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1.  Effect of age on the phenotype of metabolic syndrome in developing country 
This study aimed to determine how age groups effect on the phenotype of metabolic syndrome (MetS) among Iranian population.
Materials and Methods:
This cross-sectional study was conducted as part of Isfahan Healthy Heart Program. Height, weight, waist circumference, and blood pressure were measured by trained health-care professionals. MetS was defined as having three or more of the National Cholesterol Education Program III criteria. The relation between different age groups and different phenotypes of MetS was examined using the multinomial logistic regression.
We found low high-density lipoprotein-cholesterol (HDL-c) was the most common feature, followed by hypertriglyceridemia (HTG), abdominal obesity (ABO), hypertension (HTN), and high fasting blood glucose in decreasing order of prevalence. The most prevalent combination of MetS components was hypertrigeceridemia, low HDL-c and ABO (50.7%) in all subjects and especially in younger age group (63.2%). In elder age group, the most prevalent three components combination was HTG, Low HDL-c and HTN (43.9%). Logistic regression analysis demonstrated that elder subjects were at approximately 12 times higher risk of having the combination HTG, ABO, low HDL-c, and HTN (P < 0.001) compared to the middle age subjects who had a lower risk for the same combination; (2 [1.49-3.49]) (P < 0.001).
This study provides a nationally representative estimate of the prevalence of different phenotypes of MetS across different age groups. Regarding different phenotypes of MetS in various age groups need to have important implications in the clinical management of these patients and the implementation of public health.
PMCID: PMC4513307  PMID: 26261805
Age groups; Iran; metabolic cardiovascular syndrome; phenotype
2.  Inhibitory potential of pure isoflavonoids, red clover, and alfalfa extracts on hemoglobin glycosylation 
ARYA Atherosclerosis  2015;11(2):133-138.
Non-enzymatic glycosylation of hemoglobin is complications of diabetes. Antioxidant system imbalance can result in the emergence of free radicals’ destructive effects in the long-term. Red clover (Trifolium pratense L.) and alfalfa (Medicago sativa L.) contain isoflavonoids and have antioxidant activity. This experimental study evaluated the inhibitory activity of pure isoflavonoids (daidzein and genistein), red clover and alfalfa extracts on hemoglobin glycosylation.
This study was performed in Iran. Stock solution of hydroalcoholic extracts of red clover and alfalfa in concentrations of 1 and 10 g/100 ml and stock solution of daidzein and genistein in concentrations of 250 ng, 500 ng, 25 µg and 250 µg/100 ml were prepared as case groups. Control group was without hydroalcoholic extracts of plants and pure isoflavonoids. All experiments were performed in triplicate. Hemoglobin was prepared and antioxidant activities were investigated to estimate degree of nonenzymatic hemoglobin glycosylation.
There was no significantly difference between used extracts (extract of red clover and alfalfa) and control of the hemoglobin glycosylation but using daidzein (P = 0.046, 0.029 and 0.021, respectively) and genistein (P = 0.034, 0.036 and 0.028) significantly inhibited (P < 0.050) this reaction in 25 µg/100 ml, 250 and 500 ng/100 ml concentrations when compared to control. in 25 µg/100 ml, 250 ng and 500 ng/100 ml concentrations percentage of inhibition were 32, 80 and 74.5% respectively with used of daidzein and were 21, 83 and 76% respectively with consumption of genistein.
According to decrease of glycation of hemoglobin with isoflavonoids, two used plant in this study containing isoflavonoid may be useful on diabetes.
PMCID: PMC4568198  PMID: 26405442
Glycosylation; Genistein; Medicago sativa; Trifolium
3.  The effect of oral vitamin D on serum level of N-terminal pro-B-type natriuretic peptide 
The risk of cardiovascular disease in dialysis patients is higher than the general population. Vitamin D receptors exist in myocardium inhibit cardiac hypertrophy. N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) is a neurohormone secreted by the heart in response to ventricular mass increase. This study aimed to evaluate the effect of oral vitamin D on serum level of pro-B-type natriuretic peptide (pro-BNP) in peritoneal dialysis patients.
Materials and Methods:
In a randomized clinical trial, 84 peritoneal dialysis patients (49 males and 35 females) were randomly divided into two groups. The intervention group received 50000 units oral vitamin D per week, for 12 weeks if 25-hydroxy-vitamin D level was <10 ng/ml and for 8 weeks if it was between 10 ng/ml and 30 ng/ml. The control group received placebo. Parathyroid hormone, calcium, phosphor, 25-hydroxy-vitamin D, albumin and NT-pro-BNP were evaluated before and after the study.
The mean serum level of pro-BNP in patients receiving vitamin D and placebo group before the study was 875 pg/ml and 793 pg/ml, respectively. There was 895.9 pg/ml in the intervention group and 736.7 pg/ml in the control group (P = 0.7). Mean serum level of 25(OH) D in patients receiving oral vitamin D and placebo group before the study was 16.9 ng/ml and 31.9 ng/ml, respectively. There was 28.9 ng/ml in the intervention group and 12.9 ng/ml in the control group (P = 0.001). There were no significant differences regarding other indices (Alb, P, Ca, intact parathyroid hormone) between two groups.
Vitamin D did not significantly change the serum level of pro-BNP in peritoneal dialysis patients.
