Multifaceted role of inosine in complex diseases and human health.

Purines are chemical compounds integral to health and are crucial for the synthesis of nucleic acids. They are part of DNA and RNA and participate in various metabolic and signaling processes. They also function as neurotransmitters and serve as co-substrates for activating many metabolites. Inosine, a purine nucleoside, is a breakdown product of adenosine with similar properties and a much longer half-life (15 h vs ∼5 s) than adenosine. The purpose of this narrative review is to discuss the metabolic effects of inosine and highlight its beneficial properties and implication in complex diseases such as obesity, type 2 diabetes, cancers, cardiovascular diseases, and neurodegenerative diseases. A search was performed for purine- and inosine-related articles on the University of North Carolina (UNC) Health Sciences Library, PubMed, and Google Scholar sites. Inosine is involved in the regulation of RNA editing, metabolic enzyme activity, and signaling pathways. Animal and cell culture studies have shown inosine to be anti-inflammatory, immunomodulatory, and neuroprotective, and serving as a critical regulator of immune checkpoint inhibition therapeutic response in various tumor types. Recent studies have also implicated inosine in increasing energy expenditure, browning of adipose tissue, and improving leptin sensitivity. Human studies, however, have been limited to urate-elevating properties of inosine. These findings make inosine relevant to many complex diseases, and need to be translated to humans. Future studies should be conducted to investigate the mechanisms underlying the role of inosine in adiposity, inflammation, oxidative stress, and neuronal function.

Research gaps and opportunities in precision nutrition: an NIH workshop report.

Precision nutrition is an emerging concept that aims to develop nutrition recommendations tailored to different people's circumstances and biological characteristics. Responses to dietary change and the resulting health outcomes from consuming different diets may vary significantly between people based on interactions between their genetic backgrounds, physiology, microbiome, underlying health status, behaviors, social influences, and environmental exposures. On 11-12 January 2021, the National Institutes of Health convened a workshop entitled "Precision Nutrition: Research Gaps and Opportunities" to bring together experts to discuss the issues involved in better understanding and addressing precision nutrition. The workshop proceeded in 3 parts: part I covered many aspects of genetics and physiology that mediate the links between nutrient intake and health conditions such as cardiovascular disease, Alzheimer disease, and cancer; part II reviewed potential contributors to interindividual variability in dietary exposures and responses such as baseline nutritional status, circadian rhythm/sleep, environmental exposures, sensory properties of food, stress, inflammation, and the social determinants of health; part III presented the need for systems approaches, with new methods and technologies that can facilitate the study and implementation of precision nutrition, and workforce development needed to create a new generation of researchers. The workshop concluded that much research will be needed before more precise nutrition recommendations can be achieved. This includes better understanding and accounting for variables such as age, sex, ethnicity, medical history, genetics, and social and environmental factors. The advent of new methods and technologies and the availability of considerably more data bring tremendous opportunity. However, the field must proceed with appropriate levels of caution and make sure the factors listed above are all considered, and systems approaches and methods are incorporated. It will be important to develop and train an expanded workforce with the goal of reducing health disparities and improving precision nutritional advice for all Americans.

Purine metabolites and complex diseases: role of genes and nutrients.

PURPOSE OF REVIEW: Purines have several important physiological functions as part of nucleic acids and as intracellular and extracellular signaling molecules. Purine metabolites, particularly uric acid, have been implicated in congenital and complex diseases. However, their role in complex diseases is not clear and they have both beneficial and detrimental effects on disease pathogenesis. In addition, the relationship between purines and complex diseases is affected by genetic and nutritional factors. This review presents latest findings about the relationship between purines and complex diseases and the effect of genes and nutrients on this relationship. RECENT FINDINGS: Evidence from recent studies show strong role of purines in complex diseases. Although they are causal in only few diseases, our knowledge about their role in other diseases is still evolving. Of all the purines, uric acid is the most studied. Uric acid acts as an antioxidant as well as a prooxidant under different conditions, thus, its role in disease also varies. Other purines, adenosine and inosine have been less studied, but they have neuroprotective properties which are valuable in neurodegenerative diseases. SUMMARY: Purines are molecules with great potential in disease pathogenesis as either metabolic markers or therapeutic targets. More studies need to be conducted to understand their relevance for complex diseases.

Genome-wide association study identifying novel variant for fasting insulin and allelic heterogeneity in known glycemic loci in Chilean adolescents: The Santiago Longitudinal Study.

BACKGROUND: The genetic underpinnings of glycemic traits have been understudied in adolescent and Hispanic/Latino (H/L) populations in comparison to adults and populations of European ancestry. OBJECTIVE: To identify genetic factors underlying glycemic traits in an adolescent H/L population. METHODS: We conducted a genome-wide association study (GWAS) of fasting glucose (FG) and fasting insulin (FI) in H/L adolescents from the Santiago Longitudinal Study. RESULTS: We identified one novel variant positioned in the CSMD1 gene on chromosome 8 (rs77465890, effect allele frequency = 0.10) that was associated with FI (ß = -0.299, SE = 0.054, p = 2.72×10-8 ) and was only slightly attenuated after adjusting for body mass index z-scores (ß = -0.252, SE = 0.047, p = 1.03×10-7 ). We demonstrated directionally consistent, but not statistically significant results in African and Hispanic adults of the Population Architecture Using Genomics and Epidemiology Consortium. We also identified secondary signals for two FG loci after conditioning on known variants, which demonstrate allelic heterogeneity in well-known glucose loci. CONCLUSION: Our results exemplify the importance of including populations with diverse ancestral origin and adolescent participants in GWAS of glycemic traits to uncover novel risk loci and expand our understanding of disease aetiology.

