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.

Polymorphisms in the choline transporter SLC44A1 are associated with reduced cognitive performance in normotypic but not prenatal alcohol-exposed children.

BACKGROUND: Choline is essential for healthy cognitive development. Single nucleotide polymorphisms (SNPs; rs3199966(G), rs2771040(G)) within the choline transporter SLC44A1 increase risk for choline deficiency. In a choline intervention trial of children who experienced prenatal alcohol exposure (PAE), these alleles are associated with improved cognition. OBJECTIVE: This study aimed to determine if SNPs within SLC44A1 are differentially associated with cognition in children with PAE compared with normotypic controls (genotype × exposure). A secondary objective tested for an association of these SNPs and cognition in controls (genotype-only). DESIGN: This is a secondary analysis of data from the Collaborative Initiative on Fetal Alcohol Spectrum Disorders. Participants (163 normotypic controls, 162 PAE) underwent psychological assessments and were genotyped within SLC44A1. Choline status was not assessed. Association analysis between genotype × exposure was performed using an additive genetic model and linear regression to identify the allelic effect. The primary outcome was the interaction between SLC44A1 genotype × exposure status with respect to cognition. The secondary outcome was the cognitive-genotype association in normotypic controls. RESULTS: Genotype × exposure analysis identified 7 SNPs in SLC44A1, including rs3199966(G) and rs2771040(G), and in strong linkage (D' ≥ 0.87), that were associated (adjusted P ≤ 0.05) with reduced performance in measures of general cognition, nonverbal and quantitative reasoning, memory, and executive function (ß, 1.92-3.91). In controls, carriers of rs3199966(GT or GG) had worsened cognitive performance than rs3199966(TT) carriers (ß, 0.46-0.83; P < 0.0001), whereas cognitive performance did not differ by rs3199966 genotype in those with PAE. CONCLUSIONS: Two functional alleles that increase vulnerability to choline deficiency, rs3199966(G) (Ser644Ala) and rs2771040(G) (3' untranslated region), are associated with worsened cognition in otherwise normotypic children. These alleles were previously associated with greater cognitive improvement in children with PAE who received supplemental choline. The findings endorse that choline benefits cognitive development in normotypic children and those with PAE.

Novel Insights into the Effects of Genetic Variants on Serum Urate Response to an Acute Fructose Challenge: A Pilot Study.

Studies have shown that genetic variations can influence metabolic response to nutrient intake, and that diets rich in fructose contribute to hyperuricemia. In this pilot study, our aim was to determine the variability of serum urate in response to an acute fructose challenge and to investigate if genetic variants would affect this response in young to middle-aged adults who self-reported as Black or White. Fifty-seven participants consumed a fructose-rich beverage after an overnight fast. Blood was drawn at five time points (baseline, 30, 60, 120, and 180 min after consumption). Thirty urate-related single nucleotide polymorphisms (SNPs) were analyzed for their associations with baseline serum urate and its percent changes, using a two-step modeling approach followed by meta-analysis. At baseline, serum urate (mg/dL, mean ± SD) was higher in Whites (5.60 ± 1.01 vs. 5.37 ± 0.96), men (6.17 ± 1.14 vs. 5.24 ± 0.79), and those with obesity (5.69 ± 1.08 vs. 5.42 ± 1.06 vs. 5.34 ± 0.80). Three SNPs were significantly associated with baseline serum urate or its percent changes, and six SNPs were nominally associated with percent changes in serum urate. In summary, our results showed that genetic variants could play a role in short-term urate metabolism.

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.

PUFA, genotypes and risk for cardiovascular disease.

Polyunsaturated fatty acids (PUFAs) are long chain fatty acids that are characterized by the presence of more than one double bond. These include fatty acids such as ꞷ-3-α-linolenic acid (ALA) and ꞷ-6 -linoleic acid (LA) which can only be obtained from dietary sources and are therefore termed essential fatty acids. They contain the building blocks for dihomo-γ-linolenic acid and arachidonic acid in the ꞷ-6 family as well as eicosapentaenoic acid and docosahexaenoic acid in the ꞷ-3 family. Both ALA and LA are important constituents of animal and plant cell membranes and are important components of anti-inflammatory and pro-inflammatory hormones and therefore, often modulate cellular immunity under chronic inflammatory states. The variation in physiological PUFA levels is under significant genetic influence, the fatty acid desaturase (FADS) genes being key regulators of PUFA metabolism. These genetic variants have been shown to alter fatty acid metabolism and influence the onset and progression of various metabolic conditions. This detailed review discusses the role of PUFAs, diet and genotypes in risk for cardiovascular diseases.

