Association between the rs2241883 polymorphism of the fatty acid-binding protein-1 (FABP1) gene and obesity in a population of MASHAD study cohort.

BACKGROUND AND AIMS: The fatty acid-binding proteins (FABPs) gene polymorphisms are related to several metabolic properties. We investigated the association of SNPs rs2241883 of FABP 1 gene with obesity to evaluate the role of FABP1 gene in the pathogenesis of obesity in the population of MASHAD study cohort. METHODS: In this cross-sectional study, 2731 individuals (1883 Obese and 848 nonobese) aged 35 to 65 years old, were enrolled from the Mashhad Stroke and Heart Atherosclerotic Disorder (MASHAD) study cohort. DNA Quantitation was determined using the NanoDrop®-1000 instrument (NanoDrop-Technologies). The rs2241883 polymorphisms were genotyped by double ARMs PCR (double amplification refractory mutation system) reactions. Data analysis was carried out using SPSS 22 and a p < 0.05 was set for statistical significance. RESULTS: The results showed that after adjusting for confounding factors, subjects having the CC genotype for rs2241883 polymorphism were at a higher risk of BMI ≥ 30 mg/kg2 with OR of 1.79 (CI = 1.05-3.07; p = 0.03) and 1.76 (CI = 1.04-2.99; p = 0.04) comparing with reference group using codominant and dominant models, respectively. CONCLUSION: The results showed that CC genotype for rs2241883 polymorphism is related to an increased risk of the obesity in dominant and codominant models in a population of MASHAD study cohort.

Age and sex-specific reference intervals for prooxidant-antioxidant balance, anti-heat-shock protein 27 (anti-hsp27), and routine laboratory tests in the middle-aged adult population.

INTRODUCTION: We aimed to define specific reference intervals (RIs) for 11 biomarkers including inflammatory and oxidative stress biomarkers, liver, and renal function tests in a healthy Iranian adult population for the first time. METHODS: CLSI Ep28-A3 guidelines were then used to calculate accurate age- and sex- as well as body mass index (BMI)-specific RIs. RESULTS: RIs for studied biomarkers showed no significant age and sex-specific differences, except for uric acid, which had higher concentrations in men when compared to women. Additionally, after partitioning the participants based on the BMI with a cutoff point of 25 kg/m2 , only the levels of hs-CRP were positively associated with higher BMI (RI for BMI>25: 0.51-7.85 mg/L and for BMI<25: 0.40-4.46 mg/L). RI for PAB and anti-hsp-27 were reported 4.69-155.36 HK and 0.01-0.70 OD in men and women aged 35-65 years old. CONCLUSION: Partitioning by sex and BMI was only required for uric acid and hs-CRP, respectively, while other biomarkers required no partitioning. These results can be expected to valuably contribute to improve laboratory test result interpretation in adults for improved monitoring of various diseases in the Iranian population.

FABP1 Gene Variant is Associated with Risk of Metabolic Syndrome.

BACKGROUND: Metabolic Syndrome (MetS) is defined by a clustering of metabolic abnormalities associated with an increased risk of cardiovascular disease and type 2 diabetes mellitus. There has been an increasing interest in the associations of genetic variant involved in diabetes and obesity in the FABP1 pathway. The relationship between the rs2241883 polymorphism of FABP1 and risk of MetS remains unclear. OBJECTIVE: We aimed to examine the association between this genetic polymorphism and the presence of MetS and its constituent factors. METHODS: A total of 942 participants were recruited as part of the Mashhad Stroke and Heart Atherosclerosis Disorders (MASHAD study) Cohort. Patients with MetS were identified using the International Diabetes Federation (IDF) criteria (n=406) and those without MetS (n=536) were also recruited. DNA was extracted from peripheral blood samples that was used for genotyping for the FABP1 rs2241883T/C polymorphism using Tetra-Amplification Refractory Mutation System Polymerase Chain Reaction (Tetra-ARMS PCR). Genetic analysis was confirmed by gel electrophoresis and DNA sequencing. RESULTS: Using both univariate and multivariate analyses after adjusting for age, sex and physical activity, carriers of C allele (CT/CC genotypes) in FABP1 variant was related to an increased risk of MetS, compared to non-carriers (OR: 1.38, 95%CI: 1.04,1.82, p=0.026). CONCLUSION: The present study shows that C allele in FABP1 variant can be associated with an increased risk of MetS. The evaluation of these factors in a larger population may help further confirm these findings.