Healthy dietary patterns and risk and survival of breast cancer: a meta-analysis of cohort studies.

PURPOSES: Dietary patterns have been found to be associated with the overall cancer risk and survival. However, the associations of healthy dietary patterns and breast cancer remain unclear. We aimed to conduct a meta-analysis of prospective cohort studies to estimate the pooled results of the association of healthy dietary patterns with breast cancer risk and survival. METHODS: PubMed, EMBASE, and Web of Science were searched for literature published until June 24th, 2018 that examined the associations between healthy dietary patterns and breast cancer risk and survival. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated by using a random-effects model for meta-analysis. RESULTS: There were 32 articles retrieved for the meta-analysis, with 27 for breast cancer risk and five for breast cancer survival. There was a statistically significant lower risk of breast cancer associated with healthy dietary patterns (RR = 0.93, 95% CI: 0.88, 0.98). Subgroup analysis results suggested that there was an inverse association between breast cancer risk and posterori-derived healthy patterns, but no statistically significant associations were found in other stratified subgroups (a priori-derived diet, study region, menopausal status, or breast cancer subtypes). Healthy dietary patterns were associated inversely with all-cause mortality (RR = 0.76, 95% CI: 0.63, 0.92); however, no association was found for breast cancer-specific mortality. CONCLUSIONS: The results suggested that healthy dietary patterns might be associated with a reduced risk of breast cancer and all-cause mortality among breast cancer patients. It could be clinically relevant to promote healthy dietary patterns for breast cancer prevention and improve survival among breast cancer patients.

The Latino Eyelid: Anthropometric Analysis of a Spectrum of Findings.

PURPOSE: Published anthropometric measurements of the Latino eyelid are limited. This study describes features spanning the morphologic range from non-Latino whites to East Asians in the spectrum of the Latino eyelid. METHODS: A cross-sectional study of 68 people (32 Latinos, 18 non-Latino whites, and 18 East Asians, ages 18-39), approved by the Institutional Review Board and HIPAA-compliant, was performed. Saliva samples determined genetic components. Indirect anthropometric measurements were performed with ImageJ software. Eyelid measurements included margin reflex distance, palpebral fissure height, eyelid crease height, orbital height, horizontal fissure length, inner and outer canthal distances, medial and lateral canthal angles, and lateral canthal angle of inclination. Additionally, exophthalmometry and epicanthal folds were recorded. RESULTS: Analysis of 184 markers from HumanExome Chip data revealed distinct clustering patterns. Genetically, the Asian participants were in 1 group, the whites in another group, and the Latinos spanned the spectrum between these 2 groups. In Latinos, the inner canthal distance and lateral canthal angle of inclination were similar to Asians, whereas the eyelid crease spanned the range from Asians to whites. Half of the Latinos had epicanthal folds. CONCLUSIONS: Latinos possess a spectrum of eyelid features spanning the morphologic characteristics from those of non-Latino whites to those of East Asians. These normative data on Latinos from Texas and Mexico aid in the diagnoses of Latino eyelid disorders and are a reference for optimizing oculofacial surgery outcomes.

SLCO1B1 variants and urine arsenic metabolites in the Strong Heart Family Study.

Arsenic species patterns in urine are associated with risk for cancer and cardiovascular diseases. The organic anion transporter coded by the gene SLCO1B1 may transport arsenic species, but its association with arsenic metabolites in human urine has not yet been studied. The objective of this study is to evaluate associations of urine arsenic metabolites with variants in the candidate gene SLCO1B1 in adults from the Strong Heart Family Study. We estimated associations between % arsenic species biomarker traits and 5 single-nucleotide polymorphisms (SNPs) in the SLCO1B1 gene in 157 participants, assuming additive genetics. Linear regression models for each SNP accounted for kinships and were adjusted for sex, body mass index, and study center. The minor allele of rs1564370 was associated with lower %MMA (p = .0003) and higher %DMA (p = .0002), accounting for 8% of the variance for %MMA and 9% for %DMA. The rs1564370 minor allele homozygote frequency was 17% and the heterozygote frequency was 43%. The minor allele of rs2291075 was associated with lower %MMA (p = .0006) and higher %DMA (p = .0014), accounting for 7% of the variance for %MMA and 5% for %DMA. The frequency of rs2291075 minor allele homozygotes was 1% and of heterozygotes was 15%. Common variants in SLCO1B1 were associated with differences in arsenic metabolites in a preliminary candidate gene study. Replication of this finding in other populations and analyses with respect to disease outcomes are needed to determine whether this novel candidate gene is important for arsenic-associated disease risks.