Association of Crohn's disease-related chromosome 1q32 with ankylosing spondylitis is independent of bowel symptoms and faecal calprotectin.

BACKGROUND: Genome-wide association studies have identified a plethora of risk genes for both Crohn's disease (CD) and ankylosing spondylitis (AS). A subset of genes found to be risk factors for CD have also been found to be risk factors for AS. The objective of our study was to assess whether CD risk genes were associated with non-invasive clinical markers of gut inflammation in patients with AS, indicating a potential subset of patients with clinical as well as genetic overlap. METHODS: A total of 308 Caucasian patients who fulfilled the modified New York Criteria for AS, were assessed for bowel symptoms using the Dudley Inflammatory Bowel Symptom Questionnaire (DISQ). Of these patients, 157 also had faecal calprotectin measured. All AS patients and 568 healthy controls were genotyped for 10 CD risk loci using predesigned single nucleotide polymorphism (SNP) genotyping assays. Chi-square analysis was used to test for association between genotype and DISQ score and faecal calprotectin level. RESULTS: The minor allele of two SNPs, one in chromosome region 1q32 SNP (rs11584383), and one in the gene coding for IL23R (rs11209026) conferred protection against AS. Only the association of 1q32 remained significant after Bonferroni correction for multiple testing. Stratification by DISQ score and faecal calprotectin did not influence the association of 1q32 with AS. CONCLUSION: In patients with AS, the association of the CD 1q32 SNP was independent of non-invasive markers of bowel inflammation. Other CD related SNPs were not found have a significant association with AS.

Nonsynonymous Polymorphism in Guanine Monophosphate Synthetase Is a Risk Factor for Unfavorable Thiopurine Metabolite Ratios in Patients With Inflammatory Bowel Disease.

Background: Up to 20% of patients with inflammatory bowel disease (IBD) who are refractory to thiopurine therapy preferentially produce 6-methylmercaptopurine (6-MMP) at the expense of 6-thioguanine nucleotides (6-TGN), resulting in a high 6-MMP:6-TGN ratio (>20). The objective of this study was to evaluate whether genetic variability in guanine monophosphate synthetase (GMPS) contributes to preferential 6-MMP metabolizer phenotype. Methods: Exome sequencing was performed in a cohort of IBD patients with 6-MMP:6-TGN ratios of >100 to identify nonsynonymous single nucleotide polymorphisms (nsSNPs). In vitro assays were performed to measure GMPS activity associated with these nsSNPs. Frequency of the nsSNPs was measured in a cohort of 530 Caucasian IBD patients. Results: Two nsSNPs in GMPS (rs747629729, rs61750370) were detected in 11 patients with very high 6-MMP:6-TGN ratios. The 2 nsSNPs were predicted to be damaging by in silico analysis. In vitro assays demonstrated that both nsSNPs resulted in a significant reduction in GMPS activity (P < 0.05). The SNP rs61750370 was significantly associated with 6-MMP:6-TGN ratios ≥100 (odds ratio, 5.64; 95% confidence interval, 1.01-25.12; P < 0.031) in a subset of 264 Caucasian IBD patients. Conclusions: The GMPS SNP rs61750370 may be a reliable risk factor for extreme 6MMP preferential metabolism.

Association between ABCG2 rs2231142 and poor response to allopurinol: replication and meta-analysis.

Objective: ABCG2 rs2231142 (Q141K) has been reported to be associated with poor response to allopurinol, while there are conflicting data on the association between the genetically independent ABCG2 rs10011796 variant and allopurinol response. The aim of this study was to replicate the association of ABCG2 rs2231142 and rs10011796 with allopurinol response and perform a meta-analysis. Methods: Participants in the Long-term Allopurinol Safety Study Evaluating Outcomes in Gout Patients (LASSO) (n = 299) were studied. In patients with evidence of adherence to allopurinol therapy (plasma oxypurinol >20 µmol/l), good response was defined as serum urate <6 mg/dl on allopurinol ⩽300 mg/day and poor response as serum urate ⩾ 6 mg/dl despite allopurinol >300 mg/day. Association of rs2231142 and rs10011796 with poor response was tested in logistic regression models that included age, sex, BMI, ethnicity and estimated glomerular filtration rate. Results from the LASSO study and a subset of participants in the Genetics of Gout in Aotearoa New Zealand study (n = 296, including 264 from a previously published report) were combined by meta-analysis. Results: There was evidence for association of rs2231142 with allopurinol response [odds ratio (OR) = 2.35, P = 7.3 × 10-4] but not for rs10011796 (OR = 1.21, P = 0.33) in the LASSO cohort using an adjusted logistic regression model. Meta-analysis provided evidence of a significant association of rs2231142 with allopurinol response (OR = 2.43, P = 6.2 × 10-7), but not rs10011796 (OR = 1.06, P = 0.69). Conclusion: This study has confirmed the significant association of ABCG2 rs2231142 with poor response to allopurinol.

Reduction of Central Line-Associated Bloodstream Infection Rates in Patients in the Adult Intensive Care Unit.