PMCID: PMC4298880  PMID: 25625100
N-terminal pro-B-type natriuretic peptide; peritoneal dialysis; vitamin D
4.  Population-based metabolic syndrome risk score and its determinants: The Isfahan Healthy Heart Program 
Metabolic syndrome (MetSy), an important predisposing factor for the most of noncommunicable diseases, has become a global pandemic. Given different definitions used for the MetSy, recently using a score termed “continuous MetSy risk score (CMetSyS)” is recommended. The aim of this study was to provide a CMetSyS in a population-based sample of Iranian adults and to assess its determinants.
Materials and Methods:
We used the data of the baseline survey of a community trial entitled “the Isfahan health heart program.” The MetSy was defined according to the Revised National Cholesterol Education Program Third Adult Treatment Panel. All probable predictive models and their predictive performance were provided using leave-one-out cross-validated logistic regression and the receiver operation characteristic curve methods. Multiple linear regression was performed to assess factors associated with the CMetSyS.
The study population consisted of 8313 persons (49.9% male, mean age 38.54 ± 15.86 years). The MetSy was documented in 1539 persons (21.86%). Triglycerides and waist circumference were the best predictive components, and fasting plasma glucose had the lowest area under curve (AUC). The AUC for our best model was 95.36 (94.83-95.83%). The best predictive cutoff for this risk score was −1.151 with 89% sensitivity and 87.93% specificity.
We provided four population-based leave-one-out cross-validated risk score models, with moderate to perfect predictive performance to identify the MetSy in Iranian adults. The CMetSyS had significant associations with high sensitive C-reactive protein, body mass index, leisure time, and workplace physical activity as well as age and gender.
PMCID: PMC4333526  PMID: 25709659
Iran; metabolic syndrome; receiver operating characteristic curve; risk score
5.  Innate lymphoid cells and cytokines of the novel subtypes of helper T cells in asthma 
Asia Pacific Allergy  2014;4(4):212-221.
In this study, the expression of interleukin-9 (IL-9), IL-17, IL-22, and IL-25 genes that might be the potential predisposing factors for asthma as well as count of innate lymphoid cells (ILCs) as another source of inflammatory cytokines have been evaluated.
The aim of this study was to evaluate the expression of newly identified helper T cells signature cytokines and amount of ILCs.
Blood and sputum samples from 23 patients with moderate to severe asthma and 23 healthy volunteers were collected. The types of allergens to which our patients were sensitive were defined using immunoblotting method. Gene expression of studied cytokines was evaluated using quantitative transcription-polymerase chain reaction and ILCs were counted by the flow cytometry method.
In this research, the gene expressions of IL-9, IL-17, IL-22, and IL-25 were significantly higher in asthmatics, especially in the severe form of the disease. This increase was even higher in serum samples compared with sputum samples. Counting ILCs revealed their increase in comparison with normal people.
We showed the importance of IL-25, IL-22, IL-17, and IL-9 cytokines in patients with asthma as their expression levels are increased and these increase are correlated with the severity of the disease. We also showed that the increased amount of ILCs in asthmatics could confirm their potential role in the immunopathogenesis of asthma as another source of inflammatory cytokines.
PMCID: PMC4215431  PMID: 25379481
Asthma; Innate lymphoid cell; Inteleukin-9; Inteleukin-17; Inteleukin-22; Inteleukin-25
6.  Genome-Wide Meta-Analysis of Myopia and Hyperopia Provides Evidence for Replication of 11 Loci 
PLoS ONE  2014;9(9):e107110.
Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10−8), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10−11) and 8q12 (minimum p value 1.82×10−11) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. “Replication-level” association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.
PMCID: PMC4169415  PMID: 25233373
7.  Positive and Negative Regulation of Th17 Cell Differentiation: Evaluating The Impact of RORC2 
Cell Journal (Yakhteh)  2014;16(3):343-352.
Th17 cells are known to be involved in some types of inflammations and autoimmune disorders. RORC2 is the key transcription factor coordinating Th17 cell differentiation. Thus, blocking RORC2 may be useful in suppressing Th17-dependent inflammatory processes. The aim was to silence RORC2 by specific siRNAs in naïve T cells differentiating to Th17. Time-dependent expression of RORC2 as well as IL-17 and IL-23R were considered before and after RORC2 silencing.
Materials and Methods
In this experimental study, naïve CD4+T cells were isolated from human cord blood samples. Cytokines TGFß plus IL-6 and IL-23 were used to polarize the naïve T cells to Th17 cells in X-VIVO 15 serum free medium. A mixture of three siRNAs specific for RORC2 was applied for blocking its expression. RORC2, IL-17 and IL-23R mRNA and protein levels were measured using qRT-PCR, ELISA and flow cytometry techniques. Pearson correlation and one-way ANOVA were used for statistical analyses.
Significant correlations were obtained in time-dependent analysis of IL-17 and IL-23R expression in relation with RORC2 (R=0.87 and 0.89 respectively, p<0.05). Silencing of RORC2 was accompanied with almost complete suppression of IL-17 (99.3%; p<0.05) and significant decrease in IL-23R gene expression (77.2%, p<0.05).
Our results showed that RORC2 is the main and the primary trigger for upregulation of IL-17 and IL-23R genes in human Th17 cell differentiation. Moreover, we show that day 3 could be considered as the key day in the Th17 differentiation process.
PMCID: PMC4204187  PMID: 24611151
IL-17; IL-23R; RORC2; siRNA; Th17
8.  The relationship between health literacy with health status and healthcare utilization in 18-64 years old people in Isfahan 
Today, much attention has been paid to the patient role as the central factor in the management of their own health. It is focused on the issue that the patient has a more critical role compared with the health-care provider in controlling the patient own health. defines health literacy as the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions.
