Biomedical subjects

Cathryn M Lewis

Publications and source records attributed to Cathryn M Lewis.

At least 19 recordsLinked to original sources

PubMed2026

Metabolomic ageing across mental and behavioural disorders.

BACKGROUND: Individuals with mental disorders face excess morbidity and premature mortality. Accelerated ageing has been proposed as a contributing mechanism but population-scale evidence across diverse diagnoses is limited. OBJECTIVE: To examine whether metabolomic ageing differs across mental disorders and whether associations vary by sex, age group and genetic liability. METHODS: Using plasma metabolomic profiles from UK Biobank participants, we applied a metabolomic ageing clock (MileAge) to estimate disorder-specific differences between metabolite-predicted and chronological age. Mental disorders were ascertained from health records and self-reported physician diagnoses. We analysed nine diagnostic groups and 45 individual disorders and assessed sex and age group differences and associations with polygenic scores. FINDINGS: Among 225 212 participants (54% female; mean age 56.97), 38 524 had a diagnosis preceding baseline. Substance use, psychotic, affective and neurotic disorders were associated with a metabolite-predicted age older than chronological age, largest for psychosis (β=0.556, 95% CI 0.250 to 0.861, p<0.001). Obsessive-compulsive and eating disorders were associated with a metabolite-predicted age younger than chronological age. Several associations were stronger in males and in individuals aged <65 years. Higher genetic liability to depression, autism and attention-deficit/hyperactivity disorder predicted an older metabolomic age (β range=0.020 to 0.047), whereas polygenic scores for psychosis and tobacco use disorder predicted a younger metabolomic age (β range=-0.023 to -0.040). For obsessive-compulsive disorder and anorexia nervosa, clinical and genetic associations indicated younger metabolomic ageing. CONCLUSIONS: Metabolomic ageing in mental disorders is heterogeneous. While many disorders are associated with an older biological age, some are linked to a younger biological age. Divergence between genetic liability and clinical phenotypes suggests that non-genetic factors shape biological ageing differences. CLINICAL IMPLICATIONS: Biological age should not be assumed to uniformly exceed chronological age across mental disorders. Sex and age-specific approaches could improve understanding of biological ageing processes in psychiatry.

Humans↗

PubMed2025

Associations of Genetic Liability to Six Psychiatric Disorders With Cardiometabolic Diseases.

IMPORTANCE: Individuals with psychiatric disorders have increased risk of cardiometabolic diseases (CMDs). Evaluating how psychiatric genetic liability relates to CMD may clarify mechanisms. OBJECTIVE: Identify genetic overlap between psychiatric disorders and CMDs independent of cross-disorder pleiotropy, BMI, and smoking. DESIGN SETTING AND PARTICIPANTS: Three Northern European cohorts (the Swedish Twin Registry, the Estonian Biobank, and the Norwegian Mother, Father and Child Cohort Study [MoBa]) totaling 355,159 individuals. Associations with CMDs were estimated as adjusted odds ratios (AORs) from logistic models mutually adjusted for all psychiatric PRSs and in models additionally adjusting for body mass index (BMI) and smoking. Cohort-specific AORs were pooled by inverse-variance weighting. MAIN OUTCOMES AND MEASURES: Exposures were PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), anxiety disorder, posttraumatic stress disorder (PTSD), bipolar disorder, and schizophrenia. Outcomes were diagnoses of CMDs (hyperlipidemia, obesity, type 2 diabetes, hypertensive diseases, arteriosclerosis, ischemic heart disease, heart failure, thromboembolic disease, cerebrovascular disease, and arrhythmias), ascertained from electronic health records. RESULTS: The MDD PRS was associated with increased risk of all CMDs across analyses (AORs ranged from 1.13 [95% CI, 1.10-1.15] for heart failure to 1.02 [95% CI, 1.00-1.05] for arrhythmias). The ADHD PRS was associated with increased risk of all CMDs (AOR ranged from 1.11 [95% CI, 1.09-1.12] for obesity to 1.02 [95% CI, 1.01-1.03] for hyperlipidemia), however associations where attenuated when adjusting for BMI and smoking (lifestyle adjusted AOR for obesity: 1.03 [95% CI, 1.02-1.05]). When not mutually adjusting for all psychiatric PRSs, anxiety disorder and PTSD PRSs were associated with all CMDs; these associations diminished after adjustment. The bipolar and schizophrenia PRSs were inversely associated with most CMDs (AOR for schizophrenia PRS and obesity, 0.93 [95% CI, 0.92-0.94]). CONCLUSIONS AND RELEVANCE: Associations between psychiatric PRSs and CMDs diverged: ADHD, MDD, anxiety disorder, and PTSD PRSs were positively associated with CMDs, whereas bipolar and schizophrenia PRSs were inversely associated. Genetic liability to MDD showed robust associations with CMDs independent of cross-disorder pleiotropy, BMI, and smoking status, whereas associations between the ADHD PRS and CMDs were largely attenuated after adjustment for BMI and smoking.