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.

Genetic variants and physical activity interact to affect bone density in Hispanic children.

BACKGROUND: Our aim was to investigate if moderate to vigorous physical activity (MVPA), calcium intake interacts with bone mineral density (BMD)-related single nucleotide polymorphisms (SNPs) to influence BMD in 750 Hispanic children (4-19y) of the cross-sectional Viva La Familia Study. METHODS: Physical activity and dietary intake were measured by accelerometers and multiple-pass 24 h dietary recalls, respectively. Total body and lumbar spine BMD were measured by dual energy X-ray absorptiometry. A polygenic risk score (PRS) was computed based on SNPs identified in published literature. Regression analysis was conducted with PRSs, MVPA and calcium intake with total body and lumbar spine BMD. RESULTS: We found evidence of statistically significant interaction effects between the PRS and MVPA on total body BMD and lumbar spine BMD (p < 0.05). Higher PRS was associated with a lower total body BMD (ß = - 0.040 ± 0.009, p = 1.1 × 10- 5) and lumbar spine BMD (ß = - 0.042 ± 0.013, p = 0.0016) in low MVPA group, as compared to high MVPA group (ß = - 0.015 ± 0.006, p = 0.02; ß = 0.008 ± 0.01, p = 0.4, respectively). DISCUSSION: The study indicated that calcium intake does not modify the relationship between genetic variants and BMD, while it implied physical activity interacts with genetic variants to affect BMD in Hispanic children. Due to limited sample size of our study, future research on gene by environment interaction on bone health and functional studies to provide biological insights are needed. CONCLUSIONS: Bone health in Hispanic children with high genetic risk for low BMD is benefitted more by MVPA than children with low genetic risk. Our results may be useful to predict disease risk and tailor dietary and physical activity advice delivery to people, especially children.

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.

Sociodemographic predictors of early postnatal growth: evidence from a Chilean infancy cohort.

OBJECTIVES: Infant anthropometric growth varies across socioeconomic factors, including maternal education and income, and may serve as an indicator of environmental influences in early life with long-term health consequences. Previous research has identified sociodemographic gradients in growth with a focus on the first year and beyond, but estimates are sparse for growth before 6 months. Thus, our objective was to examine the relationship between sociodemographic factors and infant growth patterns between birth and 5 months of age. DESIGN: Prospective cohort study. SETTINGS: Low-income to middle-income neighbourhoods in Santiago, Chile (1991-1996). PARTICIPANTS: 1412 participants from a randomised iron-deficiency anaemia preventive trial in healthy infants. MAIN OUTCOME MEASURES: Longitudinal anthropometrics including monthly weight (kg), length (cm) and weight-for-length (WFL) values. For each measure, we estimated three individual-level growth parameters (size, timing and velocity) from SuperImposition by Translation and Rotation models. Size and timing changes represent vertical and horizontal growth curve shifts, respectively, and velocity change represents growth rate shifts. We estimated the linear association between growth parameters and gestational age, maternal age, education and socioeconomic position (SEP). RESULTS: Lower SEP was associated with a slower linear (length) velocity growth parameter (-0.22, 95% CI -0.31 to -0.13)-outcome units are per cent change in velocity from the average growth curve. Lower SEP was associated with later WFL growth timing as demonstrated through the tempo growth parameter for females (0.25, 95% CI 0.05 to 0.42)-outcome units are shifts in days from the average growth curve. We found no evidence of associations between SEP and the weight size, timing or velocity growth rate parameters. CONCLUSION: Previous research on growth in older infants and children shows associations between lower SEP with slower length velocity. We found evidence supporting this association in the first 5 months of life, which may inform age-specific prevention efforts aimed at infant length growth.

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.

GWAS and transcriptional analysis prioritize ITPR1 and CNTN4 for a serum uric acid 3p26 QTL in Mexican Americans.

