Searching for carbonylome biomarkers of aging - development and validation of the proteomic method for quantification of carbonylated protein in human plasma.

AIM: To develop a method for measuring protein carbonylation in human plasma and serum samples, which was previously implied in numerous age-related phenotypes. METHODS: Protein expression and carbonylation were analyzed in plasma samples obtained from 12 healthy human individuals by using a novel method that combines affinity-based albumin and immunoglobulin G removal, and aminooxy dyeing in one- or two-dimensional gels. In addition, carbonylome profile of plasma and serum was compared. Coefficients of variation and intra-class correlation coefficients were used in statistical analysis. RESULTS: Following a step-wise laboratory development and optimization process, we measured the protein expression and carbonylation for 813 proteins from the plasma. The analysis of repeated measurements suggested excellent coefficients of variation, which rarely exceeded 10%. The average value of intra-class correlation based on absolute agreement (ICC) for protein expression was 0.97±0.02, while for carbonylation it was 0.73±0.24. The removal of the most extreme protein outlier in carbonylation assessment increased the average ICC to 0.87±0.04. Low protein spot volume substantially reduced repeatability. Serum carbonylation estimates were similar to those from plasma, with the ICC in the range of 0.86-0.89. CONCLUSION: We developed a reliable method for the measurement of human plasma protein carbonylation, which can be used for the assessment of carbonylome biomarkers of aging.

White Wine Consumption Influences Inflammatory Phase of Repair After Myocardial Infarction in Rats.

Effects of white wine (WW) consumption on the expression of inflammatory markers/mediators (MMP-2, MMP-9, NF-ĸB p65 and TGF-ß1) in myocardial tissue after experimentally induced permanent myocardial ischemia was investigated. Male Sprague-Dawley rats were given either a combination of WW and water or only water, for 28 days. After coronary ligation, animals were left to survive for 24 hours. Three representative areas: infarct/ischemic, peri-infarct/border zone, and control/non-ischemic zones were analyzed for expression of immunoreactivity by measuring the threshold area % of signal density. For MMP-9, significantly smaller expression was found in all 3 zones of wine drinking animals (P < 0.001). There was no difference in MMP-2 immunoreactivity between the 2 groups, except in peri-infarct zones, where the signal was significantly decreased (P < 0.001). The same pattern of expression was found for the NF-κB p65 signal, although no differences between experimental groups were observed for TGF-ß1. White wine consumption decreases the expression of the 3 investigated inflammatory markers/mediators in the peri-infarct zone, suggesting its significant modulatory effect. For MMP-9 and MMP-2, expression was similar to the effect of postischemic reperfusion. No effect on TGF-ß1 was observed, highlighting its role in being the master-switch, changing from the inflammatory to the proliferative stage of infarct healing.

Arterial stiffness in patients with coronary artery disease: relation with in-stent restenosis following percutaneous coronary intervention.

BACKGROUND: Coronary artery disease (CAD) is one of the most important issues in modern medicine due to its high mortality and prevalence. An early detection and prevention can reduce morbidity and mortality. Arterial stiffness is a potent and independent predictor of CAD. We aimed to investigate the arterial stiffness in CAD patients undergoing the coronary angiography. Also, we investigated a possible correlation between arterial stiffness and in-stent restenosis (ISR), an important limitation of percutaneous coronary intervention (PCI). METHODS: The study included 160 patients undergoing coronary angiography, treated either with PCI or with CABG. The pulse wave velocity (PWV) and augmentation index (AIx) were measured by the Arteriograph. RESULTS: PWV in the CAD group (12.24 ± 2.78 m/s) was significantly higher compared to the control group (8.27 ± 1.89 m/s). PWV in ISR and left main (LM) stenosis group (14.03 ± 3.15 and 13.89 ± 2.95 m/s) was significantly higher compared to the control and CAD groups. Peripheral and central AIx were significantly higher in CAD group (1.38 ± 30.63 % and 38.35 ± 15.52 %) than in control group (-11.35 ± 26.74 % and 26.91 ± 10.62 %). Patients with LM stenosis have significantly higher values of peripheral and central AIx (23.37 ± 23.77 % and 49.71 ± 12.02 %) than the CAD and ISR group. CONCLUSIONS: The study confirmed a positive correlation between arterial stiffness measures, PWV and AIx, and CAD. Also, this study showed the correlation between PWV and ISR which can help to select more appropriate stent.

Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations.

Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.

Hyperbaric oxygenation affects the mechanisms of acetylcholine-induced relaxation in diabetic rats.