Journal Article↗

PubMed2007

Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass.

UNLABELLED: Several genome-wide scans have been performed to detect loci that regulate BMD, but these have yielded inconsistent results, with limited replication of linkage peaks in different studies. In an effort to improve statistical power for detection of these loci, we performed a meta-analysis of genome-wide scans in which spine or hip BMD were studied. Evidence was gained to suggest that several chromosomal loci regulate BMD in a site-specific and sex-specific manner. INTRODUCTION: BMD is a heritable trait and an important predictor of osteoporotic fracture risk. Several genome-wide scans have been performed in an attempt to detect loci that regulate BMD, but there has been limited replication of linkage peaks between studies. In an attempt to resolve these inconsistencies, we conducted a collaborative meta-analysis of genome-wide linkage scans in which femoral neck BMD (FN-BMD) or lumbar spine BMD (LS-BMD) had been studied. MATERIALS AND METHODS: Data were accumulated from nine genome-wide scans involving 11,842 subjects. Data were analyzed separately for LS-BMD and FN-BMD and by sex. For each study, genomic bins of 30 cM were defined and ranked according to the maximum LOD score they contained. While various densitometers were used in different studies, the ranking approach that we used means that the results are not confounded by the fact that different measurement devices were used. Significance for high average rank and heterogeneity was obtained through Monte Carlo testing. RESULTS: For LS-BMD, the quantitative trait locus (QTL) with greatest significance was on chromosome 1p13.3-q23.3 (p = 0.004), but this exhibited high heterogeneity and the effect was specific for women. Other significant LS-BMD QTLs were on chromosomes 12q24.31-qter, 3p25.3-p22.1, 11p12-q13.3, and 1q32-q42.3, including one on 18p11-q12.3 that had not been detected by individual studies. For FN-BMD, the strongest QTL was on chromosome 9q31.1-q33.3 (p = 0.002). Other significant QTLs were identified on chromosomes 17p12-q21.33, 14q13.1-q24.1, 9q21.32-q31.1, and 5q14.3-q23.2. There was no correlation in average ranks of bins between men and women and the loci that regulated BMD in men and women and at different sites were largely distinct. CONCLUSIONS: This large-scale meta-analysis provided evidence for replication of several QTLs identified in previous studies and also identified a QTL on chromosome 18p11-q12.3, which had not been detected by individual studies. However, despite the large sample size, none of the individual loci identified reached genome-wide significance.

Bone Density↗

PubMed2006

Investigation of association of the DLG5 gene with phenotypes of inflammatory bowel disease in the British population.

