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Genotype Groups (genotype + groups)
Selected AbstractsStudies of relationships between the GLUT10 Ala206Thr polymorphism and impaired insulin secretionDIABETIC MEDICINE, Issue 7 2005C. S. Rose Abstract Aims This study aimed to investigate if the previously observed association between the GLUT10 Ala206Thr polymorphism and variation in fasting and oral glucose-induced serum insulin concentrations could be replicated in a large-scale population-based cohort of Danish whites. Methods The GLUT10 Ala206Thr polymorphism was genotyped in a case-control study of 880 Type 2 diabetic patients and 4372 glucose-tolerant control subjects. The latter group was also enrolled in an assessment of fasting and post-OGTT circulating levels of plasma glucose and serum insulin in relation to genotype. The variant was genotyped by analysis of PCR-generated primer extension by matrix-assisted laser desorption/ionization time-of-flight analysis. Results The Ala206Thr variant was equally frequent among Type 2 diabetic patients and glucose-tolerant subjects (P = 0.9) and there was no difference in the distribution of genotype groups (P = 1.0). In the 4372 glucose-tolerant subjects there was no statistically significant association between the polymorphism and levels of fasting and post-oral glucose tolerance test plasma glucose and serum insulin along with the insulinogenic index and the homeostasis model of assessment for insulin resistance and insulin secretion. Likewise, in an age-stratified subgroup comprising 1264 subjects, we observed no relationships between the GLUT10 polymorphism and the selected metabolic features. Conclusions The GLUT10 Ala206Thr polymorphism is not associated with Type 2 diabetes in the Danish population. Furthermore, in the present large-scale cohort, the polymorphism does not associate with phenotypes such as fasting and oral glucose-induced levels of plasma glucose and serum insulin. [source] Variation in the human lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) gene is associated with plasma soluble LOX-1 levelsEXPERIMENTAL PHYSIOLOGY, Issue 9 2008Tina E. Brinkley The lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) expressed on vascular cells plays a major role in atherogenesis by internalizing and degrading oxidized low-density lipoprotein. LOX-1 can be cleaved from the cell surface and released as soluble LOX-1 (sLOX-1), and elevated sLOX-1 levels may be indicative of atherosclerotic plaque instability. We examined associations between the LOX-1 gene 3,UTR-C/T and G501C polymorphisms and plasma sLOX-1 levels in 97 healthy older men and women. The frequencies for the 3,UTR-T and 501C alleles were 46 and 10%, respectively. Plasma sLOX-1 levels were significantly higher in the 3,UTR CC genotype group compared with both the CT (P= 0.02) and TT genotype groups (P= 0.002). Plasma sLOX-1 levels were also significantly higher in the 501GC genotype group compared with the GG genotype group (P= 0.004). In univariate analyses, sLOX-1 levels were significantly associated with both the 3,UTR-C/T and G501C polymorphisms. These associations remained significant after adjusting for age, sex, race and body mass index. In conclusion, variation in the LOX-1 gene is associated with plasma sLOX-1 levels in older men and women. [source] Genetic study of the myelin oligodendrocyte glycoprotein (MOG) gene in schizophreniaGENES, BRAIN AND BEHAVIOR, Issue 1 2005G. Zai Schizophrenia (SCZ) is a neuropsychiatric disorder that affects approximately 1% of the general population. The human leukocyte antigen (HLA) system has been implicated in several genetic studies of SCZ. The myelin oligodendrocyte glycoprotein (MOG) gene, which is located close to the HLA region, is considered a candidate for SCZ due to its association with white matter abnormalities and its importance in mediating the complement cascade. Four polymorphisms in the MOG gene (CA)n (TAAA)n, and two intronic polymorphisms, C1334T and C10991T, were investigated for the possibility of association with SCZ using 111 SCZ proband and their families. We examined the transmission of the alleles of each of these polymorphisms with the transmission disequilibrium test. We did not observe significant evidence for biased transmission of alleles at the (CA)n (,2 = 2.430, 6 df, P = 0.876) (TAAA)n (,2 = 3.550, 5 df, P = 0.616), C1334T (,2 = 0.040, 1 df, P = 0.841) and C10991T (,2 = 0.154, 1 df, P = 0.695) polymorphisms. Overall haplotype analysis using the TRANSMIT program was also not significant (,2 = 7.954, 9 df, P = 0.539). Furthermore, our results comparing mean age at onset in the genotype groups using the Kruskal,Wallis Test were not significant. Our case-control analyses (182 cases age-, sex- and ethnicity-matched with healthy controls) and combined z -score [(CA)n: z -score =,1.126, P = 0.130; (TAAA)n: z -score = ,0.233, P = 0.408; C1334T: z -score = 0.703, P = 0.241; C10991T: z -score = 0.551, P = 0.291] were also not significant. Although our data are negative, the intriguing hypothesis for MOG in SCZ may warrant further investigation of this gene. [source] p73 G4C14-to-A4T14 polymorphism and risk of second primary malignancy after index squamous cell carcinoma of head and neckINTERNATIONAL JOURNAL OF CANCER, Issue 11 2009Fanglin Li Abstract P73 plays an important role in modulating cell-cycle control, inducing apoptosis, and inhibiting cell growth. A novel noncoding p73 G4C14-to-A4T14 exon 2 