GG Homozygosity Research Articles

Analysis of IL-17A, IL-17F, and miR-146a-5p Prior to Transplantation and Their Role in Kidney Transplant Recipients

Background/Objectives: The balance between regulatory and Th17 cells plays an important role in maintaining the immune tolerance after kidney transplantation (KTx) which is essential for transplantation success, defined as a long graft survival and an absence of organ rejection. The present study aimed to assess whether the pretransplant characteristics of IL-17A and IL-17F, their receptors, as well as miR-146a-5p, an miRNA associated with IL-17A/F regulation, can predict KTx outcomes. Methods: A group of 108 pre-KTx dialysis patients and 125 healthy controls were investigated for single nucleotide substitutions within genes coding for IL-17A, IL-17F, their IL-17RA/RC receptors, and miR-146a-5p. Genotyping was performed using LightSNiP assays. In addition, IL17-A/F serum concentrations were determined using ELISA while miR-146a-5p expression was analyzed by RT-PCR. Results: The IL-17F (rs763780) G allele prevailed in KTx recipients as compared to healthy individuals (OR = 23.59, p < 0.0001) and was associated with a higher IL-17F serum level (p = 0.0381) prior to transplantation. Higher miR-146a-5p expression before KTx was more frequently detected in recipients with an increased IL-17A serum concentration (p = 0.0177). Moreover, IL-17A (rs2275913) GG homozygosity was found to be associated with an increased incidence of deaths before KTx (OR = 4.17, p = 0.0307). T-cell or acute rejection episodes were more frequently observed among patients with the C allele of miR-146a-5p (rs2910164) (OR = 5.38, p = 0.0531). IL17-RA/-RC genetic variants (p < 0.05) seem to be associated with eGFR values. Conclusions: These results imply that IL-17F (rs763780) polymorphism is associated with the serum level of this cytokine and may be related to the risk of renal disease and transplant rejection together with miR-146a-5p (rs2910164), while the IL-17A (rs2275913) genotype may affect patients’ survival before KTx.

Impact of single-nucleotide variants and nutritional status on population pharmacokinetics of Doxorubicin, and its effect on cardiotoxicity in children with leukemia.

Doxorubicin is an important antineoplastic agent with wide interindividual variability in response to treatment and in its cardiotoxic effects. To determine the effect of genotypic status of three single-nucleotide variants in ABCC1, NCF4, and CBR3 genes and nutritional status assessed by body mass index, on the population pharmacokinetics of Doxorubicin and its cardiotoxic effects in pediatric patients with leukemia. Seventy pediatric patients treated with Doxorubicin were studied, in which 189 biological samples were obtained to determine Doxorubicin concentrations (1 to 3 samples per patient) at different times, for 20 h. Low body mass index and age ≤ 7 years were associated with decreased clearance of Doxorubicin, and female gender was associated with increased clearance of Doxorubicin. Low BMI and low height were associated with a decrease and increase, respectively, in the intercompartmental clearance (Q) of Doxorubicin. TT homozygosity of the single-nucleotide variant rs3743527 of the ABCC1 gene was associated with an increase in clearance and decreased area under the curve, AA homozygosity of the single-nucleotide variant rs1883112 of the NCF4 gene was associated with a decrease in the volume of distribution in the peripheral compartment (V2), and GG homozygosity of CBR3 rs1056892 with increasing area under the curve. Some covariates studied are directly related to the increase or decrease of the pharmacokinetic parameters of Doxorubicin. Decreased clearance, V2, and increased area under the curve were associated with systolic dysfunction, and decreased Q and V2 were associated with diastolic dysfunction. These results may contribute to the effective and safe use of Doxorubicin in pediatric patients with leukemia.

Polymorphisms within the RANK and RANKL Encoding Genes in Patients with Rheumatoid Arthritis: Association with Disease Progression and Effectiveness of the Biological Treatment