BACKGROUND AND AIMS: Mutations in the DLG5 gene are associated with an increased risk of inflammatory bowel disease (IBD) in some European populations. Initial investigation of a British IBD population showed evidence of association of one of three DLG5 variants, R30Q, in a family-based collection but not in a case-control cohort. We have now examined the association of the R30Q polymorphism in a large cohort of British IBD cases, tested for interaction between the DLG5 and CARD15 genes and assessed possible association of DLG5 with clinical features of Crohn's disease (CD) and ulcerative colitis (UC). MATERIALS AND METHODS: DLG5 R30Q and the CARD15 polymorphisms, Arg702Trp, Gly908Arg and Leu1007fs were genotyped in 1,148 IBD cases and 749 controls. DLG5 R30Q was also analysed in cases stratified by CARD15 genotype, disease subtype and smoking history. RESULTS/FINDINGS: No significant difference in frequencies of the R30Q variant was observed between IBD cases (9.9%) and controls (10.1%) or in cases analysed separately as CD and UC. There was also no significant difference in the frequency of R30Q between CD cases carrying risk-associated CARD15 alleles and those that did not. The frequency of R30Q was higher in CD cases with ileal disease than cases without (p=0.042) and higher in CD cases who had smoked than in nonsmokers (p=0.009). INTERPRETATION/CONCLUSION: The R30Q variant in the DLG5 gene does not appear to be associated with an overall increase in the risk of disease in a British IBD cohort, but differences in its frequency in subgroups of CD patients warrant further investigation.

Case-Control Studies↗

PubMed2006

Testing for genetic heterogeneity in the genome search meta-analysis method.

The Genome Search Meta-Analysis (GSMA) method is widely used to detect linkage by pooling results of previously published genome-wide linkage studies. The GSMA uses a non-parametric summed rank statistic in 30 cM bins of the genome. Zintzaras and Ioannidis ([2005] Genet. Epidemiol. 28:123-137) developed a method of testing for heterogeneity of evidence for linkage in the GSMA, with three heterogeneity statistics (Q, Ha, B). They implement two testing procedures, restricted versus unrestricted for the summed rank within the bin. We show here that the rank-unrestricted test provides a conservative test for high heterogeneity and liberal test for low heterogeneity in linked regions. The rank-restricted test should therefore be used, despite the extensive simulations needed. In a simulation study, we show that the power to detect heterogeneity is low. For 20 studies of affected sib pairs, simulated assuming linkage in all studies to a gene with sibling relative risk of 1.3, the power to detect low heterogeneity using the Q statistic was 14%. With linkage present in 50% of the studies (to a gene with sibling relative risk of 1.4), the Q heterogeneity statistic had power of 29% to detect high heterogeneity. The power to detect linkage using the summed rank was high in both of these situations, at 98% and 79%, respectively. Although testing for heterogeneity in the GSMA is of interest, the currently available method provides little additional information to that provided by the summed rank statistic.

Genetic Heterogeneity↗

PubMed2006

Mutation, selection, and evolution of the Crohn disease susceptibility gene CARD15.

Three common mutations in the CARD15 (NOD2) gene are known to be associated with susceptibility to Crohn disease (CD), and genetic data suggest a gene dosage model with an increased risk of 2-4-fold in heterozygotes and 20-40-fold in homozygotes. However, the discovery of numerous rare variants of CARD15 indicates that some heterozygotes for the common mutations have a rare mutation on the other CARD15 allele, which would support a recessive model for CD. We addressed this issue by screening CARD15 for mutations in 100 CD patients who were heterozygous for one of the three common mutations. We also developed a strategy for evaluating potential disease susceptibility alleles (DSAs) that involves assessing the degree of evolutionary conservation of involved residues, predicted effects on protein structure and function, and genotyping in a large sample of cases and controls. The evolutionary analysis was aided by sequencing the entire coding region of CARD15 in three primates (chimp, gibbon, and tamarin) and aligning the human sequence with these and orthologs from other species. We found that 11 of the 100 CD patients screened had a second potential pathogenic mutation within the exonic and periexonic sequences examined. Assuming that there are no additional pathogenic mutations in noncoding regions, our study suggests that most carriers of the common DSAs are true heterozygotes, and supports previous evidence for a gene dosage model. Four novel nonsynonymous mutations were detected, one of which would produce premature termination of translation c.2686C>T (p.Arg896X). Two potential DSAs--c.2107C>T (p.Arg703Cys) and g.2238T>A (c.74-7T>A)--were significantly associated with CD in the case control sample. Analysis of the evolution of CARD15 revealed strong conservation of the encoded protein, with identity to the human sequence ranging from 99.1% in the chimp to 44.5% in fugu. Higher primates possess an open reading frame (ORF) upstream of the putative initiation site in other species that encodes a further 27 N-terminal amino acids, while four regions of high conservation are observed outside of the known domains of CARD15, indicative of additional residues of functional importance. The strategy developed here may have general application to the assessment of mutation pathogenicity and genetic models in other complex disorders.