polymorphism was associated with risk of squamous cell carcinoma of the head and neck (SCCHN). We hypothesized that p73 G4C14-to-A4T14 polymorphism modulates risk of second primary malignancies (SPM) in patients after index SCCHN. We followed a cohort of 1,384 patients diagnosed with incident SCCHN between May 1995 and January 2007 for SPM development. Log-rank test and Cox proportional hazard models were used to compare SPM-free survival and SPM risk between the different genotype groups. Our results showed that patients carrying the p73 variant AT allele were less likely to develop SPM compared with the patients with p73 GC/GC genotype (Log-rank test, p = 0.013). Compared with the p73 GC/GC genotype, there was a significantly reduced risk of SPM associated with the p73 GC/AT genotype (HR, 0.61, 95% CI, 0.40,0.93) and the combined p73 GC/AT+AT/AT genotypes (HR, 0.59, 95% CI, 0.39,0.89), but a nonsignificantly reduced risk for p73 AT/AT genotype (HR, 0.44, 95% CI, 0.14,1.41). The p73 AT allele was significantly associated with risk of SPM in an allele dose-response manner (p = 0.011 for trend). The risk of SPM associated with p73 variant genotypes (GC/AT+AT/AT) was more pronounced in several subgroups (e.g., older patients, men, minorities, ever smokers, and ever drinkers). Our results support that this p73 polymorphism may be a marker for risk of SPM among patients with an incident SCCHN. © 2009 UICC [source] The thymidylate synthase tandem repeat promoter polymorphism: A predictor for tumor-related survival in neoadjuvant treated locally advanced gastric cancerINTERNATIONAL JOURNAL OF CANCER, Issue 12 2006Katja Ott Abstract We evaluated DNA polymorphisms in the thymidylate synthase (TS) and 5,10- methylene-tetrahydrofolate reductase (MTHFR) genes for an association with response and survival in locally advanced gastric cancer treated with 5-FU based preoperative chemotherapy (CTx). DNA of 238 patients (CTx-group: total n = 135, completely resected (R0) n = 102; without CTx: R0 n = 103) was isolated from blood or from nontumorous tissues. In the CTx-group, genotyping of the tandem repeat and the G/C polymorphism in the triple repeat in the promoter region of the TS gene and of the C677T polymorphism of the MTHFR gene was performed. None of the TS or MTHFR genotypes were associated with histopathological response and only the TS tandem repeat polymorphism was significantly related to survival (all patients n = 135, p = 0.002; R0 resected patients n = 102, p = 0.007; log-rank test). Multivariate analysis revealed ypN (p < 0.001) and the TS tandem repeat polymorphism as independent prognostic factors in the CTx-R0-group (p = 0.003). Analyzing the prognostic significance of the TS polymorphisms in the R0-group without CTx, TS genotypes were not significantly associated with survival. Comparing survival between R0 patients with and without CTx in the respective TS genotype groups of the tandem repeat polymorphism, a significant survival benefit for the patients with CTx was found for the 2rpt/2rpt (n = 49; p = 0.002) and 2rpt/3rpt genotypes (n = 99; p = 0.004), but not for the 3rpt/3rpt genotype (n = 57; p = 0.93). Patients' survival after CTx was associated with the TS tandem repeat polymorphism. CTx did not improve survival of patients with the 3rpt/3rpt genotype. Thus, a different therapy might be more appropriate for these patients. © 2006 Wiley-Liss, Inc. [source] Mannose-binding lectin gene polymorphisms in relation to periodontitisJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 11 2008Anna Louropoulou Abstract Aim: To investigate the correlation of six functional polymorphisms in the MBL gene with MBL plasma levels in relation to periodontitis. Material and Methods: A total of 92 periodontitis patients and 70 controls, all of Caucasian origin, were included. Patients and controls were genotyped for the L/H, X/Y, P/Q, A/D, A/B and A/C polymorphisms. Distributions of genotypes, rate of allele carriage and allele frequencies were compared between patients and controls. Patients and controls were subdivided in groups of genotypes. Plasma MBL levels were compared between different genotype groups. Results: On the basis of genotyping, three phenotypes with regard to mannose-binding lectin (MBL) production were distinguished: high-producers, low-producers and deficient subjects. No differences in the genotype frequencies were observed between patients and controls. Within patients and controls, subjects with the high-producing genotypes had significantly higher MBL plasma levels than low-producers and deficient subjects (p<0.001). Plasma MBL was higher in low-producer patients compared with low-producer controls (padjusted=0.021). Conclusion: No association could be observed between MBL gene polymorphisms and susceptibility to periodontitis in Caucasians. However, now that genotyping could distinguish the low producing and deficient subjects from the high-producers, it was observed, for the first time, that MBL acts as a weak acute-phase protein in periodontitis. [source] Fc, receptor polymorphisms and periodontal status: a prospective follow-up studyJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 10 2006D. L. Wolf Abstract Aims: The aims of this study were to assess: (i) the distribution of Fc, receptor polymorphisms among patients with chronic periodontitis ("cases") and control subjects with no/minimal loss of periodontal tissue support in a Caucasian population; (ii) whether these polymorphisms