevant mechanisms. Genome-wide association studies (GWAS) have proliferated since the first studies were published several years ago and have become an important tool in helping researchers comprehend human variation and the role genetic variants play in disease. However, the need to expand the diversity of populations in GWAS has become increasingly apparent as new knowledge is gained about genetic variation. Inclusion of diverse populations in genomic studies is critical to a more complete understanding of human variation and elucidation of the underpinnings of complex diseases. In this review, we summarize the available data on GWAS in recent African ancestry populations within the western hemisphere (i.e. African Americans and peoples of the Caribbean) and continental African populations. Furthermore, we highlight ways in which genomic studies in populations of recent African ancestry have led to advances in the areas of malaria, HIV, prostate cancer, and other diseases. Finally, we discuss the advantages of conducting GWAS in recent African ancestry populations in the context of addressing existing and emerging global health conditions.

Burden of musculoskeletal disorders in the Eastern Mediterranean Region, 1990-2013: findings from the Global Burden of Disease Study 2013.

Objectives We used findings from the Global Burden of Disease Study 2013 to report the burden of musculoskeletal disorders in the Eastern Mediterranean Region (EMR). Methods The burden of musculoskeletal disorders was calculated for the EMRs 22 countries between 1990 and 2013. A systematic analysis was performed on mortality and morbidity data to estimate prevalence, death, years of live lost, years lived with disability and disability-adjusted life years (DALYs). Results For musculoskeletal disorders, the crude DALYs rate per 100 000 increased from 1297.1 (95% uncertainty interval (UI) 924.3–1703.4) in 1990 to 1606.0 (95% UI 1141.2–2130.4) in 2013. During 1990–2013, the total DALYs of musculoskeletal disorders increased by 105.2% in the EMR compared with a 58.0% increase in the rest of the world. The burden of musculoskeletal disorders as a proportion of total DALYs increased from 2.4% (95% UI 1.7–3.0) in 1990 to 4.7% (95% UI 3.6–5.8) in 2013. The range of point prevalence (per 1000) among the EMR countries was 28.2–136.0 for low back pain, 27.3–49.7 for neck pain, 9.7–37.3 for osteoarthritis (OA), 0.6–2.2 for rheumatoid arthritis and 0.1–0.8 for gout. Low back pain and neck pain had the highest burden in EMR countries. Conclusions This study shows a high burden of musculoskeletal disorders, with a faster increase in EMR compared with the rest of the world. The reasons for this faster increase need to be explored. Our findings call for incorporating prevention and control programmes that should include improving health data, addressing risk factors, providing evidence-based care and community programmes to increase awareness.

Genetic Diversity of the Fragile X Syndrome Gene (FMR1) in a Large Sub-Saharan West African Population

Fragile X syndrome (OMIM #300624) is caused by the expansion of a CGG trinucleotide repeat found in the 5′ untranslated region of the X‐linked FMR1 gene. Although examinations of characteristics associated with repeat instability and expansion of the CGG repeat upon transmission from parent to offspring has occurred in various world populations, none has been conducted in large Sub‐Saharan African populations. We have examined the FMR1 CGG repeat structure in a sample of 350 males drawn from the general population of Ghana. We found that Ghanaians and African Americans have similar allele frequency distributions of CGG repeat and its flanking STR markers, DXS548 and FRAXAC1. However, the distribution of the more complex marker, FRAXAC2, is significantly different. The haplotype structure of the FMR1 locus indicated that Ghanaians share several haplotypes with African Americans and Caucasians that are associated with the expanded full mutation. In Ghanaians, the majority of repeat structures contained two AGG interruptions, however, the majority of intermediate alleles (35–49) lacked AGG interruptions. Overall, we demonstrate that allelic diversity of the FMR1 locus among Ghanaians is comparable to African Americans, but includes a minority of CGG array structures not found in other populations.

Reducing Health Inequities in the U.S.: Recommendations From the NHLBI's Health Inequities Think Tank Meeting

The National, Heart, Lung, and Blood Institute convened a Think Tank meeting to obtain insight and recommendations regarding the objectives and design of the next generation of research aimed at reducing health inequities in the United States. The panel recommended several specific actions, including: 1) embrace broad and inclusive research themes; 2) develop research platforms that optimize the ability to conduct informative and innovative research, and promote systems science approaches; 3) develop networks of collaborators and stakeholders, and launch transformative studies that can serve as benchmarks; 4) optimize the use of new data sources, platforms, and natural experiments; and 5) develop unique transdisciplinary training programs to build research capacity. Confronting health inequities will require engaging multiple disciplines and sectors (including communities), using systems science, and intervening through combinations of individual, family, provider, health system, and community-targeted approaches. Details of the panels remarks and recommendations are provided in this report.