Alleles↗

PubMed2006

Direct or indirect association in a complex disease: the role of SLC22A4 and SLC22A5 functional variants in Crohn disease.

A common haplotype spanning 250 kb on chromosome 5q31 is strongly associated with Crohn disease (CD). Recently, two functional variants within the SLC22A4 and SLC22A5 genes at this locus (IBD5), L503F (c.1507C > T) and G-207C (c.-207G > C), have been proposed to contribute directly to susceptibility to CD. However, extensive linkage disequilibrium at the IBD5 locus has complicated efforts to distinguish causal variants from association of the general risk haplotype. We genotyped the SLC22A4 and SLC22A5 variants and other polymorphisms across the risk haplotype in four populations of European origin, and applied regression-based haplotype analysis to over 1,200 fully genotyped case-control pairs, modeling case/control status on the presence of one or more SNPs to test for conditional association and to identify risk haplotypes. We found highly significant association of SNPs at the IBD5 locus with Crohn disease in all populations tested. However, the frequencies of L503F and G-207C in individuals who did not carry the general IBD5 risk haplotype were not significantly different in cases and controls, with associated disease odds ratios (ORs) of 0.90 (95% CI, 0.57-1.40) and 0.90 (95% CI, 0.65-1.23), respectively. Haplotype analysis showed that addition of the SLC22A4 and SLC22A5 variants to a null model that included the background risk haplotype did not significantly improve the model fit. In addition to the common risk haplotype, several rare haplotypes had an increased frequency in cases compared to controls. This study suggests that the molecular basis for Crohn disease susceptibility at the IBD5 locus remains to be defined, and highlights the challenge of the identification of causal variants in a complex disease in regions of extensive linkage disequilibrium.

Case-Control Studies↗

PubMed2006

Associations of allelic variants of the multidrug resistance gene (ABCB1 or MDR1) and inflammatory bowel disease and their effects on disease behavior: a case-control and meta-analysis study.

BACKGROUND: Allelic variants of the ATP-binding cassette, subfamily B member 1 (ABCB1), also known as the multidrug resistance gene (MDR1) that encodes the membrane-bound efflux transporter P-glycoprotein 170 (PGP-170), have been associated with inflammatory bowel disease but with conflicting results. METHODS: The present study examined the association of ABCB1 C3435T and G2677T/A in a large British case-control cohort of 828 Crohn's disease, 580 ulcerative colitis (UC) cases, and 285 healthy controls. The effect of these variants was further examined with respect to phenotypic and epidemiological characteristics. A meta-analysis was carried out of our results and those from 8 previously published association studies of the C3435T variant in inflammatory bowel disease. RESULTS: The 2677T allele was significantly increased in British UC cases compared with controls (45.2% vs. 39.6%; P = 0.034). In particular, the TT genotype was significantly associated with severe UC (odds ratio [OR] 1.90; 95% CI 1.01-3.55) and the use of steroids in UC (OR 1.77; 95% CI 1.08-2.88). No significant association was seen with C3435T and UC, Crohn's disease, or any clinical subgroup. A meta-analysis of 9 association studies of C3435T showed a significant association of the 3435T allele with UC (OR 1.12; 95% CI 1.02-1.23; P = 0.013) but not with CD. CONCLUSIONS: These results indicate that ABCB1 sequence variants are associated with a small increase in the risk of developing UC and may influence disease behavior.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2006