can serve as severity markers for periodontitis; and (iii) whether they have any bearing on the response to periodontal therapy. Methods: The study sample consisted of 132 cases and 73 controls of comparable age and gender. Full-mouth periodontal status was assessed. Subgingival plaque (PL) samples and blood samples were obtained and analysed with respect to 19 bacterial species and homologous serum immunoglobulin G titres. Polymorphisms in the Fc, receptor IIa (131R/H) and IIIb (NA1/NA2) were assessed by polymerase chain reaction. Patients underwent periodontal therapy and were followed up at 4 and 30 months. Results: Neither polymorphism showed a skewed distribution among cases and controls. At baseline, periodontitis patients with Fc, RIIa-H/H131 genotype had more PL and deeper pockets than patients in other genotype groups (p<0.05). Both bacterial levels and antibody titres were unrelated to genotype. The longitudinal analysis failed to detect an association between genotype and response to periodontal therapy. Conclusions: The present data failed to demonstrate a clinically relevant relationship between the Fc, receptor IIa (131R/H) or IIIb (NA1/NA2) polymorphism and periodontal status. [source] Homocysteine, the MTHFR 677 C,T polymorphism and family history of premature cardiovascular diseaseJOURNAL OF HUMAN NUTRITION & DIETETICS, Issue 3 2009A. Carey Background:, Cardiovascular disease (CVD) is the main cause of premature death in the UK and accounts for 36% of all premature male deaths and 27% of female deaths every year (British Heart Foundation, 2006). Although many risk factors for CVD are known, family history has been identified as being of particular importance in premature CVD (Lloyd-Jones et al., 2004). Recently, it was suggested that an elevated homocysteine (tHcy) may be associated with premature CVD (Homocystiene Studies Collaboration, 2002). The main genetic determinant of tHcy is the common 677 C,T polymorphism, in the enzyme methylenetetrahydrofolate reductase (MTHFR), which is prevalent in approximately 10% of the UK population. Relatively few studies have examined the association between tHcy and premature CVD and hardly any have considered the role of this polymorphism. The aim of this study therefore was to examine the relationships between the MTHFR 677 C,T polymorphism, tHcy and a family history of CVD in patients with established premature CVD. Methods:, An analysis was conducted on medical, lifestyle and family history data collected from patients and age-sex matched controls, recruited through the GENOVIT study in 2003. This case,control study involved n = 404 premature CVD patients and a similar number of age-sex matched controls, all of whom were screened for the TT genotype. A subset of patients (n = 196) and controls (n = 167) provided a blood sample, from which the tHcy concentration was established. Independent sample t -tests were used to determine differences between patients and controls and differences among genotype groups were examined using a one-way analysis of variance, followed by a Tukey's post hoc test. Results:, Plasma tHcy was significantly elevated in patients with a family history of CVD (compared to those without) (P = 0.013). A nonsignificant trend towards higher tHcy (compared to those without) was observed in patients with the TT genotype (P = 0.419). Furthermore, specifically in those with the TT genotype, those with a family history of CVD (compared to those without) showed significantly higher tHcy concentrations (P < 0.005). Those with the TT genotype who smoked had significantly higher tHcy (P < 0.05) than the CC and CT genotypes. Discussion:, The findings presented provide evidence to support an association between the MTHFR 677C,T polymorphism, elevated homocysteine and family history of premature CVD. Given that dietary levels of riboflavin have been shown to lower homocysteine specifically in individuals with the TT genotype (McNulty et al., 2006), these results have implications for the dietary management of premature CVD in those individuals with a genetic predisposition for elevated tHcy. In conclusion, further research in larger cohort numbers, regarding the correlation between family history, tHcy and the MTHFR polymorphism, would be beneficial for establishing their cause and effect relationship. References British Heart Foundation (2006) All Deaths and Deaths Under 75 by Cause and Sex, 2005, England, Wales, Scotland, N Ireland and United Kingdom. Available at http://www.bhf.org.uk/research_health_professionals/resources/heart_statistics.aspx. Homocystine Studies Collaboration (2002) Homocysteine and the risk of ishaemic heart disease and stroke. JAMA288, 2015,2022. Llyod-Jones, D.M., Nam, B.H., D'Agostino, R.B., Levy, D., Murabito, J.M., Wang, T.J., Wilson, P.W. & O'Donnell, C.J. (2004) Parental cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults, a prospective study of parents and offspring. JAMA291, 2204,2211. McNulty, H., Dowey le, R.C., Strain, J.J., Dunne, A., Ward, M., Molloy, A.M., McAnena. L.B., Hughes, J.P., Hannon-Fletcher, M. & Scott, J.M. Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphism. Circulation113, 74,80. [source] Cognitive profile in a large french cohort of adults with Prader,Willi syndrome: differences between genotypesJOURNAL OF INTELLECTUAL DISABILITY RESEARCH, Issue 3 2010P. Copet Abstract Background Prader,Willi syndrome (PWS) is a rare genetic disorder characterised by developmental abnormalities leading to somatic and psychological symptoms. These include dysmorphic features, impaired growth and sexual maturation, hyperphagia, intellectual delay, learning disabilities and maladaptive behaviours. PWS is caused by a lack of expression of maternally imprinted genes situated in the 15q11-13 chromosome region. The origin is a ,de novo' deletion in the paternal chromosome in 70% of the cases and a maternal uniparental disomy in 25%. The two main genotypes show differences, notably regarding cognitive and behavioural features, but the mechanisms are not clear. This study assessed cognitive impairment in a cohort of adults with genetically confirmed PWS, analysed their profiles of cognitive strengths and weaknesses, and compared the profiles in terms of genotype. Methods Ninety-nine male and female adults participated, all inpatients on a specialised unit for the multidisciplinary care of PWS. The Wechsler Adult Intelligence Scale (WAIS-III) was administered to all patients in identical conditions by the same psychologist. Eighty-five patients were able to cope with the test situation. Their scores were analysed with non-parametric statistical tools. The correlations with sex, age and body mass index were explored. Two genotype groups were compared: deletion (n = 57) and non-deletion (n = 27). Results The distribution of intelligence quotients in the total cohort was non-normal, with the following values (medians): Full Scale Intelligence Quotient (FSIQ): 52.0 (Q1:46.0; Q3:60.0), Verbal Intellectual Quotient (VIQ): 53.0 (Q1:48; Q3:62) and Performance Intellectual Quotient (PIQ): 52.5 (Q1:48; Q3:61). No correlation was found with sex, age or body mass index. Comparison between groups showed no significant difference in FSIQ or VIQ. PIQ scores were significantly better in the deletion group. The total cohort and the deletion group showed the VIQ = PIQ profile, whereas VIQ > PIQ was observed in the non-deletion group. The subtest scores in the two groups showed significant differences, with the deletion group scoring better in three subtests: object assembly, picture arrangement and digit symbol coding. Some relative strengths and weaknesses concerned the total cohort, but others concerned only one genotype. Discussion We documented a global impairment in the intellectual abilities of a large sample of French PWS patients. The scores were slightly lower than those reported in most other studies. Our data confirmed the previously published differences in the cognitive profiles of the two main PWS genotypes and offer new evidence to support this hypothesis. These results could guide future neuropsychological studies to determine the cognitive processing in PWS. This knowledge is essential to improve our understanding of gene-brain-behaviour relationships and to open new perspectives on therapeutic and educational programmes. [source] ADH Genotype Does Not Modify the Effects of Alcohol on High-Density LipoproteinALCOHOLISM, Issue 3 2003John B. Whitfield Background: Alcohol consumption has beneficial effects on mortality which are mainly due to reduction in cardiovascular disease. These are believed to be due, at least in part, to the increase in plasma high-density lipoprotein (HDL) which is associated with alcohol consumption. It has been proposed that ADH3 genotype modifies the relationships between alcohol intake and cardiovascular disease by altering the HDL response to alcohol. The aim of this paper was to test for effects of ADH2 and ADH3 genotypes on the response of HDL components to habitual alcohol consumption. Methods: Adult male and female subjects were genotyped for ADH2 and ADH3; and plasma HDL cholesterol, apolipoprotein A-I, and apolipoprotein A-II were measured. Nine hundred one subjects had both ADH2 and ADH3 genotypes and HDL cholesterol results, while 753 had both genotypes and all three lipid results. The effect of alcohol intake on the three measured HDL components, and a factor score derived from them, was estimated for each of the ADH2 and ADH3 genotype groups. Results: All the measured components of HDL increased with increasing alcohol consumption over the range of intakes studied, 0,4 drinks per day. There were no significant interactions between alcohol consumption and ADH2 or ADH3 genotypes. Conclusions: The concept that alcohol dehydrogenase genotype and alcohol metabolic rate modify the effects of alcohol on plasma HDL concentration is not supported by our results. [source] Association Between the Functional Polymorphism of Catechol- O -Methyltransferase Gene and Alcohol Consumption Among Social DrinkersALCOHOLISM, Issue 2 2000Jussi Kauhanen Background: A common functional genetic polymorphism in the catechol- O -methyltransferase (COMT) gene (Val158 Met) results in 3- to 4-fold differences in COMT enzyme activity and dopamine inactivation rate. Previous studies have shown that type I alcoholism is more common among subjects with low activity COMT genotype (LL), compared with high activity (HH) or heterozygotic (LH) genotypes. Methods: We studied alcohol consumption and the COMT genotype in middle-aged Finnish men (n= 896), who represented an unselected ethnically homogenous population sample and reported using alcohol during the past year. Average alcohol use in pure ethanol (grams per week) was compared between subjects with LL genotype and subjects with LH or HH genotypes. Results: Men with LL genotype (30% of all subjects) reported 27% higher weekly alcohol consumption