The objective of this study was to determine health literacy, health status, healthcare utilization and the relationship between them in 18 - 64 years old people in Isfahan.
Structure and Design:
This study was a descriptive analytical survey, which was conducted on 300 subjects of 18-64 years old in Isfahan with Multi-stage sampling method proportional to selected sample size.
Materials and Methods:
For collecting the data, questionnaire adapted from CHAP (Consumer Assessment of Healthcare Providers and Systems) health literacy questionnaire was used. Health status was measured based on an assessment of the physical and mental health over the past 6 months by 5° Likert scale. Data analysis was performed by using SPSS 18, descriptive statistics, Chi-square test and multivariate analysis of variance.
There was no significant correlation between health literacy, health status and healthcare utilization. Utilization was less in the urban area No. 6 of the city. In the bachelor's degree group, the health status was lower than the other groups in these cases: Older ages, married, women, large family size, undergraduates, and urban area No. 14.
Due to the average prevalence of health literacy in 18-64 years old individuals in Isfahan and low- healthcare utilization, the followings are recommended: Necessity of more attention to the issue of health literacy, improving the physician-patient relationship and community awareness, whether through health promotion programs or media for the optimum use of available resources.
PMCID: PMC4113988  PMID: 25077168
Healthcare utilization; health literacy; health status
9.  GWAS identifies an NAT2 acetylator status tag single nucleotide polymorphism to be a major locus for skin fluorescence 
Diabetologia  2014;57(8):1623-1634.
Skin fluorescence (SF) is a non-invasive marker of AGEs and is associated with the long-term complications of diabetes. SF increases with age and is also greater among individuals with diabetes. A familial correlation of SF suggests that genetics may play a role. We therefore performed parallel genome-wide association studies of SF in two cohorts.
Cohort 1 included 1,082 participants, 35–67 years of age with type 1 diabetes. Cohort 2 included 8,721 participants without diabetes, aged 18–90 years.
rs1495741 was significantly associated with SF in Cohort 1 (p < 6 × 10−10), which is known to tag the NAT2 acetylator phenotype. The fast acetylator genotype was associated with lower SF, explaining up to 15% of the variance. In Cohort 2, the top signal associated with SF (p = 8.3 × 10−42) was rs4921914, also in NAT2, 440 bases upstream of rs1495741 (linkage disequilibrium r2 = 1.0 for rs4921914 with rs1495741). We replicated these results in two additional cohorts, one with and one without type 1 diabetes. Finally, to understand which compounds are contributing to the NAT2–SF signal, we examined 11 compounds assayed from skin biopsies (n = 198): the fast acetylator genotype was associated with lower levels of the AGEs hydroimidazolones of glyoxal (p = 0.017).
We identified a robust association between NAT2 and SF in people with and without diabetes. Our findings provide proof of principle that genetic variation contributes to interindividual SF and that NAT2 acetylation status plays a major role.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-014-3286-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
PMCID: PMC4079945  PMID: 24934506
Acetylation; Genome-wide association study; NAT2; Skin autofluorescence; Skin fluorescence; Skin intrinsic fluorescence
10.  Inhibition of p38 MAPK Signaling Augments Skin Tumorigenesis via NOX2 Driven ROS Generation 
PLoS ONE  2014;9(5):e97245.
p38 mitogen-activated protein kinases (MAPKs) respond to a wide range of extracellular stimuli. While the inhibition of p38 signaling is implicated in the impaired capacity to repair ultraviolet (UV)-induced DNA damage—a primary risk factor for human skin cancers—its mechanism of action in skin carcinogenesis remains unclear, as both anti-proliferative and survival functions have been previously described. In this study, we utilized cultured keratinocytes, murine tumorigenesis models, and human cutaneous squamous cell carcinoma (SCC) specimens to assess the effect of p38 in this regard. UV irradiation of normal human keratinocytes increased the expression of all four p38 isoforms (α/β/γ/δ); whereas irradiation of p53-deficient A431 keratinocytes derived from a human SCC selectively decreased p38α, without affecting other isoforms. p38α levels are decreased in the majority of human cutaneous SCCs assessed by tissue microarray, suggesting a tumor-suppressive effect of p38α in SCC pathogenesis. Genetic and pharmacological inhibition of p38α and in A431 cells increased cell proliferation, which was in turn associated with increases in NAPDH oxidase (NOX2) activity as well as intracellular reactive oxygen species (ROS). These changes led to enhanced invasiveness of A431 cells as assessed by the matrigel invasion assay. Chronic treatment of p53-/-/SKH-1 mice with the p38 inhibitor SB203580 accelerated UV-induced SCC carcinogenesis and increased the expression of NOX2. NOX2 knockdown suppressed the augmented growth of A431 xenografts treated with SB203580. These findings indicate that in the absence of p53, p38α deficiency drives SCC growth and progression that is associated with enhanced NOX2 expression and ROS formation.
PMCID: PMC4019556  PMID: 24824222
11.  Evaluation of the T helper 17 cell specific genes and the innate lymphoid cells counts in the peripheral blood of patients with the common variable immunodeficiency 
Common variable immunodeficiency (CVID) is characterized by a deficiency in the immune system with a heterogeneous collection of disorders resulting in antibody deficiency and recurrent infections. T helper 17 (Th17) cells promote B-cell survival and synergize with the B-cell activating factor to induce their differentiation into the plasma cells. A sub-population of innate lymphoid cells (ILCs) also produces interleukin 17 (IL-17). This study aimed to measure the Th17 specific genes and ILCs counts in the CVID patients in comparison with control subjects.
