Genome-Wide Association Study Identifies Chromosome 10q24.32 Variants Associated with Arsenic Metabolism and Toxicity Phenotypes in Bangladesh

Arsenic contamination of drinking water is a major public health issue in many countries, increasing risk for a wide array of diseases, including cancer. There is inter-individual variation in arsenic metabolism efficiency and susceptibility to arsenic toxicity; however, the basis of this variation is not well understood. Here, we have performed the first genome-wide association study (GWAS) of arsenic-related metabolism and toxicity phenotypes to improve our understanding of the mechanisms by which arsenic affects health. Using data on urinary arsenic metabolite concentrations and approximately 300,000 genome-wide single nucleotide polymorphisms (SNPs) for 1,313 arsenic-exposed Bangladeshi individuals, we identified genome-wide significant association signals (P<5×10−8) for percentages of both monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) near the AS3MT gene (arsenite methyltransferase; 10q24.32), with five genetic variants showing independent associations. In a follow-up analysis of 1,085 individuals with arsenic-induced premalignant skin lesions (the classical sign of arsenic toxicity) and 1,794 controls, we show that one of these five variants (rs9527) is also associated with skin lesion risk (P = 0.0005). Using a subset of individuals with prospectively measured arsenic (n = 769), we show that rs9527 interacts with arsenic to influence incident skin lesion risk (P = 0.01). Expression quantitative trait locus (eQTL) analyses of genome-wide expression data from 950 individual's lymphocyte RNA suggest that several of our lead SNPs represent cis-eQTLs for AS3MT (P = 10−12) and neighboring gene C10orf32 (P = 10−44), which are involved in C10orf32-AS3MT read-through transcription. This is the largest and most comprehensive genomic investigation of arsenic metabolism and toxicity to date, the only GWAS of any arsenic-related trait, and the first study to implicate 10q24.32 variants in both arsenic metabolism and arsenical skin lesion risk. The observed patterns of associations suggest that MMA% and DMA% have distinct genetic determinants and support the hypothesis that DMA is the less toxic of these two methylated arsenic species. These results have potential translational implications for the prevention and treatment of arsenic-associated toxicities worldwide

The Lancet Global Health Commission on Global Eye Health: vision beyond 2020

Eye health and vision have widespread and profound implications for many aspects of life, health, sustainable development, and the economy. Yet nowadays, many people, families, and populations continue to suffer the consequences of poor access to high-quality, affordable eye care, leading to vision impairment and blindness. In 2020, an estimated 596 million people had distance vision impairment worldwide, of whom 43 million were blind. Another 510 million people had uncorrected near vision impairment, simply because of not having reading spectacles. A large proportion of those affected (90%), live in low-income and middle-income countries (LMICs). However, encouragingly, more than 90% of people with vision impairment have a preventable or treatable cause with existing highly cost-effective interventions. Eye conditions affect all stages of life, with young children and older people being particularly affected. Crucially, women, rural populations, and ethnic minority groups are more likely to have vision impairment, and this pervasive inequality needs to be addressed. By 2050, population ageing, growth, and urbanisation might lead to an estimated 895 million people with distance vision impairment, of whom 61 million will be blind. Action to prioritise eye health is needed now. This Commission defines eye health as maximised vision, ocular health, and functional ability, thereby contributing to overall health and wellbeing, social inclusion, and quality of life. Eye health is essential to achieve many of the Sustainable Development Goals (SDGs). Poor eye health and impaired vision have a negative effect on quality of life and restrict equitable access to and achievement in education and the workplace. Vision loss has substantial financial implications for affected individuals, families, and communities. Although high-quality data for global economic estimates are scarce, particularly for LMICs, conservative assessments based on the latest prevalence figures for 2020 suggest that annual global productivity loss from vision impairment is approximately US$410·7 billion purchasing power parity. Vision impairment reduces mobility, affects mental wellbeing, exacerbates risk of dementia, increases likelihood of falls and road traffic crashes, increases the need for social care, and ultimately leads to higher mortality rates. By contrast, vision facilitates many daily life activities, enables better educational outcomes, and increases work productivity, reducing inequality. An increasing amount of evidence shows the potential for vision to advance the SDGs, by contributing towards poverty reduction, zero hunger, good health and wellbeing, quality education, gender equality, and decent work. Eye health is a global public priority, transforming lives in both poor and wealthy communities. Therefore, eye health needs to be reframed as a development as well as a health issue and given greater prominence within the global development and health agendas. Vision loss has many causes that require promotional, preventive, treatment, and rehabilitative interventions. Cataract, uncorrected refractive error, glaucoma, age-related macular degeneration, and diabetic retinopathy are responsible for most global vision impairment. Research has identified treatments to reduce or eliminate blindness from all these conditions; the priority is to deliver treatments where they are most needed. Proven eye care interventions, such as cataract surgery and spectacle provision, are among the most cost-effective in all of health care. Greater financial investment is needed so that millions of people living with unnecessary vision impairment and blindness can benefit from these interventions. Lessons from the past three decades give hope that this challenge can be met. Between 1990 and 2020, the age-standardised global prevalence of blindness fell by 28·5%. Since the 1990s, prevalence of major infectious causes of blindness—onchocerciasis and trachoma—have declined substantially. Hope remains that by 2030, the transmission of onchocerciasis will be interrupted, and trachoma will be eliminated as a public health problem in every country worldwide. However, the ageing population has led to a higher crude prevalence of age-related causes of blindness, and thus an increased total number of people with blindness in some regions. Despite this progress, business as usual will not keep pace with the demographic trends of an ageing global population or address the inequities that persist in each country. New threats to eye health are emerging, including the worldwide increase in diabetic retinopathy, high myopia, retinopathy of prematurity, and chronic eye diseases of ageing such as glaucoma and age-related macular degeneration. With the projected increase in such conditions and their associated vision loss over the coming decades, urgent action is needed to develop innovative treatments and deliver services at a greater scale than previously achieved. Good eye health at the community and national level has been marginalised as a luxury available to only wealthy or urban areas. Eye health needs to be urgently brought into the mainstream of national health and development policy, planning, financing, and action. The challenge is to develop and deliver comprehensive eye health services (promotion, prevention, treatment, rehabilitation) that address the full range of eye conditions within the context of universal health coverage. Accessing services should not bring the risk of falling into poverty and services should be of high quality, as envisaged by the WHO framework for health-care quality: effective, safe, people-centred, timely, equitable, integrated, and efficient. To this framework we add the need for services to be environmentally sustainable. Universal health coverage is not universal without eye care. Multiple obstacles need to be overcome to achieve universal coverage for eye health. Important issues include complex barriers to availability and access to quality services, cost, major shortages and maldistribution of well-trained personnel, and lack of suitable, well maintained equipment and consumables. These issues are particularly widespread in LMICs, but also occur in underserved communities in high-income countries. Strong partnerships need to be formed with natural allies working in areas affected by eye health, such as non-communicable diseases, neglected tropical diseases, healthy ageing, children's services, education, disability, and rehabilitation. The eye health sector has traditionally focused on treatment and rehabilitation, and underused health promotion and prevention strategies to lessen the impact of eye disease and reduce inequality. Solving these problems will depend on solutions established from high quality evidence that can guide more effective implementation at scale. Evidence-based approaches will need to address existing deficiencies in the supply and demand. Strategic investments in discovery research, harnessing new findings from diverse fields, and implementation research to guide effective scale up are needed globally. Encouragingly, developments in telemedicine, mobile health, artificial intelligence, and distance learning could potentially enable eye care professionals to deliver higher quality care that is more plentiful, equitable, and cost-effective. This Commission did a Grand Challenges in Global Eye Health prioritisation exercise to highlight key areas for concerted research and action. This exercise has identified a broad set of challenges spanning the fields of epidemiology, health systems, diagnostics, therapeutics, and implementation. The most compelling of these issues, picked from among 3400 suggestions proposed by 336 people from 118 countries, can help to frame the future research agenda for global eye health. In this Commission, we harness lessons learned from over two decades, present the growing evidence for the life-transforming impact of eye care, and provide a thorough understanding of rapid developments in the field. This report was created through a broad consultation involving experts within and outside the eye care sector to help inform governments and other stakeholders about the path forward for eye health beyond 2020, to further the SDGs (including universal health coverage), and work towards a world without avoidable vision loss. The next few years are a crucial time for the global eye health community and its partners in health care, government, and other sectors to consider the successes and challenges encountered in the past two decades, and at the same time to chart a way forward for the upcoming decades. Moving forward requires building on the strong foundation laid by WHO and partners in VISION 2020 with renewed impetus to ultimately deliver high quality universal eye health care for all