Inconsistency of the results regarding the genetic variability within genes coding for receptor activator of nuclear factor κB (RANK) and its ligand (RANKL) in rheumatoid arthritis (RA) prompted us to study the RANK and RANKL polymorphisms as potential biomarkers associated with disease predisposition and response to anti-TNF treatment in a group of Polish patients with RA. This study enrolled 318 RA patients and 163 controls. RANK (rs8086340, C > G; rs1805034, C > T) and RANKL (rs7325635, G > A; rs7988338 G > A) alleles were determined by real-time PCR with melting curve analysis and related with clinical parameters. In addition, RANKL serum levels were measured by ELISA. The RANK rs8086340-G allele was overrepresented among patients as compared to controls (OD = 1.777, p = 0.038). C-reactive protein (CRP) levels were significantly (p < 0.05) associated with RANK rs8086340 polymorphism and were higher in the CC-homozygotes at the baseline while lower in the GG-carriers at the 12th week of the treatment. At the latter time point RANKL rs7325635-GG-positive patients also showed significantly lower CRP concentrations. Higher alkaline phosphatase levels before induction of anti-TNF therapy were observed in RANK rs8086340 and RANK rs1805034 CC homozygotes (p = 0.057 and p = 0.035, respectively). The GG homozygosity of both RANKL single nucleotide polymorphisms was significantly associated with the number of swollen joints (rs7988338 and rs7325635, before and at the 12th week of therapy, respectively, p < 0.05 in both cases). These results imply that polymorphisms within the RANK and RANKL genes affect RA susceptibility and anti-TNF treatment outcome.

Association between PNPLA3 rs738409 G variant and MRI cerebrovascular disease biomarkers

IntroductionNonalcoholic fatty liver disease (NAFLD) has been associated with greater cerebral white matter hyperintensity (WMH) volume and microbleeds. The adiponutrin (PNPLA3) rs738409 G variant, a robust NAFLD susceptibility variant, has been variably associated with carotid atherosclerosis. We hypothesized that this variant is associated with WMH volume, microbleeds, covert brain infarction (CBI), and small perivascular spaces. MethodsWe performed a cross-sectional analysis of the Northern Manhattan Study-MRI Substudy. The associations between the rs738409 G variant allele and outcomes were assessed using linear regression for WMH volume, logistic regression for microbleeds and CBI, and Poisson regression for small perivascular spaces. Models were adjusted for age, sex, principal components, diabetes, and body mass index. ResultsWe included 1063 Northern Manhattan Study participants who had brain MRI and genotype data available (mean age 70 ± 9 years, 61% women). The G allele frequency was 24%. The prevalence of any microbleeds and CBI were 8% and 18%, respectively. The median WMH volume and small perivascular space count score were 7.7 mL and 6, respectively. GG homozygosity, but not heterozygosity, was associated with WMH volume (β = 0.27; 95% CI, 0.03, 0.51) compared to non-carriers. Having at least one G allele was associated with the presence of microbleeds (Odds ratio, 1.78; 95% CI, 1.02, 3.12); the association was attenuated in other models. No associations were observed for CBI and small perivascular spaces. ConclusionThe PNPLA3 rs738409 G allele was associated with greater WMH volume, and inconsistent associations with microbleeds were seen.

Genetic basis of sleep bruxism and sleep apnea\u2014response to a medical puzzle

Sleep bruxism (SB) and obstructive sleep apnea (OSA) are co-occurring sleep conditions. The study aimed to evaluate the association of selected single-nucleotide polymorphisms (SNPs) occurring within the genes of the serotonin and dopamine pathways in SB and OSA and investigate the relationship between them. The study group included 100 Caucasian patients. SB and OSA were diagnosed in 74 and 28 patients, respectively. In addition, 125 unrelated Caucasian healthy blood donors served as randomly selected controls to enable comparison of polymorphisms. The following SNPs were analyzed: rs2770304 and rs6313 within the serotonin receptor encoding gene (HTR2A), rs4680 polymorphism of the catechol-O-methyltransferase (COMT) gene, and rs686 within the dopamine receptor (DRD1) encoding gene. The prevalence of the DRD1 rs686 G variant (GG homozygosity) was found to be high in the study group compared to the control group. Bruxism episode index (BEI) was found to be significantly increased in the HTR2A rs6313 TT homozygotes compared to the heterozygous patients. Moreover, within a group of the HTR2A rs2770304 TT homozygous cases, a statistically significant correlation was observed between BEI and apnea–hypopnea index. These results indicate that DRD1 rs686 may potentially affect predisposition to SB, that HTR2A rs6313 SNP may be involved in SB pathogenesis, and that HTR2A rs2770304 polymorphism might contribute to the association between SB and OSA. This suggests a possible genetic contribution to the etiology of primary SB.