Association of macro-and micro-nutrients dietary intakes with rs2241883 genetic variants of FABP 1 gene in MASHAD study population.

INTRODUCTION: There is a relationship between macro-nutrient-intakes and the genes implicated in lipid metabolism. In this study, we assessed the association between macro-and micro-nutrients dietary intakes with rs2241883 genetic variants of the FABP1 gene. METHODS: For this cross-sectional study 2737 subjects (including 2203 subjects with dyslipidemia and 534 healthy volunteers) were enrolled as part of the Mashhad Stroke and Heart Atherosclerotic Disorder (MASHAD) study cohort. Dyslipidemia was defined based on the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III). A NanoDrop®-1000 instrument was used to do the quantitation of DNA. The rs2241883 polymorphisms were genotyped using double ARMs PCR reactions. Genotyping reagents were obtained from Applied Biosystems. Dietary intake was evaluated using a food frequency questionnaire (FFQ) and validated by 2 consecutive 24-h food recalls. RESULTS: The results showed no significant association between subjects with and without dyslipidemia (P > 0.05), except for the zinc to copper ratio, the value for which was higher in the subjects with dyslipidemia (4.78 (1.62)) when compared to subjects without dyslipidemia (4.68 (1.82)) (p = 0.05). Using different genetic models we found that zinc and copper were significantly different in the additive (p = 0.01) and dominant (p = 0.01) genetic models. Although, this association was no longer significant after adjusting for confounding factors. CONCLUSIONS: There were no associations between macro-and micro-nutrient dietary intakes with rs2241883 genetic variants after adjusting for confounding factors in the MASHAD study population.

The association between a Fatty Acid Binding Protein 1 (FABP1) gene polymorphism and serum lipid abnormalities in the MASHAD cohort study.

INTRODUCTION: Dyslipidemia is a known risk factor for cardiovascular disease and is partially determined by genetic variations in the genes involved in lipoprotein metabolism. Therefore, we aimed to assess the association between a polymorphism of the Fatty Acid Binding Protein1 (rs2241883) gene locus and dyslipidemia in an Iranian cohort. MATERIALS AND METHODS: This is a case-control study 2737 individuals were recruited (2203 subjects with dyslipidemia and 534 controls). Dyslipidemia was defined as total cholesterol≥200 mg/dl, or TG≥150 mg/dl, or LDL-C≥130 mg/dl, or HDL-C<40 mg/dl in males and <50 mg/dl in females. Serum lipid profile was determined using a Alcyon Abbott biochemical auto analyzer, USA. Genotyping was made through double amplification refractory mutation system polymerase chain reaction (ARMs PCR). RESULT: The frequency of TT, CT, CC genotypes of rs2241883 polymorphism of FABP1 gene were 65.5, 33.4, 5.1 in subjects with dyslipidemia and 56.9%, 40.4%, 2.6% in subjects without dyslipidemia, respectively. Using a dominant genetic model, subjects carrying C allele (CC&CT genotypes) had a 22% lower risk of dyslipidemia (OR: 0.78, CI 95%: 0.62-0.98 P, 0.03). Individuals with CT vs. TT genotypes had a significantly lower risk of a high serum TC and LDL level. Further analysis showed that there was a positive association between FABP1 genotype (CT) and isolated HTG as well as combined dyslipidemia. The change of a polar amino acid (threonine) in position T94A to a hydrophobic amino acid (alanine) can cause transformation protein. CONCLUSIONS: A CC genotype of the rs2241883 polymorphism of the FABP1 gene appears to confer a higher risk of dyslipidemia in our representative cohort of Iranian individuals.