The effects of hyperbaric oxygenation (HBO2) on acetylcholine-induced vasorelaxation (AChIR) were evaluated in male Sprague-Dawley (SD) rats randomized into four groups: healthy controls (Ctrl), diabetic rats (DM), and control and diabetic rats that underwent hyperbaric oxygenation (Ctrl+HBO2 and DM+HBO2). AChIR was measured in aortic rings, with L-NAME, indomethacin, or MS-PPOH and a combination of inhibitors. mRNA expression of eNOS, iNOS, COX-1 and COX-2 was assessed by qPCR, and protein expression of CYP4A(1-3) by Western blot. Plasma antioxidative capacity and systemic oxidative stress were determined with the ferric reducing ability of plasma (FRAP) and thiobarbituric acid-reactive substances (TBARS) assays, respectively. AChIR was preserved in all groups of rats, but mediated with different mechanisms. In all experimental groups of rats, AChIR was mediated mainly by NO, with the contribution of CYP450 vasodilator metabolites. This effect was the most prominent in the DM+HBO2 group of rats. The TBARS was significantly higher in both DM and DM+HBO2 groups compared to respective controls. eNOS expression was upregulated in the DM+HBO2 group compared to other groups, COX-1 expression was upregulated in the DM+HBO2 group compared to the control. CYP450-4A1 / A2/A3protein expression was significantly higher expressed in both hyperbaric groups compared to their respective controls. In conclusion, HBO2 affected all three vasodilator pathways and shifted AChIR to CYP450 enzymes pathway.

Sea fennel (Crithmum maritimum L.): phytochemical profile, antioxidative, cholinesterase inhibitory and vasodilatory activity.

Sea fennel, a rediscovered star of the coastal cuisine, has been investigated for its phytochemical profile and biological potential. Sea fennel flowers, stems and leaves were analyzed for essential oils (EOs) isolated by hydrodistillation, as well as non-volatiles obtained by ethanolic extraction. Limonene were found to be a dominant compound in EOs and ethanolic extracts; ranging from 57.5-74.2 % and 0.7-8.1 mg/g dry plant material, respectively. In addition total phenolic content was determined for ethanolic extracts. All samples and their main phytochemicals were tested for various methods. EO and extract obtained from flowers were tested for vasodilatory activity on rat aortic rings. Antioxidant activity of EOs was extremely low in comparison to extracts, on the contrary to cholinesterase inhibition where EOs showed better activity than extracts. Flower extract and chlorogenic acid showed stronger vasodilators in comparison to EO and limonene. The obtained results point out the potential impact of the dominant compounds from EO and extract on the biological properties of the sea fennel.

Discovery and fine mapping of serum protein loci through transethnic meta-analysis.

Many disorders are associated with altered serum protein concentrations, including malnutrition, cancer, and cardiovascular, kidney, and inflammatory diseases. Although these protein concentrations are highly heritable, relatively little is known about their underlying genetic determinants. Through transethnic meta-analysis of European-ancestry and Japanese genome-wide association studies, we identified six loci at genome-wide significance (p < 5 × 10(-8)) for serum albumin (HPN-SCN1B, GCKR-FNDC4, SERPINF2-WDR81, TNFRSF11A-ZCCHC2, FRMD5-WDR76, and RPS11-FCGRT, in up to 53,190 European-ancestry and 9,380 Japanese individuals) and three loci for total protein (TNFRS13B, 6q21.3, and ELL2, in up to 25,539 European-ancestry and 10,168 Japanese individuals). We observed little evidence of heterogeneity in allelic effects at these loci between groups of European and Japanese ancestry but obtained substantial improvements in the resolution of fine mapping of potential causal variants by leveraging transethnic differences in the distribution of linkage disequilibrium. We demonstrated a functional role for the most strongly associated serum albumin locus, HPN, for which Hpn knockout mice manifest low plasma albumin concentrations. Other loci associated with serum albumin harbor genes related to ribosome function, protein translation, and proteasomal degradation, whereas those associated with serum total protein include genes related to immune function. Our results highlight the advantages of transethnic meta-analysis for the discovery and fine mapping of complex trait loci and have provided initial insights into the underlying genetic architecture of serum protein concentrations and their association with human disease.

Evidence of inbreeding depression on human height.

Stature is a classical and highly heritable complex trait, with 80%-90% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (χ(2) = 83.89, df = 1; p = 5.2 × 10(-20)). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance.