Evaluation of TNF-\u03b1 genetic polymorphisms as predictors for sepsis susceptibility and progression

BackgroundThe goal of the study was to evaluate a potential role for tumor necrosis factor alpha (TNF-α) genetic variability as biomarker in sepsis. In particular, we aimed to determine if single nucleotide polymorphisms (SNPs) of TNF-α gene are associated with sepsis in terms of risk, severity and outcome.MethodsWe performed a prospective study on 163 adult critically ill septic patients (septic shock 65, sepsis 98, further divided in 40 survivors and 123 deceased) and 232 healthy controls. Genotyping of TNF-α SNPs (-308G/A, -238G/A, -376G/A and +489G/A) was performed for all patients and controls and plasma cytokine levels were measured during the first 24 h after sepsis onset.ResultsTNF-α +489G/A A-allele carriage was associated with significantly lower risk of developing sepsis and sepsis shock (AA+AG vs GG: OR = 0.53; p = 0.004; 95% CI = 0.34–0.82 and OR = 0.39; p = 0.003; 95% CI = 0.21–0.74, respectively) but not with sepsis-related outcomes. There was no significant association between any of the other TNF-α promoter SNPs, or their haplotype frequencies and sepsis or septic shock risk. Circulating TNF-α levels were higher in septic shock; they were not correlated with SNP genotype distribution; GG homozygosity for each polymorphism was correlated with higher TNF-α levels in septic shock.ConclusionsTNF-α +489G/A SNP A-allele carriage may confer protection against sepsis and septic shock development but apparently does not influence sepsis-related mortality. Promoter TNF-α SNPs did not affect transcription and were not associated with distinct sepsis, septic shock risk or outcomes.

Association of Interleukin 10 (IL-10) Gene with Type 2 Diabetes Mellitus by Single Nucleotide Polymorphism of Its Promotor Region G/A 1082.

Interleukin 10 (IL-10) is an anti-inflammatory cytokine with lower circulating levels in patients with type 2 diabetes mellitus (T2DM). Cytokines such as IL-10 downregulate the production of pro-inflammatory cytokines, which impair proper function of insulin. So any mutation in the IL-10 gene results in increased production of proinflammatory cytokines, which in turn affect insulin action and cause T2DM. In this study, a polymorphism (rs1800896) in the gene (IL-10) and its association with T2DM was determined with the amplification-refractory mutation system with PCR (ARMS-PCR). Study subjects were divided in two groups, control and T2DM. DNA was extracted from blood, and ARMS-PCR was performed by using specific primers for the promoter region. An amplified product was obtained at 258 base pairs (bp). In the control group, heterozygous bands with both alleles (A/G) were present, whereas AA and GG homozygosity was observed in the T2DM group. This polymorphism (rs1800896) in the IL-10 gene is associated with T2DM. Physical measurements were also obtained, and significant differences between the groups were determined with an independent t-test. Significance was based on a p-value level of 0.05 or less, and highly significant was based on a p-value of 0.01 or less at 95% confidence interval.

ECCR1 and NFKB2 Polymorphisms as Potential Biomarkers of Non-small Cell Lung Cancer in a Polish Population.

Although genetic factors are presumed to account only for a part of the inter-individual variation in lung cancer susceptibility, the results are conflicting and there are no data available regarding the Polish population. We, therefore, performed a case-control study to investigate the association of seven selected single nucleotide polymorphisms (SNPs), in genes coding for excision repair cross-complimentary group 1 (ERCC1: rs11615, rs3212986, rs2298881), nuclear factor ĸB (NFKB2: rs7897947, rs12769316), bone morphogenetic protein 4 (BMP4: rs1957860), complement receptor 1 (CR1: rs7525160) and del/ins polymorphism in the family hypoxia inducible factor 2 gene (EGLN2: rs10680577), with non-small cell lung cancer (NSCLC) risk. Real-time PCR with melting curve analysis was used for genotyping of NSCLC patients and healthy individuals of Polish origin. The ERCC1 rs11615 T allele and rs3212986 GG homozygosity were found to be associated with a higher risk of developing NSCLC. In addition, NFKB2 rs12769316 GG homozygosity was more frequently detected among male patients than controls, while no significant differences were found between the five polymorphisms. ERCC1 polymorphisms may affect NSCLC risk in the Polish population, while the NFKB2 variant may be a possible marker of the disease in males.