Human tartrate-resistant acid phosphatase becomes an effective ATPase upon proteolytic activation.

Proteolytic cleavage in an exposed loop of human tartrate-resistant acid phosphatase (TRAcP) with trypsin leads to a significant increase in activity. At each pH value between 3.25 and 8.0 the cleaved enzyme is more active. Substrate specificity is also influenced by proteolysis. Only the cleaved form is able to hydrolyze unactivated substrates efficiently, and at pH >6 cleaved TRAcP acquires a marked preference for ATP. The cleaved enzyme also has altered sensitivity to inhibitors. Interestingly, the magnitude and mode of inhibition by fluoride depends not only on the proteolytic state but also pH. The combined kinetic data imply a role of the loop residue D158 in catalysis in the cleaved enzyme. Notably, at low pH this residue may act as a proton donor for the leaving group. In this respect the mechanism of cleaved TRAcP resembles that of sweet potato purple acid phosphatase.

Phosphate forms an unusual tripodal complex with the Fe-Mn center of sweet potato purple acid phosphatase.

Purple acid phosphatases (PAPs) are a family of binuclear metalloenzymes that catalyze the hydrolysis of phosphoric acid esters and anhydrides. A PAP in sweet potato has a unique, strongly antiferromagnetically coupled Fe(III)-Mn(II) center and is distinguished from other PAPs by its increased catalytic efficiency for a range of activated and unactivated phosphate esters, its strict requirement for Mn(II), and the presence of a mu-oxo bridge at pH 4.90. This enzyme displays maximum catalytic efficiency (k(cat)/K(m)) at pH 4.5, whereas its catalytic rate constant (k(cat)) is maximal at near-neutral pH, and, in contrast to other PAPs, its catalytic parameters are not dependent on the pK(a) of the leaving group. The crystal structure of the phosphate-bound Fe(III)-Mn(II) PAP has been determined to 2.5-A resolution (final R(free) value of 0.256). Structural comparisons of the active site of sweet potato, red kidney bean, and mammalian PAPs show several amino acid substitutions in the sweet potato enzyme that can account for its increased catalytic efficiency. The phosphate molecule binds in an unusual tripodal mode to the two metal ions, with two of the phosphate oxygen atoms binding to Fe(III) and Mn(II), a third oxygen atom bridging the two metal ions, and the fourth oxygen pointing toward the substrate binding pocket. This binding mode is unique among the known structures in this family but is reminiscent of phosphate binding to urease and of sulfate binding to lambda protein phosphatase. The structure and kinetics support the hypothesis that the bridging oxygen atom initiates hydrolysis.

Phosphotyrosyl peptides and analogues as substrates and inhibitors of purple acid phosphatases.

Purple acid phosphatases are metal-containing hydrolases. While their precise biological role(s) is unknown, the mammalian enzyme has been linked in a variety of biological circumstances (e.g., osteoporosis) with increased bone resorption. Inhibition of the human enzyme is a possible strategy for the treatment of bone-resorptive diseases such as osteoporosis. Previously, we determined the crystal structure of pig purple acid phosphatase to 1.55A and we showed that it is a good model for the human enzyme. Here, a study of the pH dependence of its kinetic parameters showed that the pig enzyme is most efficient at pH values similar to those encountered in the osteoclast resorptive space. Based on the observation that phosphotyrosine-containing peptides are good substrates for pig purple acid phosphatase, peptides containing a range of phosphotyrosine mimetics were synthesized. Kinetic analysis showed that they act as potent inhibitors of mammalian and plant purple acid phosphatases, with the best inhibitors exhibiting low micromolar inhibition constants at pH 3-5. These compounds are thus the most potent organic inhibitors yet reported for the purple acid phosphatases.