Novel IL10 gene family associations with systemic juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) is the most common cause of chronic childhood disability and encompasses a number of disease subgroups. In this study we have focused on systemic JIA (sJIA), which accounts for approximately 11% of UK JIA cases. This study reports the investigation of three members of the IL10 gene family as candidate susceptibility loci in children with sJIA. DNA from 473 unaffected controls and 172 patients with sJIA was genotyped for a single nucleotide polymorphism (SNP) in IL19 and IL20 and two SNPs in IL10. We examined evidence for association of the four SNPs by single marker and haplotype analysis. Significant differences in allele frequency were observed between cases and controls, for both IL10-1082 (p = 0.031) and IL20-468 (p = 0.028). Furthermore, examination of the haplotypes of IL10-1082 and IL20-468 revealed greater evidence for association (global p = 0.0006). This study demonstrates a significant increased prevalence of the low expressing IL10-1082 genotype in patients with sJIA. In addition, we show a separate association with an IL20 polymorphism, and the IL10-1082A/IL20-468T haplotype. The two marker 'A-T' haplotype confers an odds ratio of 2.24 for sJIA. This positive association suggests an important role for these cytokines in sJIA pathogenesis.

Adolescent↗

PubMed2005

GSMA: software implementation of the genome search meta-analysis method.

Meta-analysis can be used to pool results of genome-wide linkage scans. This is of great value in complex diseases, where replication of linked regions occurs infrequently. The genome search meta-analysis (GSMA) method is widely used for this analysis, and a computer program is now available to implement the GSMA.

Chromosome Mapping↗

PubMed2005

Meta-analysis of genome scans of age-related macular degeneration.

A genetic contribution to the development of age-related macular degeneration (AMD) is well established. Several genome-wide linkage studies have identified a number of putative susceptibility loci for AMD but only a few of these regions have been replicated in independent studies. Here, we perform a meta-analysis of six AMD genome screens using the genome-scan meta-analysis method, which allows linkage results from several studies to be combined, providing greater power to identify regions that show only weak evidence for linkage in individual studies. Results from non-parametric analysis for a broad AMD clinical phenotype (including two studies with quantitative traits) were extracted. For each study, 120 genomic bins of approximately 30 cM were defined and ranked according to maximum evidence for linkage within each bin. Bin ranks were weighted according to study size and summed across all studies; the summed rank (SR) for each bin was assessed empirically for significance using permutation methods. A high SR indicates a region with consistent evidence for linkage across studies. The strongest evidence for an AMD susceptibility locus was found on chromosome 10q26 where genome-wide significant linkage was observed (P=0.00025). Several other regions met the empirical significance criteria for bins likely to contain linked loci including adjacent pairs of bins on chromosomes 1q, 2p, 3p and 16. Several of the regions identified here showed only weak evidence for linkage in the individual studies. These results will help prioritize regions for future positional and functional candidate gene studies in AMD.

Aging↗

PubMed2005

A common Fanconi anemia mutation in black populations of sub-Saharan Africa.

Fanconi anemia (FA) is a genetically heterogeneous chromosomal instability syndrome associated with multiple congenital abnormalities, aplastic anemia, and cancer. We report that a deletion mutation in the FANCG gene (c.637_643delTACCGCC) was present in 82% of FA patients in the black populations of Southern Africa. These patients originated from South Africa, Swaziland, Mozambique, and Malawi. The mutation was found on the same haplotype and was present in 1% of controls from the black South African population. These data indicate that the birth incidence of FA in this population is higher than 1 in 40 000, which is much higher than previously supposed, and suggest that the FANCG deletion is an ancient founder mutation in Bantu-speaking populations of sub-Saharan Africa. Diagnostic screening is now possible by means of a simple DNA test.