Genetic profiling of ocular inflammation: further evidence for a gender-specific association of C5 with uveitis

// Ming Ming Yang 1 , Xiao Yuan Wang 1 , Ying Wei Liu 2 , Li Dong 1 , De Ju Kong 1 , Hong Yan Sun 1 , Jiao Jie Fan 1 , Xu Hui Yu 1 , and Jun Wang 3 1 Eye Hospital, The First Affiliated Hospital of Harbin Medical University, Harbin, China 2 Department of Ophthalmology, Hongqi Hospital of Mudanjiang Medical University, Mudanjiang, China 3 Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China Correspondence to: Jun Wang, email: wangjun4622@163.com Keywords: complement system; C5; ocular inflammation; uveitis; molecular genetics Received: September 19, 2017&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: February 13, 2018&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: February 17, 2018 ABSTRACT Objective: Uveitis is a major cause for visual impairment, our previous studies have made significant advancements in depicting the genetic profile of complement genes in uveitis. This study aimed to further investigate whether the terminal pathway gene, Complement component 5 ( C5 ), confers susceptibility to uveitis. Methods: Six tagging SNPs in C5 were genotyped in 592 unrelated study subjects: 141 anterior uveitis patients, 158 patients with non-infectious intermediate and posterior uveitis, and 293 controls. Multiple in-depth analyses have been conducted. Results: Among the six C5 SNPs, rs17611 was significantly associated with uveitis after adjusted for gender and SNP-gender interaction ( P = 0.017). After stratification by gender, rs17611 G allele and GG homozygosity confers an increased risk for uveitis in males ( P = 0.004, OR = 1.67 and P = 0.009, OR = 2.69, respectively) but not in females. Moreover, genotype-phenotype correlation analysis revealed an association between rs17611 and disease recurrence ( P = 0.045). The haplotype GC, defined by rs17611 and rs2269066, was also found to be associated with total uveitis and specific intermediate and posterior uveitis subtype ( P = 0.0055, OR = 1.51 and P = 0.0084, OR = 1.58, respectively). Other polymorphisms were not significantly associated with either investigated uveitis entities. Conclusions: This study shows a gender-specific association of C5 -rs17611 with uveitis, indicating that C5 may have an epistatic effect with gender in the pathogenesis of uveitis. This study help us depict the disease profile and estimate the contribution of each complement activation pathway in ocular immunologic process.

Genetic variation of the gene coding for microRNA-204 (miR-204) is a risk factor in acute myeloid leukaemia

BackgroundMicroRNAs (miRNAs or miRs) are small molecules known to be involved in post-transcriptional gene expression. Many of them have been shown to influence risk for various diseases. Recent studies suggest that lower expression of miR-204, a gene coding for miRNA-204, is correlated with shorter survival in patients with acute myeloid leukaemia (AML). This observation prompted us to analyse the effect of two polymorphisms of the miR-204 gene, one in the upstream flanking region (rs718447 A > G) and the other inside the gene itself (rs112062096 A > G), both also in intron 3 of the TRPM3 gene.MethodsThe study was conducted on DNA samples isolated from AML patients (n = 95) and healthy individuals (n = 148), who were genotyped using the Light SNiP assays.ResultsThe miR-204 rs718447 GG homozygosity was found to constitute a risk factor associated with susceptibility to AML (73/95 vs 92/148, AML patients vs healthy controls, OR = 2.020, p = 0.017). Additionally, this genotype was more frequent in patients with subtypes M0-M1 in the French-American-British (FAB) classification as compared to patients with subtypes M2-M7 (23/25 vs 39/57, p = 0.026). We also found that presence of allele A was linked to longer survival of AML patients.ConclusionsOur results show that polymorphism in miR-204 flanking region may constitute a risk and prognostic factor in AML.

Association of CD59 and CFH polymorphisms with acute anterior uveitis in Chinese population.

PurposeCD59 complement regulator and complement factor H (CFH) have important roles in complement activation pathways, which are known to affect the development of uveitis. The present study was performed to investigate whether an association exists between CD59 and CFH genetic polymorphisms and acute anterior uveitis (AAU).MethodsA total of 600 individuals (300 patients diagnosed with AAU and 300 healthy controls) were recruited for this case-control study. Five single-nucleotide polymorphisms (SNPs) in CD59 (rs831626, rs12272807, rs831625, rs11585, and rs12576440) and CFH-rs1065489 were genotyped using Sequenom MassARRAY technology. Allele and genotype frequencies were statistically compared between patients and controls using χ2 test. Analyses were stratified for gender, human leukocyte antigen (HLA)-B27, and ankylosing spondylitis (AS) status.ResultsNo significant association was found between any of the six polymorphisms and AAU. In HLA-B27-negative AAU patients, the frequencies of the G allele and GG homozygosity were lower in CD59-rs831626 when compared with controls (P=0.032). There were also significant decreases in the frequencies of T allele and TT homozygosity in CFH-rs1065489 in AAU patients with AS compared with controls (P=0.002). Furthermore, the frequencies of the T allele and TT homozygosity in CFH-rs1065489 were lower in the AAU male patients with AS compared with controls (P=0.015).ConclusionOur results revealed that SNPs CD59-rs831626 and CFH-rs1065489 were associated with the susceptibility of AAU. The influence on AAU could be gender specific and dependent on the HLA-B27 and AS status. No positive results were found in the overall group.