Materials and Methods:
Total messenger ribonucleic acid (mRNA) was extracted from the whole blood samples of 10 CVID patients and 10 healthy individuals. IL-17, retinoic acid receptor-related orphan receptor C2 (RORC2), IL-23R, and IL-9 gene expression were measured using the quantitative reverse transcriptase-polymerase chain reaction. Count of lineage negative/CD127+/CD90+ ILCs in the blood samples was performed by the flow cytometry method.
The transcript levels of IL-17 and RORC2 in CVID patients was strongly lower than control subjects (P = 0.049 and P = 0.046, respectively), but slight reduction in the IL-23R expression (P = 0.252) have seen in the CVID patients. Accordingly, the number of ILCs decreased significantly (P = 0.04). Interestingly, IL-9 mRNA level was more significantly in the CVID patients (P = 0.001).
The results presented in this study show that the Th17 cell specific genes expression (as the determiner Th17 cells) and ILCs (another lymphoid source of IL-17) are decreased in patients with CVID and this could be an explanation for the defect of their humoral immune response. In addition, elevation of the IL-9 gene expression may shed a new light into the way toward the understanding of the mechanism of autoimmunity in the CVID patients.
PMCID: PMC4078375  PMID: 25002891
Common variable immunodeficiency; innate lymphoid cells; interleukin 9; interleukin 17; interleukin 23R; T helper 17 cells
12.  Comparison of effects of soft margarine, blended, ghee, and unhydrogenated oil with hydrogenated oil on serum lipids: A randomized clinical trail 
ARYA Atherosclerosis  2013;9(6):363-371.
Trans fatty acids (TFAs) are known as the most harmful type of dietary fats. Therefore, this study was done to compare the effects of some different oils including unhydrogenated, blended, ghee, and soft magazine with hydrogenated oil on serum lipid profile of healthy adults.
This study was a randomized clinical trial conducted on 206 healthy participants of 20 to 60 years of age. Subjects were randomly divided into 5 groups and each of them was treated with a diet containing unhydrogenated oil, ghee, blended oil, soft margarine, or hydrogenated oil for 40 days. Fasting serum lipids were measured before and after the study.
Compared to hydrogenated oil, total cholesterol (TC) and triglyceride (TG) had a significant reduction in all groups, LDL-C declined in unhydrogenated oil and soft margarine groups, and apolipoprotein (Apo) B only in unhydrogenated oil group (all P < 0.05). However, there was a significant enhancement in ApoA of ghee oil (P < 0.001).
Consuming unhydrogenated oil, ghee, soft margarine, and blended oil had some beneficial effects on serum lipids.
PMCID: PMC3933054  PMID: 24575140
Clinical Trial; Dietary Fat; Commercial Oil; Lipid
13.  In Vitro Cytotoxicity Assessment of an Orthodontic Composite Containing Titanium-dioxide Nano-particles 
Background and aims. Incorporation of nano-particles to orthodontic bonding systems has been considered to prevent enamel demineralization around appliances. This study investigated cytotoxicity of Transbond XT adhesive containing 1 wt% titanium dioxide (TiO2) nano-particles.
Materials and methods. Ten composite disks were prepared from each of the conventional and TiO2-containg composites and aged for 1, 3, 5, 7 and 14 days in Dulbecco’s Modified Eagle’s Medium (DMEM). The extracts were obtained and exposed to culture media of human gingival fibroblasts (HGF) and mouse L929 fibroblasts. Cell viability was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.
Results. Both adhesives were moderately toxic for HGF cells on the first day of the experiment, but the TiO2-containing adhesive produced significantly lower toxicity than the pure adhesive (P<0.05). No significant differences were found in cell viability percentages between the two groups on the other days (P>0.05). There was a significant reduction in cell toxicity with increasing pre-incubation time (P<0.001). L929 cells showed similar toxicity trends, but lower sensitivity to detect cytotoxicity of dental composites.
Conclusion. The orthodontic adhesive containing TiO2 nano-particles indicated comparable or even lower toxicity than its nano-particle-free counterpart, indicating that incorporation of 1 wt% TiO2 nano-particles to the composite structure does not result in additional health hazards compared to that occurring with the pure adhesive.