Can genetics aggravate the health of isolated and remote populations? The case of gout, hyperuricaemia and osteoarthritis in Dalmatia.

INTRODUCTION: The aim of this study was to investigate whether genetics may be considered an additional risk factor for health in isolated and remote populations, compared with their populations of origin. In this study, two remote island population samples from Croatia (from the islands of Vis and the Korcula) were compared with mainland controls from the coastal city of Split. The analyses focused on gout, hyperuricaemia and osteoarthritis, as examples of complex, multifactorial diseases. METHODS: A total of 3006 examinees from all three sites in Dalmatia, Croatia were included in the descriptive part of the study, within a large-scale project of 10,001 Dalmatians. Additionally, a subset of 2428 subjects was genotyped and information on three genomic loci was used in this study. All three loci belong to SLC2A9 gene, considered to have a major role in the regulation of serum uric acid concentration (rs6449213, rs1014290 and rs737267). RESULTS: There was a much a higher prevalence of gout in the isolated populations compared with the mainland sample (3.3% in Vis, 2.2% in Korcula and 1.7% in Split, after age standardization). Furthermore, standardized prevalence of hyperuricaemia (defined as serum uric acid ≥403 mmol/L) was 9.9% in Vis, 5.6% in Korcula and 6.1% in Split. Analysis of the allele frequencies for the three loci of SLC2A9 suggested that in all three instances the prevalence of deleterious genotypes was highest in Vis, followed by Korcula, which had higher or comparable prevalence to the city of Split. Multivariate analysis, adjusted for the main confounder effects indicated that those on the island of Vis, which has the higher degree of isolation, had significantly higher odds ratio for both hyperuricaemia (odds ratio 1.90 95% confidence intervals [1.36-2.64]) and osteoarthritis, but not gout (3.37 [2.14-5.32]). The difference between Split and Korcula included only greater odds for osteoarthritis (1.92 [1.20-3.06]). CONCLUSIONS: Isolated and remote populations that maintain a sufficient level of genetic isolation may suffer not only from consequences of geographic and social isolation, but their population genetic structure may also further contribute to poorer health status and outcomes.

What Is the Smallest Change in Pulse Wave Velocity Measurements That Can Be Attributed to Clinical Changes in Arterial Stiffness with Certainty: A Randomized Cross-Over Study.

Pulse wave velocity (PWV), a direct measure of arterial stiffness, is a promising biomarker of cardiovascular risk and a cardiovascular surrogate outcome. The resolution for detecting its smallest clinically significant change is dependent on the expected reproducibility, but there is currently no consensus on this. We estimated the PWV reproducibility in a range of intra-subject values that were observed over a 2 week period in a broad range of participants and under clinically relevant experimental conditions (two observers, morning/afternoon sessions, and number of visits) using SphygmoCor and Arteriograph devices. Each participant was recorded 12 times with each device over three visits, one week apart, and two morning and two afternoon recordings were taken per visit. The factors affecting reproducibility and the discrepancies between the consecutive PWV measurements for each device were also examined using multilevel mixed-effect models. We show that current PWV estimation guidance recommending 2 + 1 measurements is suboptimal because the PWV range was outside of the 1 m/s threshold for most of the participants, which is proposed as a minimal clinically important difference. The best reproducibility was yielded with median of four measurements and a 1.1 m/s threshold. Although PWV reproducibility and repeatability are frequently used interchangeably in studies, we demonstrated that despite their relative measures of variability (e.g., coefficient of variation) being comparable, their ranges revealed a clinically significant difference between them. We also found that different physiological variables were predictors of the discrepancy between the consecutive measurements made by the two devices, which is likely due to their distinct modes of operation. The evidence base for PWV reproducibility is limited, and more research is needed to deepen our understanding of the variation in arterial stiffness over time, as well as fluctuations within a population group and in an intervention setting.

Long-Term Adverse Effects of Mild COVID-19 Disease on Arterial Stiffness, and Systemic and Central Hemodynamics: A Pre-Post Study.

