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William G Newman,
Katherine Payne,
Karen Tricker,
Stephen A Roberts,
Emily Fargher,
Sudeep Pushpakom,
Jane E Alder,
Gary P Sidgwick, Debbie Payne,
Rachel A Elliott, [......],
Robert Elles,
Simon C Ramsden,
Julie Andrews,
J Brian Houston,
Faeiza Qasim,
Jon Shaffer,
Christopher E M Griffiths,
David W Ray,
Ian Bruce,
William E R Ollier
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ABSTRACT: To conduct a pragmatic, randomized controlled trial to assess whether thiopurine methyltransferase (TPMT) genotyping prior to azathioprine reduces adverse drug reactions (ADRs).
A total of 333 participants were randomized 1:1 to undergo TPMT genotyping prior to azathioprine or to commence treatment without genotyping.
There was no difference in the primary outcome of stopping azathioprine due to an adverse reaction (ADR, p = 0.59) between the two study arms. ADRs were more common in older patients (p = 0.01). There was no increase in stopping azathioprine due to ADRs in TPMT heterozygotes compared with wild-type individuals. The single individual with TPMT variant homozygosity experienced severe neutropenia.
Our work supports the strong evidence that individuals with TPMT variant homozygosity are at high risk of severe neutropenia, whereas TPMT heterozygotes are not at increased risk of ADRs at standard doses of azathioprine.
Pharmacogenomics 06/2011; 12(6):815-26. · 3.97 Impact Factor
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ABSTRACT: This study provides the first analysis of the TPMT mutant allele frequency in a sample of the Jordanian population and indicates that TPMT*3A is the most common allele in Jordanian subjects.
thiopurine methyltransferase TPMT catalyses the S-methylation of thiopurine drugs such as 6-mercaptopurine, 6-thioguanine, and azathiopurine. Thiopurine methyltransferase (TPMT) polymorphisms are the major determinants of interindividual differences in the severe haematological toxicity of 6-mercaptopurine. Several variants in the TPMT gene have been identified that correlate with a low activity phenotype. Four variant alleles, TPMT*2, TPMT*3A, TPMT*3B and TPMT*3C, are responsible for over 80% of the low or undetectable enzyme activity. The allelic frequency of TPMT variants has been established in many populations.
In this study, the frequencies of four (TPMT*2, TPMT*3A, TPMT*3B and TPMT*3C) variants were investigated in 169 healthy Jordanian men (18-45 years of age). Single nucleotide polymorphisms (SNPs) were genotyped using the Sequenom MassARRAY technology (Sequenom; San Diego, CA, USA).
TPMT*3A and TPMT*3C were the only deficiency alleles detected in the Jordanian population with an allele frequency of 0.59% and 0.30% respectively. The TPMT*3A allele frequency is found to be lower than in the European Caucasian population.
TPMT*3A and TPMT*3C were the only deficiency alleles detected in the Jordanian population with an allele frequency of 0.59% and 0.30% respectively. The TPMT*3A allele frequency is found to be lower than in the European Caucasian population.
European Journal of Clinical Pharmacology 10/2010; 66(10):999-1003. · 2.85 Impact Factor
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Lynn Cotterill, Debbie Payne,
Scott Levinson,
John McLaughlin,
Emma Wesley,
Mark Feeney,
Hilary Durbin,
Simon Lal,
Alistair Makin,
Simon Campbell,
Stephen A Roberts,
Catherine O'Neill,
Cathryn Edwards,
William G Newman
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ABSTRACT: Variants in the interleukin-23 receptor (IL23R) and the autophagy-related 16-like 1 (ATG16L1) genes have been associated with an increased risk of Crohn's disease (CD). Both genes were identified through genome-wide association scans and subsequent studies have validated these associations. To assess the effect size of these variants, an independent case-control association study and meta-analysis were performed.
British Caucasian subjects with inflammatory bowel disease (n=500) and 877 ethnically matched controls were genotyped for the disease-associated variants in IL23R and ATG16L1. In addition, meta-analyses of 12,991 patients and 14,598 controls, and 11,909 patients and 15,798 controls, were conducted on independently published data for the associations between IL23R and ATG16L1 variants and CD, respectively.
In the present cohort, both susceptibility variants showed highly significant associations, including IL23R (rs11209026, P=0.0006; OR 0.37; 95% CI 0.21 to 0.67) and ATG16L1 (rs2241880, P=0.0017; OR 1.36; 95% CI 1.12 to 1.66). The meta-analysis based on the random effects model showed similar combined effects for rs11209026 (n=26, OR 0.41; 95% CI 0.37 to 0.46) and rs2241880 (n=25, OR 1.33; 95% CI 1.28 to 1.39). There was no statistically significant gene-gene interaction between caspase recruitment domain (CARD15) variants and the IL23R or ATG16L1 polymorphisms (P=0.44 and P=0.24, respectively).