compared with the two other genotype groups (p < 0.05). The difference remained statistically significant after a multivariate adjustment for sociodemographic factors and prior or existing diseases (p= 0.031). Conclusions: The results indicate that COMT polymorphism may contribute significantly to alcohol intake not only in alcoholics but also in a general male population. [source] Effect of concomitant dosing of famotidine with lansoprazole on gastric acid secretion in relation to CYP2C19 genotype statusALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2005T. FURUTA Background :,Famotidine increases Helicobacter pylori -eradication rates by a triple lansoprazole/amoxicillin/clarithromycin therapy in patients with the rapid extensive metabolizer genotype of CYP2C19. Aim :,To determine the effect of famotidine on the gastric acid inhibition by lansoprazole in relation to CYP2C19 genotypes. Methods :,Twenty healthy volunteers with different CYP2C19 genotypes , consisting of six rapid extensive metabolizers, nine intermediate metabolizers and five poor metabolizers , underwent three 7-day courses with placebo, lansoprazole 30 mg twice daily, and lansoprazole 30 mg twice plus famotidine 20 mg twice daily. Lansoprazole was dosed after breakfast and dinner. Famotidine was dosed after lunch and at bedtime. Intragastric pH monitoring was performed for 24 h on day 7 of each course. Results :,With placebo, no difference was observed in intragastric pH profiles among the three CYP2C19 genotype groups. With lansoprazole 30 mg twice daily, the median of 24-h intragastric pH in poor metabolizers (6.1) was significantly higher than those of rapid extensive metabolizers (4.5) and intermediate metabolizers (5.0), respectively (P = 0.0176 and 0.0388), whereas with lansoprazole 30 mg twice and famotidine 20 mg twice daily, the medians were 5.4, 5.7, and 6.1, respectively (not significant). Conclusion :,Acid inhibition by lansoprazole was influenced by CYP2C19 genotype status. This influence was offset by the concomitant use of famotidine. [source] Dopamine Receptor D2 Polymorphism Moderates the Effect of Parental Education on Adolescents' School PerformanceMIND, BRAIN, AND EDUCATION, Issue 2 2008Liisa Keltikangas-Järvinen ABSTRACT, High parental socioeconomic status is known to have a positive effect on students' academic achievement. We examined whether variation in the dopamine receptor gene (DRD2 polymorphism, rs 1800497) modifies the association between parental educational level and school performance in adolescence. The participants were a randomly selected subsample of individuals participating in the Cardiovascular Risk in Young Finns study (921 girls and 742 boys) aged 12,15 years at the time school performance was assessed. The genotyping was performed using TaqMan 5,'-nuclease assay. A significant interaction was found between childhood parental educational level and students' DRD2 polymorphism on academic achievement after adjustment for age, gender, household income, parental occupation, maternal nurturance, hyperactivity, and sociability. Parental educational level was significantly positively associated with school achievement in the A2/A2 (n = 1,061) and the A1/A2 (n = 529) genotype groups, but was negative and statistically insignificant in participants carrying the A1/A1 (n = 73) genotype. It is concluded that the extent to which parental education status affects an individual's academic achievement may be dependent on the individual's genetic constitution. The findings may increase an acceptance of genetic influence in education, and, consequently, may increase accurateness of educational interventions. [source] COMT genotypes and use of antipsychotic medication: linking population-based prescription database to the HUNT study,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 4 2008Dr Knut Hagen Abstract Purpose The aim of this prospective study was to evaluate the impact of codon 158 polymorphism at the catechol- O -methyltransferase (COMT) gene on prescription of antipsychotic medication in a general population. Methods The sample comprised 2623 non-diabetic individuals who participated in the Nord-Trøndelag Health Study (HUNT) in the period 1995,97 and who were alive 1 January 2004. The subjects were followed up with respect to prescription of antipsychotic medication based on data obtained from the Norwegian prescription database. Results Among the group of 76 individuals who had been prescribed antipsychotic medication the distribution did not differ between genotypes and alleles when compared to a control group. For 47 individuals with at least three prescriptions a correlation between median total defined daily doses (DDDs) and genotype groups was found (Spearman's rho, ,0.40, p,=,0.01), being highest for the Met/Met genotype (250), intermediate for the Met/Val genotype (126) and lowest for the Val/Val genotype (47) (p,=,0.03). Conclusion In this population-based cohort of 2623 adults, the Val158Met polymorphism at the COMT gene had no major impact on number of individuals who had been prescribed antipsychotic medication. However, linkage to the prescription database may in an indirect way indicate an association between the COMT Val158Met polymorphism and treatment response or dose requirements of antipsychotic medication. Copyright © 2008 John Wiley & Sons, Ltd. [source] Association of a single-nucleotide polymorphism in CD40 with the rate of joint destruction in rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 8 2009Michael P. M. van der Linden Objective The severity of joint destruction in rheumatoid arthritis (RA) is highly variable from patient to patient and is influenced by genetic factors. Genome-wide association studies have enormously boosted the field of the genetics of RA susceptibility, but risk loci for RA severity remain poorly defined. A recent meta-analysis of genome-wide association studies identified 6 genetic regions for susceptibility to autoantibody-positive RA: CD40, KIF5A/PIP4K2C, CDK6, CCL21, PRKCQ, and MMEL1/TNFRSF14. The purpose of this study was to investigate whether these newly described genetic regions are associated with the rate of joint destruction. Methods RA patients enrolled in the Leiden Early Arthritis Clinic were studied (n = 563). Yearly radiographs were scored using the Sharp/van der Heijde method (median followup 5 years; maximum followup 9 years). The rate of joint destruction between genotype groups was compared using a linear mixed model, correcting for age, sex, and treatment strategies. A total of 393 anti,citrullinated protein antibody (ACPA),positive RA patients from the North American Rheumatoid Arthritis Consortium (NARAC) who had radiographic data available were used for the replication study. Results The TT and CC/CG genotypes of 2 single-nucleotide polymorphisms, rs4810485 (CD40) and rs42041 (CDK6), respectively, were associated with a higher rate of joint destruction in ACPA-positive RA patients (P = 0.003 and P = 0.012, respectively), with rs4810485 being significant after Bonferroni correction for multiple testing. The association of the CD40 minor allele with the rate of radiographic progression was replicated in the NARAC cohort (P = 0.021). Conclusion A polymorphism in the CD40 locus is associated with the rate of joint destruction in patients with ACPA-positive RA. Our findings provide one of the first non,HLA-related genetic severity factors that has been replicated. [source] Association of interleukin-6 and interleukin-10 genotypes with radiographic damage in rheumatoid arthritis is dependent on autoantibody statusARTHRITIS & RHEUMATISM, Issue 8 2007I. Marinou Objective Recent evidence has highlighted a major genetic contribution to radiographic damage in rheumatoid arthritis (RA). The objective of this study was to determine whether genetic variants in the loci for interleukin-1 (IL-1), IL-6, IL-10, protein tyrosine phosphatase N22 (PTPN22), and selenoprotein S are associated with radiographic damage. Methods Modified Larsen scores of radiographic damage were determined in a cross-sectional population of patients with RA (n = 964). Rheumatoid factor (RF) and anti,cyclic citrullinated peptide (anti-CCP) were also assayed. The Kruskal-Wallis nonparametric test was used to compare median radiographic damage scores across genotype groups, followed by the Cuzick nonparametric test for trend to assess gene-dose effects. Results An allele-dose association of IL-6 ,174G with increasing radiographic damage was present (P = 0.005), but only in patients who were RF positive (P = 0.004) or anti-CCP positive (P = 0.01). Patients with the IL-10 ,592CC genotype had more extensive radiographic damage than did those with the AC or AA genotype (P = 0.006), but this was observed only among patients who were RF negative (P = 0.002) or anti-CCP negative (P = 0.002). However, RF status and anti-CCP status were not associated with the IL-6 or IL-10 genotype. No other genetic associations were detected, apart from a marginal association of PTPN22 +1858T with increased radiographic damage. Conclusion The reported associations of IL-6 ,174G with high IL-6 production and IL-10 ,592 with low IL-10 production and our own results support a role of genetically determined dysregulated cytokine production in disease severity. The lack of association of these genotypes with RF and anti-CCP antibody status suggests that they act downstream of autoantibody production. We conclude that IL-6 and IL-10 genotypes may be useful in predicting disease severity in autoantibody-positive and autoantibody-negative patients, respectively. [source] HLA,DRB1 genotype associations in 793 white patients from a rheumatoid arthritis inception cohort: Frequency, severity, and treatment biasARTHRITIS & RHEUMATISM, Issue 9 2002James F. Fries Objective The HLA,DRB1 "shared epitope" (SE) genotypes are associated with rheumatoid arthritis (RA), but it remains controversial whether the association is with incidence, severity, or both, whether there are associations in seronegative patients, and whether different DRB1 alleles that contain the SE have similar effects on RA susceptibility and/or severity. The present study was undertaken to study these issues in a large cohort of patients with RA. Methods White patients with RA of <6 months' duration (n = 793) were enrolled in an inception cohort. HLA,DRB1 typing was performed, and patients were categorized into 21 DRB1 genotype groups. The disability index of the Health Assessment Questionnaire was the primary outcome measure. Results DRB1 associations in seronegative RA patients closely resembled those in controls. Of seropositive patients, 21% had 2 copies of the epitope, 52% had 1 copy, and 27% had none. However, not all genotypes with 1 copy were associated with increased susceptibility; for example, frequencies of DRB1*0404/X and *01/X did not differ from those in controls. Absolute differences between seropositive