COVID-19-associated vascular disease complications are primarily associated with endothelial dysfunction; however, the consequences of disease on vascular structure and function, particularly in the long term (>7 weeks post-infection), remain unexplored. Individual pre- and post-infection changes in arterial stiffness as well as central and systemic hemodynamic parameters were measured in patients diagnosed with mild COVID-19. As part of in-laboratory observational studies, baseline measurements were taken up to two years before, whereas the post-infection measurements were made 2-3 months after the onset of COVID-19. We used the same measurement protocol throughout the study as well as linear and mixed-effects regression models to analyze the data. Patients (N = 32) were predominantly healthy and young (mean age ± SD: 36.6 ± 12.6). We found that various parameters of arterial stiffness and central hemodynamics-cfPWV, AIx@HR75, and cDBP as well as DBP and MAP-responded to a mild COVID-19 disease. The magnitude of these responses was dependent on the time since the onset of COVID-19 as well as age (pregression_models ≤ 0.013). In fact, mixed-effects models predicted a clinically significant progression of vascular impairment within the period of 2-3 months following infection (change in cfPWV by +1.4 m/s, +15% in AIx@HR75, approximately +8 mmHg in DBP, cDBP, and MAP). The results point toward the existence of a widespread and long-lasting pathological process in the vasculature following mild COVID-19 disease, with heterogeneous individual responses, some of which may be triggered by an autoimmune response to COVID-19.

Sex-specific association of anthropometric measures of body composition with arterial stiffness in a healthy population.

BACKGROUND: Anthropometric measures of body composition and arterial stiffness are commonly used as indicators of cardiovascular risk. Little is known, however, about the association of the anthropometric measures with arterial stiffness, especially in a healthy, generally non-obese population. MATERIAL/METHODS: In a sample of 352 healthy subjects (200 premenopausal women), 3 arterial stiffness indices were analyzed (pulse wave velocity, augmentation index and central systolic blood pressure) in relation to 5 anthropometric measures of body composition (body mass index - BMI, body fat percentage by skinfold measurements -%BF, waist circumference - WC, waist-hip ratio - WHpR, and waist-height ratio - WHtR). Data were analyzed using correlation and regression analyses, with adjustment for the following confounders: age, blood pressures, height, heart rate, blood lipids and smoking. RESULTS: Most correlations between anthropometric measures and arterial stiffness indices were significant and positive in both sex groups (r=0.14-0.40, P<0.05). After adjustment for confounding effects, BMI, WC and WHtR remained significant (but inverse) predictors of arterial stiffness (ß from -0.06 to -0.16; P<0.05) in the females, while in the males BMI was the only measure inversely predicting arterial stiffness (ß from -0.09 to -0.13; P<0.05). CONCLUSIONS: Measures of body composition are weak and inverse predictors of arterial stiffness and their influence is sex-dependent. BMI, WC and WHtR were key predictors of arterial stiffness in the females, while BMI was the principal predictor in the males. The associations of anthropometric measures with arterial stiffness are strongly and differently confounded by various factors that have to be taken into account when explaining results of similar studies.

The effects of experimental, meteorological, and physiological factors on short-term repeated pulse wave velocity measurements, and measurement difficulties: A randomized crossover study with two devices.

Background: Large longitudinal studies with repeated pulse wave velocity (PWV) measurements, a direct measure of arterial stiffness, are required to realize the full potential of arterial stiffness in clinical practice. To facilitate such studies it is important to increase the power of a study by reducing within-subject variability of PWV, and to ease the use of a PWV device in clinical settings by minimizing PWV measurement difficulties. Methods: We systematically investigated experimental setting and meteorological conditions, as well as physiological factors and participant characteristics, to determine whether and to what extent they affected: between- and within-subjects variability of PWV recordings, and measurement difficulties of a particular device. We conducted a 2-week longitudinal block-randomized cross-over study with two blinded observers and two commonly used devices: applanation tonometry SphygmoCor CvMS and oscillometric Arteriograph to assess carotid-femoral (cfPWV) or aortic (PWVao) PWV, respectively. Our sample had uniform and wide-spread distribution of age, blood pressures, hypertensive status and BMI. Each participant (N = 35) was recorded 12 times over 3 visiting days, 7 days apart. On each day, recordings were made twice in the morning (7-10 a.m.) and afternoon (16-18 p.m.). Data were analyzed using multilevel mixed-effects models, separately for each device. Results: In addition to age and mean arterial pressure (MAP) that strongly affected both cfPWV and PWVao, other significant factors appeared to indicate a measurement approach. cfPWV as a more direct measure of arterial stiffness was additionally affected by hypertension status, outdoor temperature, interaction of MAP with outdoor temperature and the order of visit, with MAP within-subject variability contributing on average 0.27 m/s to difference in repeated measurements at 5°C and 0.004 m/s at 25°C. PWVao measurements derived at a single brachial site were more dependent on age than cfPWV and also depended on personal characteristics such as height and sex, and heart rate; with within-subject MAP variability adding on average 0.23 m/s to the difference in repeated measures. We also found that female sex significantly increased, and recording in afternoon vs. morning significantly decreased measurement difficulties of both devices. Conclusion: We identified factors affecting PWV recordings and measurement-difficulties and propose how to improve PWV measuring protocols.