The present cohort and meta-analysis provides strong evidence that, in addition to CARD15, polymorphisms in both IL23R and ATG16L1 alter susceptibility to CD and that these effects are consistent across all populations of European ancestry; however, only ATG16L1 is relevant to inflammatory bowel disease in the Asian population.
Canadian journal of gastroenterology = Journal canadien de gastroenterologie 05/2010; 24(5):297-302. · 1.21 Impact Factor
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David M Lee,
Aslan Ulubaev,
Abdelouahid Tajar,
Stephen R Pye,
Neil Pendleton,
Nitin Purandare,
Terence W O'Neill,
Daryl B O'Connor,
Fernand Labrie,
Hazel Platt, [......],
Gianni Forti,
Aleksander Giwercman,
Thang S Han,
Ilpo T Huhtaniemi,
Krzysztof Kula,
Michael E J Lean,
Margus Punab,
Alan J Silman,
Dirk Vanderschueren,
Frederick C W Wu
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ABSTRACT: Data remain divergent regarding the activational effects of endogenous hormones on adult cognitive function. We examined the association between cognition, hormones and androgen receptor (AR) CAG repeat length in a large cohort of men.
Community-based, cross-sectional study of 3369 men aged 40-79 years.
Cognition tests were the Rey-Osterrieth Complex Figure, Camden Topographical Recognition Memory and Digit-Symbol Substitution. A fluid cognition (FC) z-score was computed from the individual tests. Testosterone, oestradiol (OE(2)) and 5alpha-dihydrotestosterone were measured by gas chromatography-mass spectrometry; DHEAS, LH, FSH and sex hormone-binding globulin (SHBG) by electrochemiluminescence. Free testosterone and OE(2) were calculated from total hormone, SHBG and albumin. CAG repeat lengths were assayed by PCR genotyping.
Total testosterone and free testosterone were associated with higher FC z-scores, LH and FSH with lower FC z-scores in age-adjusted linear regressions. After adjusting for health, lifestyle and centre, a modest association was only observed between DHEAS and a lower FC z-score (beta=-0.011, P=0.02), although this was driven by subjects with DHEAS levels >10 micromol/l. Locally weighted plots revealed no threshold effects between hormones and FC. There was no association between CAG repeat length and FC z-score after adjustment for age and centre (beta=-0.007, P=0.06), nor any interaction effect between CAG repeat length and hormones.
Our results suggest that endogenous hormones are not associated with a vision-based measure of FC among healthy, community-dwelling men. Further studies are warranted to determine whether 'high' DHEAS levels are associated with poorer performance on a broader range of neuropsychological tests.
European Journal of Endocrinology 03/2010; 162(6):1155-64. · 3.42 Impact Factor
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Ilpo T Huhtaniemi,
Stephen R Pye,
Kate L Holliday,
Wendy Thomson,
Terence W O'Neill,
Hazel Platt, Debbie Payne,
Sally L John,
Min Jiang,
György Bartfai, [......],
Aleksander Giwercman,
Thang S Han,
Krzysztof Kula,
Michael E J Lean,
Neil Pendleton,
Margus Punab,
Alan J Silman,
Dirk Vanderschueren,
Fernand Labrie,
Frederick C W Wu
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ABSTRACT: Polymorphisms in genes involved in regulation, biosynthesis, metabolism, and actions of testicular sex hormones may influence hormone balance and phenotype of aging men.
We investigated the relationships between polymorphisms in genes related to pituitary-testicular endocrine function and health status.
Using cross-sectional baseline data, we conducted a multinational prospective cohort observational study consisting of a population survey of community-dwelling men.
A total of 2748 men, aged 40-79 (mean +/- sd, 60.2 + 11.2) yr, were randomly recruited from eight European centers. Forty-three polymorphisms were genotyped in the following genes: androgen receptor (AR), estrogen receptor-alpha and -beta (ESR1 and ESR2), steroid 5alpha-reductase type II (SRD5A2), 17alpha-hydroxylase/17,20-lyase (CYP17A1), aromatase (CYP19A1), sex hormone-binding globulin (SHBG), LH beta-subunit (LHB), and LH receptor (LHCGR).
We measured the associations between gene polymorphisms and endocrine, metabolic, and phenotypic parameters related to aging and sex hormone action.