BACKGROUND: The variation in serum uric acid concentrations is under significant genetic influence. Elevated SUA concentrations have been linked to increased risk for gout, kidney stones, chronic kidney disease, and cardiovascular disease whereas reduced serum uric acid concentrations have been linked to multiple sclerosis, Parkinson's disease and Alzheimer's disease. Previously, we identified a novel locus on chromosome 3p26 affecting serum uric acid concentrations in Mexican Americans from San Antonio Family Heart Study. As a follow up, we examined genome-wide single nucleotide polymorphism data in an extended cohort of 1281 Mexican Americans from multigenerational families of the San Antonio Family Heart Study and the San Antonio Family Diabetes/Gallbladder Study. We used a linear regression-based joint linkage/association test under an additive model of allelic effect, while accounting for non-independence among family members via a kinship variance component. RESULTS: Univariate genetic analysis indicated serum uric acid concentrations to be significant heritable (h (2) = 0.50 ± 0.05, p < 4 × 10(-35)), and linkage analysis of serum uric acid concentrations confirmed our previous finding of a novel locus on 3p26 (LOD = 4.9, p < 1 × 10(-5)) in the extended sample. Additionally, we observed strong association of serum uric acid concentrations with variants in following candidate genes in the 3p26 region; inositol 1,4,5-trisphosphate receptor, type 1 (ITPR1), contactin 4 (CNTN4), decapping mRNA 1A (DCP1A); transglutaminase 4 (TGM4) and rho guanine nucleotide exchange factor (GEF) 26 (ARHGEF26) [p < 3 × 10(-7); minor allele frequencies ranged between 0.003 and 0.42] and evidence of cis-regulation for ITPR1 transcripts. CONCLUSION: Our results confirm the importance of the chromosome 3p26 locus and genetic variants in this region in the regulation of serum uric acid concentrations.

Successful pharmaceutical-grade streptozotocin (STZ)-induced hyperglycemia in a conscious tethered baboon (Papio hamadryas) model.

BACKGROUND: Non-human primate (NHP) diabetic models using chemical ablation of ß-cells with STZ have been achieved by several research groups. Chemotherapeutic STZ could lead to serious adverse events including nephrotoxicity, hepatotoxicity, and mortality. METHODS: We implemented a comprehensive therapeutic strategy that included the tether system, permanent indwelling catheter implants, an aggressive hydration protocol, management for pain with IV nubain and anxiety with IV midazolam, moment-by-moment monitoring of glucose levels post-STZ administration, and continuous intravenous insulin therapy. RESULTS: A triphasic response in blood glucose after STZ administration was fully characterized. A dangerous hypoglycemic phase was also detected in all baboons. Other significant findings were hyperglycemia associated with low levels of plasma leptin, insulin and C-peptide concentrations, hyperglucagonemia, and elevated non-esterified fatty acids (NEFA) concentrations. CONCLUSIONS: We successfully induced frank diabetes by IV administering a single dose of pharmaceutical-grade STZ safely and without adverse events in conscious tethered baboons.

Linkage Analysis of Urine Arsenic Species Patterns in the Strong Heart Family Study.

Arsenic toxicokinetics are important for disease risks in exposed populations, but genetic determinants are not fully understood. We examined urine arsenic species patterns measured by HPLC-ICPMS among 2189 Strong Heart Study participants 18 years of age and older with data on ~400 genome-wide microsatellite markers spaced ~10 cM and arsenic speciation (683 participants from Arizona, 684 from Oklahoma, and 822 from North and South Dakota). We logit-transformed % arsenic species (% inorganic arsenic, %MMA, and %DMA) and also conducted principal component analyses of the logit % arsenic species. We used inverse-normalized residuals from multivariable-adjusted polygenic heritability analysis for multipoint variance components linkage analysis. We also examined the contribution of polymorphisms in the arsenic metabolism gene AS3MT via conditional linkage analysis. We localized a quantitative trait locus (QTL) on chromosome 10 (LOD 4.12 for %MMA, 4.65 for %DMA, and 4.84 for the first principal component of logit % arsenic species). This peak was partially but not fully explained by measured AS3MT variants. We also localized a QTL for the second principal component of logit % arsenic species on chromosome 5 (LOD 4.21) that was not evident from considering % arsenic species individually. Some other loci were suggestive or significant for 1 geographical area but not overall across all areas, indicating possible locus heterogeneity. This genome-wide linkage scan suggests genetic determinants of arsenic toxicokinetics to be identified by future fine-mapping, and illustrates the utility of principal component analysis as a novel approach that considers % arsenic species jointly.