Africa South of the Sahara↗

PubMed2005

Association of DLG5 R30Q variant with inflammatory bowel disease.

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the gastrointestinal system known as the inflammatory bowel diseases (IBD). Recently, Stoll and colleagues reported a novel finding of genetic variation in the DLG5 gene that is associated with IBD (CD and UC combined). We present here a study of the genetic variation described in that report in two well-powered, independent case-control cohorts and one family-based collection, and confirm the proposed association between IBD and the R30Q variant of DLG5 in two of the three studies. We are, however, unable to replicate the other proposed association to the common haplotype described in Stoll et al and suggest that this other finding could conceivably have been partially a statistical fluctuation and partially a result of LD with the replicated R30Q association. This study provides support for the hypothesis that DLG5 constitutes a true IBD risk factor of modest effect.

Case-Control Studies↗

PubMed2005

Genetic variation in the MTHFR gene influences thiopurine methyltransferase activity.

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Genetic Variation↗

PubMed2004

Meta-analysis of genome-wide scans for hypertension and blood pressure in Caucasians shows evidence of susceptibility regions on chromosomes 2 and 3.

Individual genome-wide scans of blood pressure (BP) and hypertension (HT) have shown inconsistent results. The aim of this study was to investigate whether there was any consistent evidence of linkage across multiple studies with similar ethnicity. We applied the genome-search meta-analysis method (GSMA) to nine published genome-wide scans of BP (n = 5) and HT (n = 4) from Caucasian populations. For each study, the genome was divided into 120 bins and ranked according to the maximum evidence of linkage within each bin. The ranks were summed and averaged across studies and significance levels were estimated, on the basis of a distribution function of summed ranks or permutation tests without (PU) or with (PW) a study sample size weighting factor. Chromosome 3p14.1-q12.3 showed consistent evidence of linkage to HT (PU = 0.0001 and PW = 0.0001), diastolic BP (DBP) (PU = 0.007 and PW = 0.02), HT and DBP pooled (PU = 0.00002 and PW = 0.0001) and HT and systolic BP (SBP) pooled (PU = 0.0003 and PW = 0.0005). Chromosome 2p12-q22.1 showed evidence of linkage to HT (PU = 0.003 and PW = 0.009), DBP (PU = 0.05 and PW = NS), HT and DBP pooled (PU = 0.001 and PW = 0.004) and HT and SBP pooled (PU = 0.001 and P W = 0.005). The summed ranks of the HT analysis correlated significantly with those of the DBP (r = 0.20, P = 0.03) but not with those of the SBP. Both loci showed clustering of significant bins in the analysis of HT and DBP. We conclude that modest or non-significant linkage on chromosomes 3p14.1-q12.3 and 2p12-q22.1 in each individual study translates into genome-wide significant or highly suggestive linkages to HT and DBP in our GSMA analysis.

Blood Pressure↗

PubMed2004

Inflammatory bowel disease susceptibility loci defined by genome scan meta-analysis of 1952 affected relative pairs.