Effects of Moderate Consumption of Red Wine on Hepcidin Levels in Patients with Type 2 Diabetes Mellitus.

Iron overload is often associated with type 2 diabetes (T2D), indicating that hepcidin, the master regulator of iron homeostasis, might be involved in diabetes pathogenesis. Alcohol consumption may also result in increased body iron stores. However, the moderate consumption of wine with meals might be beneficial in T2D. This effect has been mainly attributed to both the ethanol and the polyphenolic compounds in wine. Therefore, we examined the effects of red wine on hepcidin in T2D patients and non-diabetic controls. The diabetic patients (n = 18) and age- and BMI-matched apparently healthy controls (n = 13) were men, aged 40−65 years, non-smoking, with BMI < 35 kg/m2. Following a 2-week alcohol-free period, both groups consumed 300 mL of red wine for 3 weeks. The blood samples for the iron status analysis were taken at the end of each period. The red wine intake resulted in a decrease in serum hepcidin in both the diabetic subjects (p = 0.045) and controls (p = 0.001). The levels of serum ferritin also decreased after wine in both groups, reaching statistical significance only in the control subjects (p = 0.017). No significant alterations in serum iron, transferrin saturation, or soluble transferrin receptors were found. The suppression of hepcidin, a crucial iron-regulatory hormone and acute-phase protein, in T2D patients and healthy controls, is a novel biological effect of red wine. This may deepen our understanding of the mechanisms of the cardiometabolic effects of wine in T2D.

Thermally treated wine retains vasodilatory activity in rat and guinea pig aorta.

In contrast to the intact wine, cardiovascular effects of the thermally treated wine have not been studied, despite widespread habits of cooking with wine and consumption of mulled wine. Vasodilatory effects of the red wine heated at 75 and 125°C were examined in the isolated rat and guinea pig aorta and compared with the intact and wine dealcoholized without thermal stress. Samples were analyzed for their phenolic content, antioxidant capacity, resveratrol and ethanol contents. Heating-induced degradation of individual phenolic fraction was observed only in the samples treated at 125°C, although total phenolic concentration and related antioxidant activity increased in the thermally treated samples due to the reduction in their volume. All wine samples regardless of treatment caused similar maximal relaxation in both species, but the response was stronger in aortas from guinea pigs. At the lowest concentrations up to 1‰, dealcoholized wine produced vasodilation greater than that produced by intact wine and wines treated at 75 and 125°C, which showed similar vasodilating activity at all concentrations. Our results indicate that wine thermally treated under heating conditions applicable to the preparation of a mulled wine and cooking with wine largely retains vasodilatory activity in vitro despite significant heat-induced changes in its composition.

Ethical aspects of human biobanks: a systematic review.

AIM: To systematically assess the existing literature on ethical aspects of human biobanks. METHOD: We searched the Web of Science and PubMed databases to find studies addressing ethical problems in biobanks with no limits set (study design, study population, time period, or language of publication). All identified articles published until November 2010 were included. We analyzed the type of published articles, journals publishing them, involvement of countries/institutions, year of publication, and citations received, and qualitatively assessed every article in order to identify ethical issues addressed by the majority of published research on human biobanking. RESULTS: Hundred and fifty four studies satisfied our review criteria. The studies mainly came from highly developed countries and were all published in the last two decades, with over half of them published in 2009 or 2010. They most commonly discussed the informed consent, privacy and identifiability, return of results to participants, importance of public trust, involvement of children, commercialization, the role of ethics boards, international data exchange, ownership of samples, and benefit sharing. CONCLUSIONS: The focus on ethical aspects is strongly present through the whole biobanking research field. Although there is a consensus on the old and most typical ethical issues, with further development of the field and increasingly complex structure of human biobanks, these issues will likely continue to arise and accumulate, hence requiring constant re-appraisal and continuing discussion.

A meta-analysis of genome-wide data from five European isolates reveals an association of COL22A1, SYT1, and GABRR2 with serum creatinine level.