Utility of large consanguineous family-based model for investigating the genetics of type 2 diabetes mellitus.

OBJECTIVES: This study examined the utility of a family-based model for replicating the results of genome-wide association studies (GWAS) of type 2 diabetes (T2D). METHODS AND RESULTS: In a total of 232 members of a large consanguineous Omani Arab pedigree (age: 16-80years), there were 27 diabetics and 50 prediabetics (17 with impaired fasting glucose and 33 with impaired glucose tolerance). All 232 individuals underwent anthropometric and biochemical investigations and genotyped for 14 known common gene variants of modest effect on T2D risk. Power analysis at a LOD score of 3, gave 80% power to locate a single specific locus that accounts for 52% of the total phenotypic variation. Measured genotype analysis (MGA) was used to determine heritability of various quantitative traits (QTs) which ranged 25-56%. Using MGA, some common gene variants were found to have little (<5%) but significant impact on the heritability of T2D related QTs [KCNJ11 (rs5219), p=0.004]; [IGF2BP2 (rs4402960), p=0.02]; [SLC30A8 (rs13266634), p=0.05]; [CAPN10 (rs2975760), p=0.031]; [FTO (rs8050136), p=0.023]; [FTO (rs9939609), p=0.018] and [SLC30A8 (rs13266634), p=0.05]. Sib-TDT analysis showed that some gene variants were significantly associated with T2D risk but didn't reach the level of significance after Bonferroni correction [KCNJ11 (rs5219), p=0.047] and [CAPN10 (rs41266971), p=0.035]. CONCLUSION: We have demonstrated that, in principle, a family-based model with minor limitations could be used to replicate some of the results of large GWAS case-control studies. This model could successfully be applied for the future discovery, by deep sequencing, of rare gene variants.

Genetic variants associated with fasting glucose and insulin concentrations in an ethnically diverse population: results from the Population Architecture using Genomics and Epidemiology (PAGE) study.

BACKGROUND: Multiple genome-wide association studies (GWAS) within European populations have implicated common genetic variants associated with insulin and glucose concentrations. In contrast, few studies have been conducted within minority groups, which carry the highest burden of impaired glucose homeostasis and type 2 diabetes in the U.S. METHODS: As part of the 'Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we investigated the association of up to 10 GWAS-identified single nucleotide polymorphisms (SNPs) in 8 genetic regions with glucose or insulin concentrations in up to 36,579 non-diabetic subjects including 23,323 European Americans (EA) and 7,526 African Americans (AA), 3,140 Hispanics, 1,779 American Indians (AI), and 811 Asians. We estimated the association between each SNP and fasting glucose or log-transformed fasting insulin, followed by meta-analysis to combine results across PAGE sites. RESULTS: Overall, our results show that 9/9 GWAS SNPs are associated with glucose in EA (p = 0.04 to 9 × 10-15), versus 3/9 in AA (p= 0.03 to 6 × 10-5), 3/4 SNPs in Hispanics, 2/4 SNPs in AI, and 1/2 SNPs in Asians. For insulin we observed a significant association with rs780094/GCKR in EA, Hispanics and AI only. CONCLUSIONS: Generalization of results across multiple racial/ethnic groups helps confirm the relevance of some of these loci for glucose and insulin metabolism. Lack of association in non-EA groups may be due to insufficient power, or to unique patterns of linkage disequilibrium.

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.

Genome-wide association analysis confirms and extends the association of SLC2A9 with serum uric acid levels to Mexican Americans.