PMCID: PMC3935549  PMID: 24578816
Adhesive; biocompatibility; cytotoxicity; nano-particles; orthodontics; titanium dioxide
14.  Genome-wide meta-analyses of multi-ethnic cohorts identify multiple new susceptibility loci for refractive error and myopia 
Verhoeven, Virginie J.M. | Hysi, Pirro G. | Wojciechowski, Robert | Fan, Qiao | Guggenheim, Jeremy A. | Höhn, René | MacGregor, Stuart | Hewitt, Alex W. | Nag, Abhishek | Cheng, Ching-Yu | Yonova-Doing, Ekaterina | Zhou, Xin | Ikram, M. Kamran | Buitendijk, Gabriëlle H.S. | McMahon, George | Kemp, John P. | St. Pourcain, Beate | Simpson, Claire L. | Mäkelä, Kari-Matti | Lehtimäki, Terho | Kähönen, Mika | Paterson, Andrew D. | Hosseini, S. Mohsen | Wong, Hoi Suen | Xu, Liang | Jonas, Jost B. | Pärssinen, Olavi | Wedenoja, Juho | Yip, Shea Ping | Ho, Daniel W. H. | Pang, Chi Pui | Chen, Li Jia | Burdon, Kathryn P. | Craig, Jamie E. | Klein, Barbara E. K. | Klein, Ronald | Haller, Toomas | Metspalu, Andres | Khor, Chiea-Chuen | Tai, E-Shyong | Aung, Tin | Vithana, Eranga | Tay, Wan-Ting | Barathi, Veluchamy A. | Chen, Peng | Li, Ruoying | Liao, Jiemin | Zheng, Yingfeng | Ong, Rick T. | Döring, Angela | Evans, David M. | Timpson, Nicholas J. | Verkerk, Annemieke J.M.H. | Meitinger, Thomas | Raitakari, Olli | Hawthorne, Felicia | Spector, Tim D. | Karssen, Lennart C. | Pirastu, Mario | Murgia, Federico | Ang, Wei | Mishra, Aniket | Montgomery, Grant W. | Pennell, Craig E. | Cumberland, Phillippa M. | Cotlarciuc, Ioana | Mitchell, Paul | Wang, Jie Jin | Schache, Maria | Janmahasathian, Sarayut | Igo, Robert P. | Lass, Jonathan H. | Chew, Emily | Iyengar, Sudha K. | Gorgels, Theo G.M.F. | Rudan, Igor | Hayward, Caroline | Wright, Alan F. | Polasek, Ozren | Vatavuk, Zoran | Wilson, James F. | Fleck, Brian | Zeller, Tanja | Mirshahi, Alireza | Müller, Christian | Uitterlinden, Andre’ G. | Rivadeneira, Fernando | Vingerling, Johannes R. | Hofman, Albert | Oostra, Ben A. | Amin, Najaf | Bergen, Arthur A.B. | Teo, Yik-Ying | Rahi, Jugnoo S. | Vitart, Veronique | Williams, Cathy | Baird, Paul N. | Wong, Tien-Yin | Oexle, Konrad | Pfeiffer, Norbert | Mackey, David A. | Young, Terri L. | van Duijn, Cornelia M. | Saw, Seang-Mei | Wilson, Joan E. Bailey | Stambolian, Dwight | Klaver, Caroline C. | Hammond, Christopher J.
Nature genetics  2013;45(3):314-318.
Refractive error is the most common eye disorder worldwide, and a prominent cause of blindness. Myopia affects over 30% of Western populations, and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses including 37,382 individuals from 27 studies of European ancestry, and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in subjects of European ancestry, of which 8 were shared with Asians. Combined analysis revealed 8 additional loci. The new loci include genes with functions in neurotransmission (GRIA4), ion channels (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2, BMP2), and eye development (SIX6, PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1. Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for subjects with the highest genetic load. Our results, accumulated across independent multi-ethnic studies, considerably advance understanding of mechanisms involved in refractive error and myopia.
PMCID: PMC3740568  PMID: 23396134
15.  The Direct Medical Costs of Breast Cancer in Iran: Analyzing the Patient's Level Data from a Cancer Specific Hospital in Isfahan 
Breast cancer is one of the main causes of mortality and morbidity world-wide. The estimation of the direct medical costs of breast cancer can help payers of the cost to understand the burden of breast cancer on their limited financial resources as well as the society.
We used a cross-sectional study to calculate the direct medical costs of breast cancer among women in Isfahan, Iran. The medical records of all patients which were registered in Seyed Al-Shohada Hospital between March 2005 and March 2010 were reviewed. The relevant data from patients’ profiles extracted. The direct medical costs of received services were calculated with both public and private tariffs.
The total numbers of 467 patients in various disease stages were included into the study. The average age of patients was 49 years. The average direct cost per patient per month in stages I to IV were 222.17, 224.61, 316.51 and 828.52 US$, respectively. The surgery cost was the main cost driver for stages I and II with private tariffs. However for stages III and IV, the medication cost was the main cost component for managing breast cancer.
The direct economic cost of breast cancer in Iran is very high; nonetheless, as the age of breast cancer in Iran is nearly 10 years lower than Western countries, the burden of the disease in Iran is expected to be significantly high. Medication therapy is the main cost component of the breast cancer.
PMCID: PMC3775213  PMID: 24049592
Breast cancer; costs analysis; direct medical cost; Iran
16.  First Report on Self-Rated Health in a Nationally-Representative Sample of Iranian Adolescents: The CASPIAN-iii study 
To evaluate predictive factors of adolescents’ appraisal of their health.
The nationwide study, entitled “Childhood and Adolescence Surveillance and Prevention of Adult Non-communicable Diseases (CASPIAN) study”, was conducted in 2010 among Iranian school students, aged 10-18. In addition to demographic factors and physical examination, variables as family structure, nutrition habits, physical activity, smoking, hygienic habits, violence, school attachment, family smoking, and family history of chronic diseases were assessed. The dependent variable is the self-rated health (SRH) and it was measured by 12 items, which had already been combined through latent class analysis. We had taken a dichotomous variable, i.e. the higher values indicate better SRH. The dependent variable was regressed on all predictors by generalized additive models.