BACKGROUND: Serum creatinine (S CR) is the most important biomarker for a quick and non-invasive assessment of kidney function in population-based surveys. A substantial proportion of the inter-individual variability in S CR level is explicable by genetic factors. METHODS: We performed a meta-analysis of genome-wide association studies of S CR undertaken in five population isolates ('discovery cohorts'), all of which are part of the European Special Population Network (EUROSPAN) project. Genes showing the strongest evidence for an association with SCR (candidate loci) were replicated in two additional population-based samples ('replication cohorts'). RESULTS: After the discovery meta-analysis, 29 loci were selected for replication. Association between SCR level and polymorphisms in the collagen type XXII alpha 1 (COL22A1) gene, on chromosome 8, and in the synaptotagmin-1 (SYT1) gene, on chromosome 12, were successfully replicated in the replication cohorts (p value = 1.0 x 10(-6) and 1.7 x 10(-4), respectively). Evidence of association was also found for polymorphisms in a locus including the gamma-aminobutyric acid receptor rho-2 (GABRR2) gene and the ubiquitin-conjugating enzyme E2-J1 (UBE2J1) gene (replication p value = 3.6 x 10(-3)). Previously reported findings, associating glomerular filtration rate with SNPs in the uromodulin (UMOD) gene and in the schroom family member 3 (SCHROOM3) gene were also replicated. CONCLUSIONS: While confirming earlier results, our study provides new insights in the understanding of the genetic basis of serum creatinine regulatory processes. In particular, the association with the genes SYT1 and GABRR2 corroborate previous findings that highlighted a possible role of the neurotransmitters GABAA receptors in the regulation of the glomerular basement membrane and a possible interaction between GABAA receptors and synaptotagmin-I at the podocyte level.

Uric acid and antioxidant effects of wine.

The aim of this article is to review the role of uric acid in the context of antioxidant effects of wine and its potential implication to human health. We described and discussed the mechanisms of increase in plasma antioxidant capacity after consumption of moderate amounts of wine. Because this effect is largely contributed by acute elevation in plasma uric acid, we paid special attention to wine constituents and metabolic processes that are likely to be involved in uric acid elevation.

Interactions between genetic variants in glucose transporter type 9 (SLC2A9) and dietary habits in serum uric acid regulation.

AIM: To investigate possible interactions between genetic variants in glucose transporter type 9 (SLC2A9) gene and dietary habits in serum uric acid regulation. METHODS: Participants for this study were recruited from two isolated Croatian island communities of Vis (n=918) and Korcula (n=898). Three single nucleotide polymorphisms (SNP) from the SLC2A9 gene (rs1014290, rs6449213, rs737267) were correlated with dietary habits and uric acid. RESULTS: A significant decrease in uric acid levels was recorded with increasing consumption of milk, sour cream, duck and turkey, and eggs. The only significant interaction was found between potato consumption and rs737267 and a near-significant interaction was found between soft drinks and rs1014290 (interaction P=0.068). Increased consumption of soft drinks interacting with the TT genotype at rs1014290 increased serum uric acid. No significant interactions were observed between food products consumption and rs6449213. CONCLUSION: There is a certain extent of interaction between SLC2A9 and dietary patterns in serum uric acid determination. The metabolic effect of soft drinks seems to be determined by the underlying genotype of rs1014290.

Predictive value of 8 genetic loci for serum uric acid concentration.

AIM: To investigate the value of genomic information in prediction of individual serum uric acid concentrations. METHODS: Three population samples were investigated: from isolated Adriatic island communities of Vis (n=980) and Korcula (n=944), and from general population of the city of Split (n=507). Serum uric acid concentration was correlated with the genetic risk score based on 8 previously described genes: PDZK1, GCKR, SLC2A9, ABCG2, LRRC16A, SLC17A1, SLC16A9, and SLC22A12, represented by a total of 16 single-nucleotide polymorphisms (SNP). The data were analyzed using classification and regression tree (CART) and general linear modeling. RESULTS: The most important variables for uric acid prediction with CART were genetic risk score in men and age in women. The percent of variance for any single SNP in predicting serum uric acid concentration varied from 0.0%-2.0%. The use of genetic risk score explained 0.1%-2.5% of uric acid variance in men and 3.9%-4.9% in women. The highest percent of variance was obtained when age, sex, and genetic risk score were used as predictors, with a total of 30.9% of variance in pooled analysis. CONCLUSION: Despite overall low percent of explained variance, uric acid seems to be among the most predictive human quantitative traits based on the currently available SNP information. The use of genetic risk scores is a valuable approach in genetic epidemiology and increases the predictability of human quantitative traits based on genomic information compared with single SNP approach.