Increased serum uric acid (SUA) is a risk factor for gout and renal and cardiovascular disease (CVD). The purpose of this study was to identify genetic factors that affect the variation in SUA in 632 Mexican Americans participants of the San Antonio Family Heart Study (SAFHS). A genome-wide association (GWA) analysis was performed using the Illumina Human Hap 550K single nucleotide polymorphism (SNP) microarray. We used a linear regression-based association test under an additive model of allelic effect, while accounting for non-independence among family members via a kinship variance component. All analyses were performed in the software package SOLAR. SNPs rs6832439, rs13131257, and rs737267 in solute carrier protein 2 family, member 9 (SLC2A9) were associated with SUA at genome-wide significance (p < 1.3 × 10(-7)). The minor alleles of these SNPs had frequencies of 36.2, 36.2, and 38.2%, respectively, and were associated with decreasing SUA levels. All of these SNPs were located in introns 3-7 of SLC2A9, the location of the previously reported associations in European populations. When analyzed for association with cardiovascular-renal disease risk factors, conditional on SLC2A9 SNPs strongly associated with SUA, significant associations were found for SLC2A9 SNPs with BMI, body weight, and waist circumference (p < 1.4 × 10(-3)) and suggestive associations with albumin-creatinine ratio and total antioxidant status (TAS). The SLC2A9 gene encodes an urate transporter that has considerable influence on variation in SUA. In addition to the primary association locus, suggestive evidence (p < 1.9 × 10(-6)) for joint linkage/association (JLA) was found at a previously-reported urate quantitative trait locus (Logarithm of odds score = 3.6) on 3p26.3. In summary, our GWAS extends and confirms the association of SLC2A9 with SUA for the first time in a Mexican American cohort and also shows for the first time its association with cardiovascular-renal disease risk factors.

Short-term weight loss in overweight/obese low-income women improves plasma zinc and metabolic syndrome risk factors.

Metabolic syndrome is a group of disorders involving obesity, insulin resistance, dyslipidemia and hypertension. Obesity is the most crucial risk factor of metabolic syndrome, because it is known to precede other risk factors. Obesity is also associated with disturbances in the metabolism of the trace mineral, zinc. The overall purpose of this study was to investigate the effects of short-term weight loss on plasma zinc and metabolic syndrome risk factors. An 8-week weight loss intervention study was conducted with 90 low-income overweight/obese mothers, whose youngest child was 1-3 years old. Plasma levels of zinc, glucose, insulin, leptin, triglycerides, total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol were measured and compared at weeks 0 and 8 of the weight loss program. At pre-study, plasma zinc was low in 39% and, within normal values in 46%, of obese/overweight mothers. By the end of intervention, plasma zinc rose by 22% and only 5% of the mothers continued to exhibit low plasma zinc. At post-study, the metabolic syndrome risk factors of waist circumference, HDL cholesterol, and diastolic blood pressure (p<0.05) showed significant improvements. Plasma zinc increased by a greater margin (67%) in women with low zinc, as compared to those with normal zinc (18%); weight reduction was similar in both the groups. Finally, changes in % body fat were related negatively with changes in plasma zinc (r=- 0.28, p<0.05). The circulating levels of zinc, as well as the metabolic syndrome components, showed significant improvements in overweight/obese low-income women after weight loss.

Bivariate genetic association of KIAA1797 with heart rate in American Indians: the Strong Heart Family Study.

Heart rate (HR) has been identified as a risk factor for cardiovascular disease (CVD), yet little is known regarding genetic factors influencing this phenotype. Previous research in American Indians (AIs) from the Strong Heart Family Study (SHFS) identified a significant quantitative trait locus (QTL) for HR on chromosome 9p21. Genetic association on HR was conducted in the SHFS. HR was measured from electrocardiogram (ECG) and echocardiograph (Echo) Doppler recordings. We examined 2248 single-nucleotide polymorphisms (SNPs) on chromosome 9p21 for association using a gene-centric statistical test. We replicated the aforementioned QTL [logarithm of odds (LOD) = 4.83; genome-wide P= 0.0003] on chromosome 9p21 in one SHFS population using joint linkage of ECG and Echo HR. After correcting for effective number of SNPs using a gene-centric test, six SNPs (rs7875153, rs7848524, rs4446809, rs10964759, rs1125488 and rs7853123) remained significant. We applied a novel bivariate association method, which was a joint test of association of a single locus to two traits using a standard additive genetic model. The SNP, rs7875153, provided the strongest evidence for association (P = 7.14 x 10(-6)). This SNP (rs7875153) is rare (minor allele frequency = 0.02) in AIs and is located within intron 9 of the gene KIAA1797. To support this association, we applied lymphocyte RNA expression data from the San Antonio Family Heart Study, a longitudinal study of CVD in Mexican Americans. Expression levels of KIAA1797 were significantly associated (P = 0.012) with HR. These findings in independent populations support that KIAA1797 genetic variation may be associated with HR but elucidation of a functional relationship requires additional study.