Central line-associated bloodstream infections (CLABSIs) prolong hospital stays and increase cost, morbidity, and mortality. An intensive care unit (ICU) in a suburban Baltimore hospital reduced CLABSI rates to zero in 2012, by revising central venous access device policies and initiatives, which included a bloodstream infection alert system, bundle compliance monitoring and routine evaluation, and use of positive displacement needleless connectors. The hospital's ICU infection rate decreased from 2.9/1000 central-line days in 2010 to 0.8 by 2011, 0 by 2012, and 0.91 in 2013. The utilization ratio was 0.64 in 2011, 0.60 in 2012, and 0.58 in 2013. CLABSI prevention involves all disciplines and requires staff accountability for patient safety.

A human leukocyte antigen locus haplotype confers risk for allopurinol-related adverse effects in Caucasian patients with gout.

A human leukocyte antigen haplotype comprising six single-nucleotide polymorphisms (SNPs) confers risk for allopurinol hypersensitivity syndrome in Caucasians. The objective of the current study was to test for association of this haplotype with other, less severe adverse effects (AEs) of allopurinol therapy in a large New Zealand gout cohort. A total of 626 Caucasian and 766 Polynesian patients were genotyped for six SNPs (rs2844665, rs9263715, rs3130931, rs3130501, rs3094188, rs9469003) using TaqMan SNP assays. The CACGAC haplotype occurred at a frequency of 0.018 in Caucasians and 0.009 in Polynesians. The CACGAC haplotype occurred at a significantly higher frequency in Caucasian patients who experienced allopurinol-related AEs (13.3 vs. 1.7%, P=8.9e-06, odds ratio=8.9, 95% confidence interval 2.8-27.9), but it was not associated with overall allopurinol toxicity in Polynesians (P>0.05). Our study is the first to demonstrate the potential utility of this six-SNP haplotype as a predictor of milder allopurinol AEs.

Correlation between trough plasma dabigatran concentrations and estimates of glomerular filtration rate based on creatinine and cystatin C.

AIMS: Dabigatran is largely cleared by renal excretion. Renal function is thus a major determinant of trough dabigatran concentrations, which correlate with the risk of thromboembolic and haemorrhagic outcomes. Current dabigatran dosing guidelines use the Cockcroft-Gault (CG) equation to gauge renal function, instead of contemporary equations including the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations employing creatinine (CKD-EPI_Cr), cystatin C (CKD-EPI_Cys) and both renal biomarkers (CKD-EPI_CrCys). METHODS: A linear regression model including the dabigatran etexilate maintenance dose rate, relevant interacting drugs and genetic polymorphisms (including CES1), was used to analyse the relationship between the values from each renal function equation and trough steady-state plasma dabigatran concentrations. RESULTS: The median dose-corrected trough steady-state plasma dabigatran concentration in 52 patients (38-94 years) taking dabigatran etexilate was 60 µg/L (range 9-279). The dose-corrected trough concentration in a patient on phenytoin and phenobarbitone was >3 standard deviations below the cohort mean. The CG, CKD-EPI_Cr, CKD-EPI_Cys and CKD-EPI_CrCys equations explained (R (2), 95 % CI) 32 % (9-55), 37 % (12-60), 41 % (16-64) and 47 % (20-69) of the variability in dabigatran concentrations between patients, respectively. One-way analysis of variance (ANOVA) comparing the R (2) values for each equation was not statistically significant (p = 0.74). DISCUSSION: Estimates of renal function using the four equations accounted for 32-47 % of the variability in dabigatran concentrations between patients. We are the first to provide evidence that co-administration of phenytoin/phenobarbitone with dabigatran etexilate is associated with significantly reduced dabigatran exposure.

Identification of a novel thiopurine S-methyltransferase allele (TPMT*37).

Thiopurine S-methyltransferase (TPMT) is a key enzyme in the methylation of the thiopurine drugs azathioprine and 6-mercaptopurine. TPMT is subject to genetic polymorphism that results in a trimodal distribution of enzyme activity. All poor methylators (PMs) and 30-60% of intermediate methylators develop potentially life-threatening myelosuppression on standard doses of azathioprine and 6-mercaptopurine because of excess production of the thioguanine nucleotides (6-TGNs). Over 95% of PMs are explained by the alleles TPMT*2 and TPMT*3, whereas one in 20 intermediate methylators are heterozygous for a novel PM allele. In this brief report, we describe the identification of a novel allele (TPMT*37) in a Caucasian male who had a red blood cell TPMT activity of 8.9 U/ml (reference range: 9.3-17.6 U/ml). TPMT*37 introduces a premature stop codon at position 216, resulting in loss of the last 29 amino acid residues from the C terminal of the TPMT protein.

Frequency of CYP2C9 polymorphisms in Polynesian people and potential relevance to management of gout with benzbromarone.