Several polymorphisms in SHBG, ESR2, AR, CYP19A1, and LHB were significantly associated with circulating levels of SHBG, LH, total, free, and bioavailable testosterone and estradiol, the LH x testosterone product, and indices of insulin sensitivity. Apart from several previously reported associations between genes affecting estrogen levels and heel ultrasound parameters, no associations existed between polymorphisms and nonhormonal variables (anthropometry, blood lipids, blood pressure, hemoglobin, prostate symptoms, prostate-specific antigen, sexual dysfunction, cognition).
In aging men, polymorphisms in genes related to the pituitary-testicular endocrine function significantly influence circulating LH, testosterone, and estradiol levels, but the downstream effects may be too small to influence secondary phenotypic parameters.
The Journal of clinical endocrinology and metabolism 02/2010; 95(4):1898-908. · 6.50 Impact Factor
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ABSTRACT: Streptococcus pneumoniae (pneumococcus) is responsible for over one million deaths per year, with young children, the elderly and immunocompromised individuals being most at risk. Approximately half of East African children have been reported to be asymptomatic carriers of pneumococcus with invasive infection occurring after the disruption of the respiratory membrane which is believed to be caused by the host immune response. Racial incidence of invasive pneumococcal disease (IPD) is higher in certain populations even after adjusting for environmental factors suggesting a genetic component to disease susceptibility. The nitric oxide synthase 2A (NOS2A) gene is responsible for the production of nitric oxide under pathological conditions including host defence against bacterial infection. Nitric oxide is a modulator of apoptotic and inflammatory cascades and endothelial permeability. We hypothesised that genetic variants within this gene may predispose to disease risk and survival.
A cohort of 299 children with IPD (221 meningitis, 41 pneumonia and 37 with bacteraemia) and 931 age matched controls from Malawi were used in this study. We investigated nine haplotype tagging single nucleotide polymorphisms within the NOS2A gene and compared the presence or absence of the minor alleles in cases and controls and survivors and non-survivors within the cases.
We observed no significant associations between cases and controls or with survival in either all IPD cases or in the separate analysis of meningitis cases. A near significant association was obtained for the comparison of rs8078340 in cases and controls (p-value, 0.078). However, results were unadjusted for multiple testing.
Our results suggest that polymorphic variation within the NOS2A gene does not influence invasive pneumococcal disease susceptibility or survival.
BMC Medical Genetics 02/2009; 10:28. · 2.33 Impact Factor
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ABSTRACT: Abstract
Background
Streptococcus pneumoniae (pneumococcus) is responsible for over one million deaths per year, with young children, the elderly and immunocompromised individuals being most at risk. Approximately half of East African children have been reported to be asymptomatic carriers of pneumococcus with invasive infection occurring after the disruption of the respiratory membrane which is believed to be caused by the host immune response. Racial incidence of invasive pneumococcal disease (IPD) is higher in certain populations even after adjusting for environmental factors suggesting a genetic component to disease susceptibility. The nitric oxide synthase 2A (NOS2A) gene is responsible for the production of nitric oxide under pathological conditions including host defence against bacterial infection. Nitric oxide is a modulator of apoptotic and inflammatory cascades and endothelial permeability. We hypothesised that genetic variants within this gene may predispose to disease risk and survival.
Methods
A cohort of 299 children with IPD (221 meningitis, 41 pneumonia and 37 with bacteraemia) and 931 age matched controls from Malawi were used in this study. We investigated nine haplotype tagging single nucleotide polymorphisms within the NOS2A gene and compared the presence or absence of the minor alleles in cases and controls and survivors and non-survivors within the cases.
Results
We observed no significant associations between cases and controls or with survival in either all IPD cases or in the separate analysis of meningitis cases. A near significant association was obtained for the comparison of rs8078340 in cases and controls (p-value, 0.078). However, results were unadjusted for multiple testing.
Conclusion
Our results suggest that polymorphic variation within the NOS2A gene does not influence invasive pneumococcal disease susceptibility or survival.
BMC Medical Genetics. 01/2009;
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Ilpo T Huhtaniemi,
Stephen R Pye,
Kate L Limer,
Wendy Thomson,
Terence W O'Neill,
Hazel Platt, Debbie Payne,
Sally L John,
Min Jiang,
Steven Boonen, [......],
Joseph D Finn,
Gianni Forti,
Aleksander Giwercman,
Thang S Han,
Krzysztof Kula,
Michael E J Lean,
Neil Pendleton,
Margus Punab,
Alan J Silman,
Frederick C W Wu
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ABSTRACT: The individual variability in the waning androgenic-anabolic functions of aging men may be influenced by the CAG repeat polymorphism in exon 1 of the androgen receptor (AR), affecting androgen sensitivity. However, findings on its phenotypic effects are inconclusive. Objective: The aim was to investigate the relationships between health status, various reproductive hormones, and the AR CAG repeat length.