Crohn's disease and ulcerative colitis (the inflammatory bowel diseases) have a strong genetic component. Although over 20 putative susceptibility loci have been identified by individual genome scans, the majority of these loci have not been replicated. Many individual studies are at the lower limit of acceptable power for complex disease linkage analysis. Genome scan meta-analysis (GSMA), by use of sample sizes an order of magnitude greater than individual linkage studies, has increased power to detect novel loci, may confirm or refute regions detected in smaller individual studies, and enables regions to be prioritized for further gene identification efforts. Genome scan data (markers, significance scores) were obtained from 10 separate studies and meta-analysis was performed using the GSMA method. These studies comprised 1952 inflammatory bowel disease, 1068 Crohn's disease and 457 ulcerative colitis affected relative pairs. Study results were divided into 34 cM chromosomal bins, ranked, weighted by study size, summed across studies and bin-by-bin significance obtained by simulation. A region on chromosome 6p (containing the HLA) met genome wide significance for inflammatory bowel disease. Loci meeting suggestive significance for inflammatory bowel disease were 2q, 3q, 5q, 7q and 16 (NOD2/CARD15 region); Crohn's disease, 2q, 3q, 6p, 16 (NOD2/CARD15 region), 17q, 19p; and ulcerative colitis, 2q. Clustering of adjacent bins was observed for chromosomes 6p, 16, 19p. The meta-analysis has identified novel loci and prioritized genomic regions for further gene identification studies.

Chromosomes↗

PubMed2004

Genetics of inflammatory bowel disease: progress and prospects.

Strong epidemiological evidence for a genetic contribution to pathogenesis in inflammatory bowel disease (IBD) has stimulated efforts to identify susceptibility genes for both of its major clinical forms, Crohn's disease and ulcerative colitis. Genome scans for linkage have indicated multiple regions of interest, but replication of these has been limited. The detection of linkage on chromosome 16 (IBD1) led to the unequivocal identification of the NOD2 gene (now called CARD15) as a susceptibility gene for Crohn's disease. This seminal discovery has provided proof of principle for positional cloning and candidate gene approaches to identify IBD genes. It has also led to useful strategic insights in complex disease genetics, and generated new directions in the investigation of the molecular pathways to pathogenesis. Linkage and association studies have also provided strong support for IBD susceptibility genes on chromosomes 5q31, 6p21 and 19p, while loci of interest at 3p, 3q and 14q require further follow-up. Although important obstacles to further progress will need to be overcome, the successes of the past 2 years suggest that a detailed description of the genetic basis of inflammatory bowel disease is a realistic goal.

Colitis, Ulcerative↗

PubMed2004

Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase).

Adverse drug reactions to azathioprine (AZA), the pro-drug of 6-mercaptopurine (6-MP), occur in 15% to 28% of patients and the majority are not explained by thiopurine methyltransferase (TPMT) deficiency. Inosine triphosphate pyrophosphatase (ITPase) deficiency results in the benign accumulation of the inosine nucleotide ITP. 6-MP is activated through a 6-thio-IMP intermediate and, in ITPase deficient patients, potentially toxic 6-thio-ITP is predicted to accumulate. The association between polymorphism in the ITPA gene and adverse drug reactions to AZA therapy was studied in patients treated for inflammatory bowel disease. Sixty-two patients with inflammatory bowel disease suffering adverse drug reactions to AZA therapy were genotyped for ITPA 94C>A and IVS2 + 21A>C polymorphisms, and TPMT*3A, *3C, *2 polymorphisms. Genotype frequencies were compared to a consecutive series of 68 controls treated with AZA for a minimum of 3 months without adverse effect. The ITPA 94C>A deficiency-associated allele was significantly associated with adverse drug reactions [odds ratio (OR) 4.2, 95% confidence interval (CI) 1.6-11.5, P = 0.0034]. Significant associations were found for flu-like symptoms (OR 4.7, 95% CI 1.2-18.1, P = 0.0308), rash (OR 10.3, 95% CI 4.7-62.9, P = 0.0213) and pancreatitis (OR 6.2,CI 1.1-32.6, P = 0.0485). Overall, heterozygous TPMT genotypes did not predict adverse drug reactions but were significantly associated with a subgroup of patients experiencing nausea and vomiting as the predominant adverse reaction to AZA therapy (OR 5.5, 95% CI 1.4-21.3, P = 0.0206). Polymorphism in the ITPA gene predicts AZA intolerance. Alternative immunosuppressive drugs, particularly 6-thioguanine, should be considered for AZA-intolerant patients with ITPase deficiency.

Adolescent↗