An insight into the transcriptome of the digestive tract of the bloodsucking bug, Rhodnius prolixus.

The bloodsucking hemipteran Rhodnius prolixus is a vector of Chagas' disease, which affects 7-8 million people today in Latin America. In contrast to other hematophagous insects, the triatomine gut is compartmentalized into three segments that perform different functions during blood digestion. Here we report analysis of transcriptomes for each of the segments using pyrosequencing technology. Comparison of transcript frequency in digestive libraries with a whole-body library was used to evaluate expression levels. All classes of digestive enzymes were highly expressed, with a predominance of cysteine and aspartic proteinases, the latter showing a significant expansion through gene duplication. Although no protein digestion is known to occur in the anterior midgut (AM), protease transcripts were found, suggesting secretion as pro-enzymes, being possibly activated in the posterior midgut (PM). As expected, genes related to cytoskeleton, protein synthesis apparatus, protein traffic, and secretion were abundantly transcribed. Despite the absence of a chitinous peritrophic membrane in hemipterans - which have instead a lipidic perimicrovillar membrane lining over midgut epithelia - several gut-specific peritrophin transcripts were found, suggesting that these proteins perform functions other than being a structural component of the peritrophic membrane. Among immunity-related transcripts, while lysozymes and lectins were the most highly expressed, several genes belonging to the Toll pathway - found at low levels in the gut of most insects - were identified, contrasting with a low abundance of transcripts from IMD and STAT pathways. Analysis of transcripts related to lipid metabolism indicates that lipids play multiple roles, being a major energy source, a substrate for perimicrovillar membrane formation, and a source for hydrocarbons possibly to produce the wax layer of the hindgut. Transcripts related to amino acid metabolism showed an unanticipated priority for degradation of tyrosine, phenylalanine, and tryptophan. Analysis of transcripts related to signaling pathways suggested a role for MAP kinases, GTPases, and LKBP1/AMP kinases related to control of cell shape and polarity, possibly in connection with regulation of cell survival, response of pathogens and nutrients. Together, our findings present a new view of the triatomine digestive apparatus and will help us understand trypanosome interaction and allow insights into hemipteran metabolic adaptations to a blood-based diet.Journal ArticleResearch Support, N.I.H. IntramuralResearch Support, Non-U.S. Gov'tSCOPUS: ar.jSCOPUS: ar.jinfo:eu-repo/semantics/publishe