We conducted a multinational prospective cohort observational study with cross-sectional baseline data.
This was a population survey of community-dwelling men. Participants: Men (40-79 yr old; n = 3369) were randomly recruited from centers in eight European countries; CAG repeat analysis was performed in 2878 men.
We measured the correlations of the CAG repeat length with selected endocrine, metabolic, and phenotypic parameters related to aging and sex hormone action.
Only minor differences were found in CAG repeat lengths between the eight European countries. They showed significant positive association with total, free, and bioavailable levels of testosterone (T) and estradiol. FSH but not LH correlated inversely with CAG repeat length. Significant associations were found with bone ultrasound parameters at the calcaneus. Negative correlation was found with triglycerides, but not with other blood lipids or with anthropometry, blood pressure, hemoglobin, insulin sensitivity, or sexual and prostatic functions.
The AR CAG repeat length correlates significantly with serum T and estradiol of aging men. Weaker transcriptional activity of the AR with longer CAG-encoded polyglutamine repeats appears to be totally or nearly totally compensated for by higher T levels. The residual phenotypic correlations may reflect differences in estrogen levels/actions after aromatization of the higher T levels.
Journal of Clinical Endocrinology & Metabolism 11/2008; 94(1):277-84. · 6.50 Impact Factor
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Kate L Limer,
Stephen R Pye,
Wendy Thomson,
Steven Boonen,
Herman Borghs,
Dirk Vanderschueren,
Ilpo T Huhtaniemi,
Judith E Adams,
Kate A Ward,
Hazel Platt, [......],
Gianni Forti,
Aleksander Giwercman,
Thang S Han,
Krzysztof Kula,
Michael E Lean,
Neil Pendleton,
Margus Punab,
Alan J Silman,
Frederick C Wu,
Terence W O'Neill
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ABSTRACT: Genes involved in sex hormone pathways are candidates for influencing bone strength. Polymorphisms in these genes were tested for association with heel quantitative ultrasound (QUS) parameters in middle-aged and elderly European men. Men 40-79 yr of age were recruited from population registers in eight European centers for the European Male Aging Study (EMAS). Polymorphisms were genotyped in AR, ESR1, ESR2, CYP19A1, CYP17A1, SHBG, SRD5A2, LHB, and LHCGR. QUS parameters broadband ultrasound attenuation (BUA) and speed of sound (SOS) were measured in the heel and used to derive BMD. The relationships between QUS parameters and polymorphisms were assessed using linear regression adjusting for age and center. A total of 2693 men, with a mean age of 60.1 +/- 11.1 (SD) yr were included in the analysis. Their mean BUA was 80.0 +/- 18.9 dB/Mhz, SOS was 1550.2 +/- 34.1 m/s, and BMD was 0.542 +/- 0.141 g/cm(2). Significant associations were observed between multiple SNPs in a linkage disequilibrium (LD) block within CYP19A1, peaking at the TCT indel with the deletion allele associating with reduced ultrasound BMD in heterozygotes (beta =-0.016, p = -0.005) and homozygotes (beta = -0.029, p = 0.001). The results for BUA and SOS were similar. Significant associations with QUS parameters were also observed for the CAG repeat in AR and SNPs in CYP17A1, LHCGR, and ESR1. Our data confirm evidence of association between bone QUS parameters and polymorphisms in CYP19A1, as well as modest associations with polymorphisms in CYP17A1, ESR1, LHCGR, and AR in a population sample of European men; this supports a role for genetically determined sex hormone actions in influencing male bone health.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 10/2008; 24(2):314-23. · 6.04 Impact Factor
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ABSTRACT: A defect in hypothalamic-pituitary-adrenal (HPA) axis function has been suggested to contribute to susceptibility to rheumatoid arthritis (RA).
To investigate polymorphisms of the glucocorticoid receptor (GR) gene and determine any associations with RA.
Three GR polymorphisms that tag 95% of all haplotypes across the GR gene were genotyped. These are an intron B Bcl1 polymorphism, a ttg insertion/deletion within intron F (rs2307674) and the single nucleotide polymorphism (SNP) lying in the 3' untranslated region of exon 9b (rs6198). The dye terminator-based SNaPshot method or size resolution by capillary electrophoresis was performed. The study population comprised 198 UK Caucasian RA cases and 393 ethnically matched controls.
No significant single point or haplotypic associations were found for GR polymorphisms with RA susceptibility. Furthermore, no evidence for GR polymorphisms with aspects of RA severity was seen.
In this study of the most comprehensive coverage of GR polymorphisms with RA, no significant contributing role for GR polymorphisms with RA was found.
Clinical Endocrinology 10/2007; 67(3):342-5. · 3.17 Impact Factor