RA patients and controls were greatest for DRB1*0401 homozygosity (3.8% versus 0.8%, respectively) and *0401/0404 heterozygosity (4.7% versus 1.0%). DRB1*0404 was increased in frequency in seropositive RA but, unlike *0401, an increased frequency was seen only with 2 epitope copies. The relatively rare DRB1*10 had an unexpected association with seropositive RA, being present in 1.7% of seropositive RA patients and 0.7% of controls, and also showed a trend toward association with greater disease severity. The presence of 2 epitope copies was associated with increased frequency of seropositivity and younger age at disease onset, not with disease severity. Treatment indication bias was substantial and may have accounted for some of these effects. HLA,DRB1*0401/0404 was found much more frequently in men and in patients with a lower age at disease onset, and there was a trend toward a higher frequency of *0404/0401 in women. Conclusion This large inception cohort study confirms previously identified major associations and provides additional insights. Only one dominant association was found: *0401, which differs from other SE alleles in a single Lys-for-Arg substitution. The association of the rare DRB1*10 allele has not previously been postulated. Sex associations were confirmed. Associations with seronegative RA were not seen. Not all genotypes containing an SE copy showed increased susceptibility to RA. The association of SE genotypes found in this study related to disease susceptibility rather than severity. [source] Plasma concentrations of haloperidol are related to CYP2D6 genotype at low, but not high doses of haloperidol in Korean schizophrenic patientsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2001Hyung-Keun Roh Aims, This study was carried out to evaluate the influence of CYP2D6 genotype on the steady state plasma concentrations of haloperidol and reduced haloperidol in Korean schizophrenic patients. Methods, One hundred and twenty Korean schizophrenic patients treated with various, clinically determined, doses of haloperidol (range 3,60, median 20 mg day,1) during monotherapy were recruited. CYP2D6 genotypes were determined by analysis of the CYP2D6*10 allele using allele-specific PCR and the CYP2D6*5 allele by long-PCR. Steady state plasma concentrations of haloperidol and reduced haloperidol were analysed by h.p.l.c. Results, Twenty-three (19.2%), 60 (50.0%), 1 (0.8%), 33 (27.5%) and 3 patients (2.5%) possessed the CYP2D6 genotypes *1/*1, *1/*10, *1/*5, *10/*10 and *10/*5, respectively. The allele frequencies of CYP2D6*1, *10 and *5 were 44.6%, 53.8% and 1.7%, respectively. Significant relationships between dose and plasma concentrations of haloperidol (linear; r2 = 0.60, P < 0.0001) and reduced haloperidol (quadratic equation; r2 = 0.67) were observed. Overall, the concentrations normalized for dose (C/D) of haloperidol were significantly different between the CYP2D6*1/*1, *1/*10 and*10/*10 genotype groups (one-way anova; P = 0.028). No significant differences between the genotype groups were found with respect to the C/D of reduced haloperidol (P = 0.755). However, in patients with daily doses less than 20 mg, significant differences in the C/D of haloperidol (P = 0.003), but not of reduced haloperidol, were found between the three major genotype groups. In patients with doses higher than 20 mg, no differences were found between the genotype groups for either haloperidol or reduced haloperidol. 68 patients (57%) used benztropine, an antimuscarinic agent. All four patients with a *5 allele (one together with *1 and three with *10) were found to use benztropine. The patients homozygous for the *1 allele seemed to need less benztropine than the patients with one or two mutated alleles (Fisher's exact test; P = 0.036). Conclusions, The dose-corrected steady state plasma concentrations of haloperidol, but not of reduced haloperidol, were significantly different between the CYP2D6*1/*1, *1/*10 and *10/*10 genotype groups when doses lower than 20 mg haloperidol were given. No differences were found at higher doses. These results suggest the involvement of CYP2D6 in the metabolism of haloperidol at low doses of haloperidol (< 20 mg daily), while another enzyme, probably CYP3A4, contributes at higher doses. [source] Interactions between TCF7L2 genotype and growth hormone-induced changes in glucose homeostasis in small for gestational age childrenCLINICAL ENDOCRINOLOGY, Issue 1 2010Sandra W. K. De Kort Summary Context, The Transcription factor 7-like 2 (TCF7L2) rs7903146 gene polymorphism has been associated with risk of developing type 2 diabetes mellitus (DM), possibly by decreasing insulin secretion. Small for gestational age (SGA) birth has been associated with type 2 DM in later life. Growth hormone (GH) treatment reduces insulin sensitivity and increases insulin secretion. Therefore, GH-treated SGA children are an ideal group to investigate whether the TCF7L2 rs7903146 genotype is associated with changes in glucose homeostasis. Objective, To determine the impact of the TCF7L2 rs7903146 polymorphism on changes in insulin secretion and insulin sensitivity during 4 years of GH treatment in children born SGA. Subjects, A total of 246 Caucasian short children born SGA, with a median age of 7·8 years. Outcome measures, Insulin sensitivity and insulin secretion were measured by the frequently sampled intravenous glucose tolerance test (FSIGT) (n = 68) and homeostasis model assessment (HOMA) calculations (all). Results, There was no association between rs7903146 genotype and insulin sensitivity or insulin secretion at baseline but after adjustment for possible confounders, insulin secretion was higher in the CT/TT group than in the CC group. During GH treatment, carriers of the rs7903146 T allele had an increase in insulin secretion similar to that of carriers of the CC genotype. The decrease in insulin sensitivity was only significant in the CT/TT group, but the difference in decrease between genotype groups did not reach significance (P = 0·06). The disposition index (insulin secretion × insulin sensitivity), which is an estimate of beta cell function, was not associated with genotype and did not change during GH treatment. Conclusion, The TCF7L2 rs7903146 polymorphism is not associated with the change in insulin secretion during GH treatment in short SGA children. [source] Identification of adiponectin and its receptors in human osteoblast-like cells and association of T45G polymorphism in exon 2 of adiponectin gene with lumbar spine bone mineral density in Korean womenCLINICAL ENDOCRINOLOGY, Issue 5 2006Won Young Lee Summary Objective, The role of adiponectin in bone metabolism has been recently reported in in vitro and in vivo studies. There has been no report on the association of adiponectin gene polymorphism and bone mineral density (BMD). Therefore, we investigated whether two single nucleotide polymorphisms (SNPs), T45G and G276T, in the adiponectin gene were related to BMD in Koreans. We also report on the identification of adiponectin and its receptors 1 and 2 in human osteoblast-like cell lines. Patients and measurements, MG-63 cells were cultured and osteogenic and adipogenic differentiations from human mesenchymal stem cells (hMSCs) were performed. RNA was then extracted from the cultured cells and reverse transcriptase-polymerase chain reaction (RT-PCR) was performed using primers for adiponectin and for the adiponectin receptor genes. In 249 female and 80 male subjects, measurements were made of their lumbar spine and femoral neck BMDs, and biochemical markers of bone turnover. The genotyping of the T45G polymorphism in exon 2 and the G276T polymorphisms in intron 2 in the adiponectin gene was performed using an allelic discrimination assay with a TaqMan probe. Analyses were performed separately in each cohort. Results, We found that the mRNAs for adiponectin and for adiponectin receptor 1 (AdipoR1) and 2 (AdipoR2) were expressed in the MG-63 cells. Sequencing of the PCR products revealed that they were identical to human adiponectin, AdipoR1 and AdipoR2, respectively. mRNAs for adiponectin, AdipoR1 and AdipoR2 were also expressed in the osteoblastic and adipogenic cell lines differentiated from hMSCs. For the polymorphism study, the frequencies of T45G and G276T in the adiponectin gene were in compliance with Hardy,Weinberg equilibrium and the two polymorphisms were in complete linkage disequilibrium (D, = ,1·0, P < 0·001). In the female cohort, subjects with G alleles at the T45G locus had significantly lower lumbar spine BMD than those subjects with the TT genotype. Although BMD levels showed no association with the G276T locus, the GT genotype group showed significantly higher urine deoxypyridinoline levels than other genotype groups. In the male cohort, no association was observed between adiponectin genotypes and BMD levels. Conclusions, We observed the expression of adiponectin, AdipoR1 and AdipoR2 in the MG-63 cell line and the osteoblastic cell line differentiated from hMSCs. T45G polymorphism in exon 2 of the adiponectin gene is associated with lumbar spine BMD and G276T polymorphism in intron 2 of the adiponectin gene is associated with the urine deoxypyridinoline level in Korean women. Additional studies are needed to elucidate the precise contribution of adiponectin to bone mineral metabolism. [source] NADH/NADPH oxidase p22 phox C242T polymorphism and lipid peroxidation in coronary artery diseaseCLINICAL PHYSIOLOGY AND FUNCTIONAL IMAGING, Issue 6 2001O. Stanger The nicotinamide adenine dinucleotide (NADH)/nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system is a major source of superoxide anion (·O2,) production in the human vasculature and may therefore influence lipid peroxidation and severity of atherosclerosis. This study aimed to investigate a hypothetical influence of the p22 phox C242T polymorphism on the generation of malondialdehyde (MDA), extent and clinical onset of coronary artery disease (CAD) in patients. We studied 108 male Caucasians with angiographically documented CAD and 45 controls free of vascular disease under 60 years of age. p22 phox C242T genotypes and MDA levels were determined. Additional information was obtained from each subject on classic risk factors and clinical events of CAD. Genotype distribution in CAD-patients and controls was thymine,thymine (TT): 13·8% (13·3%), cytosine,thymine (CT): 46·3% (53·3%) and cytosine,cytosine (CC): 39·8% (33·3%), respectively. No significant influence was seen of the p22 phox C242T polymorphism on corresponding mean MDA levels in both groups. Furthermore, age at onset of first time angina pectoris (AP) and myocardial infarction (MCI) was not significantly different between genotype groups. It is concluded that the C242T polymorphism of the p22 phox gene is not associated with lipid peroxidation as measured by MDA, and is not a genetic risk marker for CAD Caucasians. [source] | |||||||||||||