Observationally and Genetically High YKL-40 and Risk of Venous Thromboembolism in the General Population: Cohort and Mendelian Randomization Studies.

High baseline YKL-40 is associated with later development of ischemic stroke, but not with myocardial infarction. Whether high YKL-40 levels are associated with increased risk of venous thromboembolism is presently unknown. We tested the hypothesis that observationally and genetically high YKL-40 is associated with increased risk of venous thromboembolism in the general population. Cohort and Mendelian randomization studies in 96 110 individuals from the Danish general population, with measured plasma levels of YKL-40 (N=21 647) and CHI3L1 rs4950928 genotype (N=94 579). From 1977 to 2013, 1489 individuals developed pulmonary embolism, 2647 developed deep vein thrombosis, and 3750 developed venous thromboembolism (pulmonary embolism and deep vein thrombosis). For the 91% to 100% versus 0% to 33% YKL-40 percentile category, the multifactorially adjusted hazard ratio was 2.38 (95% confidence interval, 1.25-4.55) for pulmonary embolism, 1.98 (1.09-3.59) for deep vein thrombosis, and 2.13 (1.35-3.35) for venous thromboembolism. Compared with rs4950928 GG homozygosity, presence of C-allele was associated with a doubling (CG) or tripling (CC) in YKL-40 levels, but not with risk of venous thromboembolism. A doubling in YKL-40 was associated with a multifactorially adjusted observational hazard ratio for pulmonary embolism of 1.17 (1.00-1.38) and a genetic odds ratio of 0.97 (0.76-1.23). Corresponding risk estimates were 1.28 (1.12-1.47) observationally and 1.11 (0.91-1.35) genetically for deep vein thrombosis and 1.23 (1.10-1.38) observationally and 1.08 (0.92-1.27) genetically for venous thromboembolism. High YKL-40 levels were associated with a 2-fold increased risk of venous thromboembolism, but the association was not causal.

Genetic Investigation of Complement Pathway Genes in Type 2 Diabetic Retinopathy: An Inflammatory Perspective.

Diabetic retinopathy (DR) has complex multifactorial pathogenesis. This study aimed to investigate the association of complement pathway genes with susceptibility to DR. Eight haplotype-tagging SNPs of SERPING1 and C5 were genotyped in 570 subjects with type 2 diabetes: 295 DR patients (138 nonproliferative DR [NPDR] and 157 proliferative DR [PDR]) and 275 diabetic controls. Among the six C5 SNPs, a marginal association was first detected between rs17611 and total DR patients (P = 0.009, OR = 0.53 for recessive model). In stratification analysis, a significant decrease in the frequencies of G allele and GG homozygosity for rs17611 was observed in PDR patients compared with diabetic controls (P corr = 0.032, OR = 0.65 and P corr = 0.016, OR = 0.37, resp.); it was linked with a disease progression. A haplotype AA defined by the major alleles of rs17611 and rs1548782 was significantly predisposed to PDR with increased risk of 1.54 (P corr = 0.023). Regarding other variants in C5 and SERPING1, none of the tagging SNPs had a significant association with DR and its subgroups (all P > 0.05). Our study revealed an association between DR and C5 polymorphisms with clinical significance, whereas SERPING1 is not a major genetic component of DR. Our data suggest a link of complement pathway with DR pathogenesis.

Elevated plasma YKL-40, lipids and lipoproteins, and ischemic vascular disease in the general population.