OBJECTIVES: Gout is a major health problem in Polynesians and allopurinol, the drug of choice for the management gout, appears to be less effective in Polynesian patients. The uricosuric drug benzbromarone is an alternative treatment but CYP2C9 poor metabolisers (PMs) may be at a heightened risk of benzbromarone-induced hepatotoxicity. The objectives of this study were to determine the frequency of the PM alleles CYP2C9*2 and CYP2C9*3 in New Zealand (NZ) Caucasian and Polynesian gout cohorts; and then to test for novel CYP2C9 polymorphisms in Polynesians. METHODS: Eight hundred and fifty-two Caucasians (537 controls, 315 gout patients) and 1072 Maori and Pacific Island (Polynesian) people (620 controls, 452 gout patients) were genotyped for CYP2C9*2 and CYP2C9*3. Forty Polynesians were screened for novel CYP2C9 polymorphisms using whole genome sequencing. RESULTS: Frequency of CYP2C9 PM alleles was significantly higher in Caucasians compared to Polynesians (CYP2C9*2: 13.5% versus 3.1%; CYP2C9*3: 5.5% versus 1.6%, P<1.2E-11). Within Polynesians, CYP2C9 PM alleles were rarer in Western Polynesians (Samoa, Tonga) than Eastern Polynesians (NZ and Cook Island Maori; CYP2C9*2: 0.6% versus 2.5%; CYP2C9*3: 0.4% versus 2.0%; P<0.03). A total of 152 SNPs were found by sequencing. None of these variants were predicted by in silico analysis to significantly impact on CYP2C9 expression or activity. CONCLUSION: Prospective CYP2C9 genotyping of Caucasian gout patients may be warranted for benzbromarone, whereas the low frequencies of CYP2C9 PM alleles in Polynesians suggests that the CYP2C9 polymorphism may be of little or no relevance to benzbromarone prescribing in this population.

Prevalence of HLA-B27 in the New Zealand population: effect of age and ethnicity.

INTRODUCTION: HLA-B27 genotyping is commonly used to support a diagnosis of ankylosing spondylitis (AS). A recent study has suggested that HLA-B27 may adversely affect longevity. The objectives of this study were to determine, for the first time, the prevalence of HLA-B27 in the New Zealand population, and to test whether HLA-B27 prevalence declines with age. METHODS: 117 Caucasian controls, 111 New Zealand Maori controls, and 176 AS patients were directly genotyped for HLA-B27 using PCR-SSP. These participants and a further 1103 Caucasian controls were genotyped for the HLA-B27 tagging single nucleotide polymorphisms (SNPs) rs4349859 and rs116488202. All AS patients testing positive for HLA-B27 of New Zealand Maori ancestry underwent high resolution typing to determine sub-allele status. RESULTS: HLA-B27 prevalence was 9.2% in New Zealand Caucasian controls and 6.5% in Maori controls. No decline in HLA-B27 prevalence with age was detected in Caucasian controls (p = 0.92). Concordance between HLA-B27 and SNP genotypes was 98.7-99.3% in Caucasians and 76.9-86% in Maori. Of the 14 AS patients of Maori ancestry, 1 was negative for HLA-B27, 10 were positive for HLAB*2705, and 3 positive for HLAB*2704. All cases of genotype discordance were explained by the presence of HLAB*2704. CONCLUSIONS: HLA-B27 prevalence in New Zealand Caucasians is consistent with that of Northern European populations and did not decline with increasing age. In Maori with AS who were HLA-B27 positive, 76.9% were positive for HLA-B*2705, suggesting that genetic susceptibility to AS in Maori is primarily due to admixture with Caucasians.

Association of the HLA locus and TNF with type I autoimmune hepatitis susceptibility in New Zealand Caucasians.

PURPOSE: The precise etiology of autoimmune hepatitis (AIH) remains unknown, although a number of genetic loci have been implicated in the susceptibility of type 1 AIH. The purpose of this study was to test for association of these loci with type 1 AIH in New Zealand Caucasians. METHODS: 77 AIH patients and 485 healthy controls were genotyped for the SNPs rs2187668 (HLA-DRB*03:01), rs660895 (HLA-DRB*04:01), rs3749971 (HLA-A1-B8-DR3), rs231775 (CLTLA4), rs1800629 (TNF), and rs1800682 (FAS) using predesigned TaqMan SNP genotyping assays. Chi square analysis was used to test for association of allele and genotype with overall AIH, and with severe fibrosis and ALT levels at 6 months. RESULTS: Significant risk of AIH was conferred by the minor alleles of rs2187668 (OR = 2.45, 95% CI 1.65-3.61, p < 0.0001), rs3749971 (OR = 1.89, 95% CI 1.21-2.94, p = 0.004) and rs1800629 (OR = 2.06, 95% CI 1.41-3.01, p = 0.0001). Multivariate analysis showed that rs2187668 was independently associated with type 1 AIH susceptibility (OR = 2.40, 95% CI 1.46-3.93, p = 0.001). The C allele of FAS SNP rs1800682 was associated with increased risk of severe fibrosis at diagnosis (OR = 2.03, 95% CI 1.05-3.93, p = 0.035) and with incomplete normalization of ALT levels at 6 months post-diagnosis (OR = 3.94, 95% CI 1.62-9.54, p = 0.0015). CONCLUSIONS: This is the first population-based study to investigate genetic risk loci for type 1 AIH in New Zealand Caucasians. We report significant independent association of HLA-DRB1*03:01 with overall susceptibility to type 1 AIH, as well as FAS with a more aggressive disease phenotype.