75% of adolescents had a good SRH. The linear and smooth effects of independent variables on SRH were observed. Among all the variables, physical activity had a positive linear effect on SRH (β = 0.08, P value = 0.003). Smoking, violence, and family history of disease associated to SRH non-linearly (P value < 0.05). Family smoking (β = −0.01) and hygienic habits (β = 0.27) related to SRH both linearly and non-linearly.
Physical health and high risk behavior, either of linear or non-linear effect, are factors, which seem to shape the adolescents’ perception of health.
PMCID: PMC3604845  PMID: 23543891
Adolescents; health status; health status indicator; logistic models; non-parametric statistics; school; self-report
17.  RORC2 Gene Silencing in Human Th17 Cells by siRNA: Design and Evaluation of Highly Efficient siRNA 
RNA interference-based gene silencing has recently been applied as an efficient tool for functional gene analysis. RORC2 is the key transcription factor orchestrating Th17 cells differentiation, the cells that are known as the pathogenic elements in various autoimmune diseases. The aim of this study was to design efficient siRNAs specific for RORC2 and to evaluate different criteria affecting their functionality.
Three siRNA duplexes specific for RORC2 mRNA were designed. Th17 cells were produced from IL-6 and IL-1 treated cord blood CD4+ T cells. The T cells were transfected with three different designed siRNAs against RORC2 and the expression of RORC2 gene was measured using quantitative real time PCR.
Different levels of RORC2 down regulation were observed in the presence of each of the designed siRNAs. Efficient siRNA with 91.1% silencing activity met the majority of the established bioinformatics criteria while the one with 46.6% silencing activity had more deviations from these criteria.
The more bioinformatics criteria are considered, the more functionality were observed for silencing RORC2. However, the importance of the type of criteria per se should not be neglected. Although all recommended criteria are important for designing siRNA but their value is not the same.
PMCID: PMC3572701  PMID: 23626872
RNAi; siRNA; Th17 cells
18.  New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes 
Sandholm, Niina | Salem, Rany M. | McKnight, Amy Jayne | Brennan, Eoin P. | Forsblom, Carol | Isakova, Tamara | McKay, Gareth J. | Williams, Winfred W. | Sadlier, Denise M. | Mäkinen, Ville-Petteri | Swan, Elizabeth J. | Palmer, Cameron | Boright, Andrew P. | Ahlqvist, Emma | Deshmukh, Harshal A. | Keller, Benjamin J. | Huang, Huateng | Ahola, Aila J. | Fagerholm, Emma | Gordin, Daniel | Harjutsalo, Valma | He, Bing | Heikkilä, Outi | Hietala, Kustaa | Kytö, Janne | Lahermo, Päivi | Lehto, Markku | Lithovius, Raija | Österholm, Anne-May | Parkkonen, Maija | Pitkäniemi, Janne | Rosengård-Bärlund, Milla | Saraheimo, Markku | Sarti, Cinzia | Söderlund, Jenny | Soro-Paavonen, Aino | Syreeni, Anna | Thorn, Lena M. | Tikkanen, Heikki | Tolonen, Nina | Tryggvason, Karl | Tuomilehto, Jaakko | Wadén, Johan | Gill, Geoffrey V. | Prior, Sarah | Guiducci, Candace | Mirel, Daniel B. | Taylor, Andrew | Hosseini, S. Mohsen | Parving, Hans-Henrik | Rossing, Peter | Tarnow, Lise | Ladenvall, Claes | Alhenc-Gelas, François | Lefebvre, Pierre | Rigalleau, Vincent | Roussel, Ronan | Tregouet, David-Alexandre | Maestroni, Anna | Maestroni, Silvia | Falhammar, Henrik | Gu, Tianwei | Möllsten, Anna | Cimponeriu, Danut | Ioana, Mihai | Mota, Maria | Mota, Eugen | Serafinceanu, Cristian | Stavarachi, Monica | Hanson, Robert L. | Nelson, Robert G. | Kretzler, Matthias | Colhoun, Helen M. | Panduru, Nicolae Mircea | Gu, Harvest F. | Brismar, Kerstin | Zerbini, Gianpaolo | Hadjadj, Samy | Marre, Michel | Groop, Leif | Lajer, Maria | Bull, Shelley B. | Waggott, Daryl | Paterson, Andrew D. | Savage, David A. | Bain, Stephen C. | Martin, Finian | Hirschhorn, Joel N. | Godson, Catherine | Florez, Jose C. | Groop, Per-Henrik | Maxwell, Alexander P.
PLoS Genetics  2012;8(9):e1002921.
Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ∼2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2×10−8) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0×10−9). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1×10−7), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.
Author Summary
The global prevalence of diabetes has reached epidemic proportions, constituting a major health care problem worldwide. Diabetic kidney disease, or diabetic nephropathy (DN)—the major long term microvascular complication of diabetes—is associated with excess mortality among patients with type 1 diabetes. Even though DN has been shown to cluster in families, the underlying genetic and molecular pathways remain poorly defined. We have undertaken the largest genome-wide association study and meta-analysis to date on DN and on its most severe form of kidney disease, end-stage renal disease (ESRD). We identified new loci significantly associated with diabetic ESRD: AFF3 and an intergenic locus on chromosome 15q26 residing between RGMA and MCTP2. Our functional analyses suggest that AFF3 influences renal tubule fibrosis, a pathological hallmark of severe DN. Another locus in ERBB4 was suggestively associated with DN and resides in the same intronic region as a variant affecting the expression of ERBB4. Subsequent pathway analysis of the genes co-expressed with ERBB4 indicated involvement of fibrosis.