We tested the hypothesis that observationally and genetically elevated YKL-40 is associated with elevated lipids and lipoproteins and with increased risk of ischemic vascular disease. We conducted cohort and Mendelian randomization studies in 96 110 individuals from the Danish general population, with measured plasma levels of YKL-40 (n=21 647), plasma lipids and lipoproteins (n=94 461), and CHI3L1 rs4950928 genotype (n=94 579). From 1977 to 2013, 3256 individuals developed ischemic stroke, 5629 ischemic cerebrovascular disease, 4183 myocardial infarction, and 10 271 developed ischemic heart disease. The 91% to 100% versus 0% to 33% YKL-40 percentile category was associated with a 34% increase in triglycerides, but only with minor changes in other lipids and lipoproteins. For these categories, the multifactorially adjusted hazard ratio was 1.99 (95% confidence interval, 1.49-2.67) for ischemic stroke, 1.85 (1.44-2.37) for ischemic cerebrovascular disease, 1.28 (0.95-1.73) for myocardial infarction, and 1.23 (1.01-1.51) for ischemic heart disease. When compared with rs4950928 CC homozygosity, the presence of G-allele was associated with a doubling (GC) or tripling (GG) in YKL-40 levels, but not with triglyceride levels or with risk of ischemic vascular disease. A doubling in YKL-40 was associated with a multifactorially adjusted observational hazard ratio for ischemic stroke of 1.18 (1.11-1.27), and a genetic odds ratio of 1.04 (0.95-1.15). Corresponding risk estimates were 1.15 (1.09-1.22) observationally and 1.06 (0.99-1.14) genetically for ischemic cerebrovascular disease, 1.08 (1.00-1.15) observationally and 1.04 (0.96-1.13) genetically for myocardial infarction, and 1.07 (1.02-1.12) observationally and 1.01 (0.96-1.07) genetically for ischemic heart disease. Elevated YKL-40 was associated with a 34% increase in triglyceride levels and with a 2-fold increased risk of ischemic stroke, whereas genetically elevated YKL-40 were not.

The TNFSF15 gene single nucleotide polymorphism rs7848647 is associated with surgical diverticulitis.

To determine if single nuclear polymorphisms (SNPs) in the TFNSF15 gene play a role in patients requiring surgery for diverticulitis. A role for a genetic predisposition in diverticulitis is suggested by its association with hereditary connective tissue disorders, youthful onset in some patients, and the observation of families with multiple affected individuals. The TNFSF15 gene has been associated with other inflammatory diseases affecting the colon such as medically refractory ulcerative colitis (UC), aggressive Crohn's disease (CD), and pouchitis after restorative proctocolectomy. In the discovery phase of this study, 21 sporadic surgical diverticulitis (SD) patients (9 female, mean age = 52 ± 5) and 5 individuals from a single family with surgically managed diverticulitis [familial diverticulitis (FD), 4 female, mean age = 51.1 ± 7] were studied. SD patients were age and sex matched with 3 separate groups of healthy, CD and UC control patients. All patients were genotyped for 5 known TNFSF15-associated SNPs. The SNP discovered to be associated with diverticulitis (rs7848647) was then confirmed in a separate test group composed of 34 additional patients (20 female, mean age 57.7 ± 2) who also underwent surgical treatment for diverticulitis. These patients were age matched to a new control cohort of patients having no history of diverticulitis (26 female). Patients were genotyped using a TaqMan assay. In the discovery phase, logistical regression on matched subjects was performed to determine an association of TNFSF SNP with diverticulitis versus the control groups. In the test phase, significance for the rs7848647 SNP was assessed by the Fischer's exact test. In the discovery phase, the TNFSF15 SNP rs7848647 was significantly associated with SD (p = 0.0003) versus all control groups studied. The risk allele for this SNP (G substituted for A) was found in all SD patients. The homozygous GG allele was found in 62% (13/21) of SD patients versus only 5% (1/21) of healthy controls (p = 0.001) and 24% (10/42) of all UC + CD controls (p = 0.002). All 5 members of the FD cohort were homozygous for the at-risk "G" allele. In the test group, the homozygous GG genotype was found in 56% of SD patients compared with 17% of healthy controls (p = 0.006). Risk of SD seemed to increase with number of the G alleles with 8% of SD patients having AA homozygosity, 35% of SD patients having AG heterozygosity, and 56% of SD patients having GG homozygosity. The SNP rs7848647 associated with the TNFSF15 gene is associated with surgical diverticulitis. This finding suggests a fundamental role for TNFSF15, a T-cell receptor gene involved in T-cell maturation, in the pathophysiology of diverticulitis requiring surgery. This SNP may be a marker of diverticular disease severity that might assist in surgical decision making.