Big Data Science: Opportunities and Challenges to Address Minority Health and Health Disparities in the 21st Century

Addressing minority health and health disparities has been a missing piece of the puzzle in Big Data science. This article focuses on three priority opportunities that Big Data science may offer to the reduction of health and health care disparities. One opportunity is to incorporate standardized information on demographic and social determinants in electronic health records in order to target ways to improve quality of care for the most disadvantaged populations over time. A second opportunity is to enhance public health surveillance by linking geographical variables and social determinants of health for geographically defined populations to clinical data and health outcomes. Third and most importantly, Big Data science may lead to a better understanding of the etiology of health disparities and understanding of minority health in order to guide intervention development. However, the promise of Big Data needs to be considered in light of significant challenges that threaten to widen health disparities. Care must be taken to incorporate diverse populations to realize the potential benefits. Specific recommendations include investing in data collection on small sample populations, building a diverse workforce pipeline for data science, actively seeking to reduce digital divides, developing novel ways to assure digital data privacy for small populations, and promoting widespread data sharing to benefit under-resourced minority-serving institutions and minority researchers. With deliberate efforts, Big Data presents a dramatic opportunity for reducing health disparities but without active engagement, it risks further widening them.

Endothelial dysfunction: a unifying hypothesis for the burden of cardiovascular diseases in sub-Saharan Africa

Abstract It is well established that the leading causes of death and disability worldwide are cardiovascular diseases (CVD), chief among which is ischaemic heart disease. However, it is also recognised that ischaemic heart disease frequently coexists with other vascular conditions, such as cerebrovascular, renovascular and peripheral vascular disease, thus raising the notion of a common underlying pathobiology, albeit with differing manifestations, dictated by the implicated vascular bed. The understanding that common metabolic and behavioural risk factors as well as social determinants and drivers are convergent in the development of CVD evokes the idea that the dysfunction of a common bio-molecular platform is central to the occurrence of these diseases. The state of endothelial activation, otherwise known as endothelial dysfunction, occurs when reactive oxygen signalling predominates due to an uncoupled state of endothelial nitric oxide synthase (eNOS). This can be a physiological response to stimulation of the innate immune system or a pathophysiological response triggered by cardiovascular disease risk factors. The conventional wisdom is that the endothelium plays an important role in the initiation, progression and development of CVD and other non-communicable diseases. Consequently, the endothelium has remarkable relevance in clinical and public health practice as well as in health education, health promotion, and disease- and risk-factor prevention strategies. It also presents a plausible unifying hypothesis for the burden of CVD seen globally and in sub-Saharan Africa. Importantly, the heterogeneity in individual responses to metabolic, behavioural, and social drivers of CVD may stem from a complex interplay of these drivers with genomic, epigenetic and environmental factors that underpin eNOS uncoupling. Therefore, further biomedical research into the underlying genetic and other mechanisms of eNOS uncoupling may enlighten and shape strategies for addressing the burden of CVD in sub-Saharan Africa and other regions of the world.

DNA repair/replication transcripts are down regulated in patients with Fragile X Syndrome

BackgroundFragile X Syndrome (FXS) and its associated disorders are caused by the expansion of the CGG repeat in the 5’ untranslated region of the fragile X mental retardation 1 (FMR1) gene, with disease classification based on the number of CGG repeats. The mechanisms of repeat expansion are dependent on the presence of cis elements and the absence of trans factors both of which are not mutually exclusive and contribute to repeat instability. Expansions associated with trans factors are due to the haploinsuffient or reduced expression of several DNA repair/metabolizing proteins. The reduction of expression in trans factors has been primarily conducted in animal models without substantial examination of many of these expansion mechanisms and trans factors in humans.ResultsTo understand the trans factors and pathways associated with trinucleotide repeat expansion we have analyzed two microarray datasets which characterized the transcript expression in patients with FXS and in controls.ConclusionWe observed significant down regulation of DNA damage/repair pathway transcripts. This observation was consistent in both datasets, which used different populations. Within these datasets, several transcripts overlapped in the direction of association and fold change. Further characterization of these genes will be critical to understand their role in trinucleotide repeat instability in FXS.

A global health strategy to capitalize on proven-effective interventions for heart, lung, and blood diseases.

Global health research has historically been a high priority endeavor at the National Institutes of Health (NIH) and currently represents one of the five priorities of the NIH Director.1 Recognizing that science and disease have no national borders, NIH has encouraged its Institutes, Centers, and Offices to work with the Fogarty International Center to support biomedical research and research training across the globe.2, 3 In this effort, many Institutes including the National Institute of Allergy and Infectious Disease, National Cancer Institute, National Eye Institute and National Institute of Environmental Health Sciences, and others, have established or expanded their global health programs. More recently, the US Council on Foreign Relations (CFR) produced a report calling for a more robust US engagement in global health, especially for non-communicable diseases (NCDs).4, 5 In the report, a task force commissioned by CFR analyzed the case for increased U.S. focus on NCDs by examining countries that received significant U.S. health assistance and found that the premature burden of death and disability in many of these countries was heavily NCD-related.5 The CFR finds two compelling global health interests that justify increasing the US engagement with NCDs. First, NCDs undermine the effectiveness of existing U.S. global health investments. Second, NCDs represent an opportunity for the U.S. government to build on existing U.S. global health platforms that can achieve sustainable reductions in premature death and disability that disproportionately affect the poor.