PMCID: PMC3447939  PMID: 23028342
19.  Effects of dietary supplementation with ghee, hydrogenated oil, or olive oil on lipid profile and fatty streak formation in rabbits 
ARYA Atherosclerosis  2012;8(3):119-124.
Coronary heart disease is the leading cause of mortality worldwide. A high-fat diet, rich in saturated fatty acids and low in polyunsaturated fatty acids, is said to be an important cause of atherosclerosis and cardiovascular diseases.
In this experimental study, 40 male rabbits were randomly assigned to eight groups of five to receive normal diet, hypercholesterolemic diet, normal diet plus ghee, normal diet plus olive oil, normal diet plus hydrogenated oil, hypercholesterolemic diet plus ghee, hypercholesterolemic diet plus olive oil, and hypercholesterolemic diet plus hydrogenated oil. They received rabbit chow for a period of 12 weeks. At the start and end of the study, fasting blood samples were taken from all animals to measure biochemical factors including total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride (TG), fasting blood sugar (FBS), and C-reactive protein (CRP). Moreover, aorta, left and right coronary arteries were dissected at the end of the study to investigate fatty streak formation (FSF). Data was analyzed in SPSS at a significance level of 0.05.
In rabbits under normal diet, ghee significantly increased TC, LDL, and HDL compared to the beginning (P < 0.01) and also to the other two types of fat (P < 0.05). Moreover, normal diet plus olive oil significantly enhanced FSF in left coronary arteries and aorta compared to normal diet plus ghee. In groups receiving hypercholesterolemic diets, ghee significantly increased HDL and CRP (P < 0.05) and significantly decreased FBS (P < 0.01). The hypecholesterolemic diet plus olive oil significantly increased HDL (P < 0.01). Supplementation of hypecholesterolemic diet with ghee significantly increased HDL and FBS in comparison with hydrogenated oil. Significant increase of FBS was also detected with the use of ghee compared to olive oil. Ghee also significantly reduced FSF in left and right coronary arteries compared to olive oil. FSF in left coronary arteries was significantly lower in the hypecholesterolemic diet plus ghee group compared to the hypecholesterolemic diet plus hydrogenated oil group.
According to the achieved results, future clinical trial studies and investigation of other risk factors such as inflammatory factors are required.
PMCID: PMC3557004  PMID: 23358722
Fatty Streak; Ghee; Hypercholesterolemic; Olive Oil
20.  Common Genetic Determinants of Intraocular Pressure and Primary Open-Angle Glaucoma 
PLoS Genetics  2012;8(5):e1002611.
Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p = 1.4×10−8), and with rs7555523, located in TMCO1 at 1q24.1 (p = 1.6×10−8). In a meta-analysis of 4 case-control studies (total N = 1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p = 2.4×10−2 for rs11656696 and p = 9.1×10−4 for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation.
Author Summary
Glaucoma is a major eye disease in the elderly and is the second leading cause of blindness worldwide. The numerous familial glaucoma cases, as well as evidence from epidemiological and twin studies, strongly support a genetic component in developing glaucoma. However, it has proven difficult to identify the specific genes involved. Intraocular pressure (IOP) is the major risk factor for glaucoma and the only target for the current glaucoma therapy. IOP has been shown to be highly heritable. We investigated the role of common genetic variants in IOP by performing a genome-wide association study. Discovery analyses in 11,972 participants and subsequent replication analyses in a further 7,482 participants yielded two common genetic variants that were associated with IOP. The first (rs11656696) is located in GAS7 at chromosome 17, the second (rs7555523) in TMCO1 at chromosome 1. Both variants were associated with glaucoma in a meta-analysis of 4 case-control studies. GAS7 and TMCO1 are expressed in the ocular tissues that are involved in glaucoma. Both genes functionally interact with the known glaucoma disease genes. These data suggest that we have identified two genes involved in IOP regulation and glaucomatous neuropathy.
PMCID: PMC3342933  PMID: 22570627
21.  The relationship between occupational radiation exposure and thyroid nodules 
Considering that thyroid nodules and thyroid cancer occur more frequently in people chronically exposed to radiation, the aim of this study was to evaluate the prevalence of thyroid nodules in a population occupationally exposed to radiation in hospitals of Isfahan, Iran.
Materials and Methods:
In this case-control study, the prevalence of thyroid nodules in staff members occupationally exposed to radiation was determined by ultrasonography. The results were compared with the results of another study among the adult population of Isfahan which selected by cluster random sampling method. The 2 studied groups were matched according to sex and age.
The case and control groups included 124 and 471 persons, respectively. The prevalence of thyroid nodules in the case and control groups was 22.6% and 24.6%, respectively (p > 0.05). Although thyroid nodules were significantly more prevalent in females in the control group, no such difference was observed between females and males of the case group (p > 0.05). The number of thyroid nodules (single or multiple) and calcification were not different between the two groups (p > 0.05). In addition, hypoechogenicity of thyroid nodules was not different between the two groups for (p > 0.05).
In our study, there was not any correlation between chronic occupational exposure to low dose of radiation and the risk of developing thyroid nodules. Further studies with larger sample sizes, at different doses of radiation, and considering iodine status and thyroid function are thus required.