Impact of insulin-like growth factor 2, insulin-like growth factor receptor 2, insulin receptor substrate 2 genes polymorphisms on susceptibility and clinicopathological features of hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) is one of the major causes of cancer-related death worldwide. Insulin-like growth factor-2 (IGF-2) is an important autocrine and paracrine growth factor which may induce cell proliferation and inhibit cell apoptosis leading to the transformation of normal cells into malignant cells. This study aimed to evaluate the possible roles of IGF-2, insulin-like growth factor-2 receptor (IGF-2R), and insulin receptor substrate (IRS)-2 genes polymorphisms in susceptibility and clinicopathological features of HCC in Egyptian population. Materials and methodsFour hundred and twenty-six HCC patients and 334 controls were enrolled in the study. Polymorphisms of IGF-2+3580, IGF-2+3123, IGF-2R 1619, and IRS-2 1057 gene were detected using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Serum IGF-2 were determined using ELISA. ResultsSerum IGF-2 levels were significantly lower in HCC patients than in healthy controls. IGF-2+3580 AA genotype, IGF-2+3123 GG genotype or G allele, IRS-2 1057 DD genotype and D allele were significantly associated with HCC risk. The combination of IGF-2+3580 AA homozygosity and IGF-2R 1619 GG homozygosity presented a significant protective effect against HCC (OR=0.16,95% CI=0. 08–0.34, P=0. 005). Serum IGF-2 concentrations were significantly increased in HCC patients with the IGF-2+3580 AA genotype. We also observed that increased alpha-fetoprotein (AFP), Child–Pugh grade, tumor size, and number of malignant lesions were accompanied by a significant increase of serum IGF-2 mean values of in HCC patients. ConclusionIGF-2, IGF-2R, and IRS-2 genes polymorphisms and their combinations are associated with risk of HCC.

HbA1c‐based diabetes diagnosis among patients with glucokinase mutation (GCK‐MODY) is affected by a genetic variant of glucose‐6‐phosphatase (G6PC2)

Genetic variation at the rs560887 locus of the glucose-6-phosphatase, catalytic 2 gene (G6PC2) is known to affect regulation of fasting glycaemia. We determined the rs560887 genotype of patients with monogenic diabetes and glucokinase gene mutations (GCK-MODY) and correlated the genotypes with HbA(1c) levels. Patients from families with GCK-MODY were recruited from two large cohorts from Poland (n = 128) and the Czech Republic (n = 154). Genotypes at the rs560887 polymorphic site in G6PC2 were examined using real-time quantitative polymerase chain reaction. The effect of rs560887 genotype on age at diagnosis of GCK-MODY and initial HbA(1c) levels were evaluated separately within both cohorts. Following that, a meta-analysis of rs560887 genotype-HbA(1c) associations of both Polish and Czech cohorts was performed to confirm homogeneity of findings and validate cohort-specific results. GG homozygosity at rs560887 was associated with marginally elevated HbA(1c) levels (P = 0.07 in both cohorts). The effects observed in both groups were very homogeneous (Q = 0.18; P = 0.68). Meta-analysis showed that GG homozygosity at rs560887 was associated with mean HbA(1c) levels higher by 2.4 mmol/mol (0.24%), 95% CI 0.5-4.4 mmol/mol (0.05-0.44%) than in individuals with other genotypes. Additionally, meta-analysis of both cohorts showed that GG homozygous individuals had higher odds of reaching the 48 mmol/mol (6.5%) diagnostic threshold of diabetes; (odds ratio 1.90; 95% CI 1.07-3.36; P = 0.03). No such effects were observed for age at diagnosis of diabetes. Variation at the rs560887 locus of G6PC2 is associated with worse glycated haemoglobin levels in individuals with GCK mutations; GG homozygotes are more likely to meet diagnostic criteria for diabetes based on HbA(1c) level.

IL-23A, IL-23R, IL-17A and IL-17R polymorphisms in different psoriatic arthritis clinical manifestations in the northern Italian population

To investigate the genetic variability of IL-17A, IL17-RA, IL-23A and IL-23R genes on an in-depth phenotypically characterized northern Italian Psoriatic arthritis (PsA) case-control cohort, in search for associations specific to different PsA clinical sub-phenotypes. We examined 118 patients with PsA according to CASPAR criteria (mean age 57 ± 13, female 38.4 %, mean disease duration 13.9 ± 8.6 years, peripheral disease 83.8 %, axial manifestations 34.5 %, radiological erosive disease 49 %) compared with 248 controls of the same ethnic origin matched for age and sex. The presence of axial disease was defined by the clinical axial involvement and/or the presence of radiological alteration consistent with spondyloarthropathy according to New York criteria. The presence of peripheral disease (arthritis and/or enthesitis) was defined only on clinical basis. A total of 40 SNPs, mapping within the genes mentioned above, were genotyped in both groups and used to perform association analyses by subdividing the PsA sample into subgroups according to different clinical manifestations on the basis of axial and peripheral involvements. No differences between patients and controls were found in the distribution of the IL-17A, IL17-RA, IL-23A and IL-23R genes allelic variants. Comparing patients with axial disease versus those without, we found that axial manifestations were significantly associated with the presence of IL-23R rs12401432 GG homozygosity (26.8 % vs. 5.3 %, p corr = 0.019, OR 2.63 [95 % CI 1.13-6.16]). No differences in distribution of the allelic variants were found comparing patients with versus those without peripheral disease or patients with versus without radiological peripheral erosions. In PA patients of northern Italian origin, IL-17A, IL17-RA, IL-23A and IL-23R genes allelic variants are not associated with disease susceptibility. However, a strong association with the IL-23RA rs12401432 GG genotype is associated with axial involvement of the disease.

The rs10757278 Polymorphism of the 9p21.3 Locus Is Associated with Premature Coronary Artery Disease in Polish Patients

Recently, genome-wide association studies have revealed a locus associated with coronary artery disease (CAD) and myocardial infarction, namely, 9p21.3. Its participation in the conditioning of the disease has been proven in many populations of European descent, but not yet in Slavs. Allelic variants of the rs10757278 polymorphism functionally affect the activity of the 9p21.3 locus; therefore, we conducted a study to determine whether the rs10757278 is associated with premature CAD in Polish patients. We studied 320 subjects aged 25-55 years, divided into two groups matched by sex and age: (1) patients with angiographically proven premature CAD (n=160), and (2) blood donors as a control group (n=160). The rs10757278 was genotyped using the method of fluorescently labeled allele-specific oligonucleotides. The frequency of the G allele was significantly higher in patients than in controls (58.2% vs. 42.8%, respectively, p=0.011) and was similar to the frequency of the GG homozygotes (30.6% vs. 17.5%, respectively, p=0.006). Both the GG homozygosity (odds ratio [OR]=2.08, 95% confidence interval [CI]: 1.19-3.66) as well as the G allele (OR=1.49, 95% CI: 1.08-2.07) have been associated with CAD in the analyzed population. These variants may be considered as risk factors, also in the Polish population.

Tumor necrosis factor-α −308 G/A and interleukin 10 −1082 A/G gene polymorphisms in patients with acne vulgaris

Cytokines play an important role in the pathogenesis of acne vulgaris together with other genetic and environmental factors. To check for the association of TNF-α and IL-10 gene polymorphisms with the susceptibility and severity of acne in Saudi patients. Study subjects included 166 Saudi patients (65 males, 101 females) with acne vulgaris. Their mean age±SD was 21.6±5.1 years. These cases were compared to 390 unrelated healthy controls (208 males, 182 females) with a mean age±SD of 20.1±3.3 years. Cases were sub-grouped on the basis of their severity of acne affection into mild, moderate and severe groups. For all participants, genotypic variants of the TNF-α -308 G/A and IL-10 -1082 A/G genes were determined using the real time PCR technique. Frequencies of genotypic variants of the TNF-α -308 polymorphism were significantly different in acne cases compared to controls. Further analysis showed that acne cases had significantly higher frequency of both the GG and AA homozygous forms than controls (73.8% vs. 63.6%, p=0.02, odds ratio=1.6). It was also interestingly noticed that the amount of GG homozygosity was notably higher among female cases than male ones (76.0% vs. 54.7%, p=0.006, odds ratio=2.6) whereas male cases had a higher frequency of AA and GA genotypes than female ones (9.4% and 35.9% vs. 4% and 20% respectively). Differences in the frequencies of IL-10 -1082 genotypic variants were statistically insignificant comparing cases to controls (p=0.3). On the other hand, comparing cases-subgroups in terms of the age of onset of the disease, consanguinity, family history, obesity and acne severity; no statistical significance was observed regarding frequencies of genotypic variants related to the both TNF-α -308 and IL-10 -1082 polymorphisms (>0.05). TNF-α -308 polymorphic variants might be a predisposing factor for acne susceptibility, with no apparent relation to its severity whereas IL-10 -1082 variants showed no association with both acne susceptibility and severity.