PMCID: PMC3634267  PMID: 23626606
Thyroid Nodule; Radiation; Occupational Exposure; Ultrasonography
22.  Assessing Awareness Level about Warning Signs of Cancer and its Determinants in an Iranian General Population 
The present study was aimed at investigating the awareness level about warning signs of cancer and its determinants in an Iranian general population. This cross-sectional interview-based survey investigated 2,500 people aged 18 years and over, as a representative sample of Tehran population. Latent class regression was applied for analyzing data. A small (18.8%) proportion of the respondents had high level of knowledge, and 54.5% had moderate awareness, and 26.7% had low level of awareness. Most effective predictors for awareness were educational attainment, sex, and marital status. The findings suggest that the overall level of knowledge about warning signs of cancer among the public is low, particularly about some specific signs. Accordingly, educational and intervention programmes, with special attention placed on particular at-risk populations, to increase awareness about the disease leading to its early diagnosis are needed.
PMCID: PMC3259730  PMID: 22283041
Awareness; Cancer; Cross-sectional studies; Health education; Neoplasms; Public education; Signs and symptoms; Iran
23.  Genome-Wide Association Identifies the ABO Blood Group as a Major Locus Associated With Serum Levels of Soluble E-Selectin 
Elevated serum soluble E-selectin levels have been associated with a number of diseases. Although E-selectin levels are heritable, little is known about the specific genetic factors involved. E-selectin levels have been associated with the ABO blood group phenotype.
Methods and Results
We performed a high-resolution genome-wide association study of serum soluble E-selectin levels in 685 white individuals with type 1 diabetes from the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Intervention and Complications (EDIC) study to identify major loci influencing levels. Highly significant evidence for association (P=10−29) was observed for rs579459 near the ABO blood group gene, accounting for 19% of the variance in E-selectin levels. Levels of E-selectin were higher in O/O than O/A heterozygotes, which were likewise higher than A/A genotypes. Analysis of subgroups of A alleles reveals heterogeneity in the association, and even after this was accounted for, an intron 1 SNP remained significantly associated. We replicate the ABO association in nondiabetic individuals.
ABO is a major locus for serum soluble E-selectin levels. We excluded population stratification, fine-mapped the association to sub-A alleles, and also document association with additional variation in the ABO region.
PMCID: PMC3147250  PMID: 19729612
E-selectin; ABO blood group; genome-wide association; SNP
24.  A Genome-Wide Association Study Identifies a Novel Major Locus for Glycemic Control in Type 1 Diabetes, as Measured by Both A1C and Glucose 
Diabetes  2009;59(2):539-549.
Glycemia is a major risk factor for the development of long-term complications in type 1 diabetes; however, no specific genetic loci have been identified for glycemic control in individuals with type 1 diabetes. To identify such loci in type 1 diabetes, we analyzed longitudinal repeated measures of A1C from the Diabetes Control and Complications Trial.
We performed a genome-wide association study using the mean of quarterly A1C values measured over 6.5 years, separately in the conventional (n = 667) and intensive (n = 637) treatment groups of the DCCT. At loci of interest, linear mixed models were used to take advantage of all the repeated measures. We then assessed the association of these loci with capillary glucose and repeated measures of multiple complications of diabetes.
We identified a major locus for A1C levels in the conventional treatment group near SORCS1 (10q25.1, P = 7 × 10−10), which was also associated with mean glucose (P = 2 × 10−5). This was confirmed using A1C in the intensive treatment group (P = 0.01). Other loci achieved evidence close to genome-wide significance: 14q32.13 (GSC) and 9p22 (BNC2) in the combined treatment groups and 15q21.3 (WDR72) in the intensive group. Further, these loci gave evidence for association with diabetic complications, specifically SORCS1 with hypoglycemia and BNC2 with renal and retinal complications. We replicated the SORCS1 association in Genetics of Diabetes in Kidneys (GoKinD) study control subjects (P = 0.01) and the BNC2 association with A1C in nondiabetic individuals.
A major locus for A1C and glucose in individuals with diabetes is near SORCS1. This may influence the design and analysis of genetic studies attempting to identify risk factors for long-term diabetic complications.
PMCID: PMC2809960  PMID: 19875614
25.  Barriers to Physical Activity in a Population-based Sample of Children and Adolescents in Isfahan, Iran 
This study was conducted to explore the barriers to physical activity in a representative sample of Iranian children and adolescents.
The study was conducted in 2007 in urban and rural areas of Isfahan district in Iran. In the qualitative part, we used the grounded theory approach, including semi-structured focus group discussions and indepth interviews. The quantitative part comprised 600 randomly selected students.
The qualitative study included 34 school students (16 girls), 20 parents (11 mothers) and 11 school staff. All students disclosed that studying was a priority. They pointed to lack of safe and easy-access place for physical activity and unsupportive family as the main barriers. Lack of self-confidence and low selfworth were the two other concepts developed in this context. Parents pointed to lack of safe and easy-access place for activity followed by the priority of studying. The concepts derived from interviews with school staff included unhealthy modeling of parents, priority of studying, and inadequate public knowledge about how to integrate physical activity in routine daily life. The quantitative survey comprised 600 students including 286 (47.8%) girls. Parents’ education level had inverse association with children’s physical activity level. Significant inverse associations of self-efficacy and physical activity levels were documented.
Increasing the public knowledge about adopting physical activity habits in routine daily life, informing the families and students about the benefits of physical activity to improve learning, as well as providing safe places such as using the school facilities in non-school hours should be considered in planning effective preventive strategies and interventions.
PMCID: PMC3075475  PMID: 21566774
Physical activity; Pediatric; Barriers; Prevention; Iran

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