This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effect of computerised decision support systems (DSSs) on transfusion practice.
DNA polymorphisms in a region on chromosome 5q33.1 which contains two genes, immunity related GTPase related family, M (IRGM) and zinc finger protein 300 (ZNF300), are associated with Crohn's disease ...(CD). The deleted allele of a 20 kb copy number variation (CNV) upstream of IRGM was recently shown to be in strong linkage disequilibrium (LD) with the CD-associated single nucleotide polymorphisms and is itself associated with CD (P < 0.01). The deletion was correlated with increased or reduced expression of IRGM in transformed cells in a cell line-dependent manner, and has been proposed as a likely causal variant. We report here that small insertion/deletion polymorphisms in the promoter and 5′ untranslated region of IRGM are, together with the CNV, strongly associated with CD (P = 1.37 × 10−5 to 1.40 × 10−9), and that the CNV and the 5′-untranslated region variant −308(GTTT)5 contribute independently to CD susceptibility (P = 2.6 × 10−7 and P = 2 × 10−5, respectively). We also show that the CD risk haplotype is associated with a significant decrease in IRGM expression (P < 10−12) in untransformed lymphocytes from CD patients. Further analysis of these variants in a Japanese CD case–control sample and of IRGM expression in HapMap populations revealed that neither the IRGM insertion/deletion polymorphisms nor the CNV was associated with CD or with altered IRGM expression in the Asian population. This suggests that the involvement of the IRGM risk haplotype in the pathogenesis of CD requires gene–gene or gene–environment interactions which are absent in Asian populations, or that none of the variants analysed are causal, and that the true causal variants arose after the European–Asian split.
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 ∼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.
SUMMARY
Background/Objectives
Blood donors attending a donation session may be deemed ineligible to donate blood due to a failure to meet low haemoglobin (Hb) thresholds. Several studies have ...identified factors associated with a donor falling below these Hb thresholds. A review of these factors will inform future prospective studies and form the basis for predictive models of deferral due to low Hb.
Materials/Methods
Studies were identified by searching MEDLINE, EMBASE, The Cochrane Library and the WHO International Clinical Trials Registry from 1980 to September 2012. Demographic data, donor history, haematological/biological factors and the primary outcome of deferral due to low Hb were extracted. Analyses were descriptive and quantitative; pooled odds ratios (ORs) were obtained by meta‐analysis.
Results
Fifty‐five studies met the inclusion criteria. A consistently higher rate of low Hb deferral was reported in females compared with males; meta‐analysis showed a significantly greater risk of deferral due to low Hb in females compared with males in studies with universal Hb thresholds for males and females (OR 14·91, 95% confidence interval (CI) 12·82–17·34) and in studies with sex‐specific Hb thresholds (OR 8·19, 95% CI 4·88–13·74). Greater rates of deferral due to low Hb were also associated with increasing age, higher ambient temperature, low body weight, shorter inter‐donation interval and in donors of Hispanic or African descent.
Conclusion
This work will help to define the criteria that should be considered in any large scale study of blood donor deferral, especially those that measure or aim to change failure to meet low Hb thresholds.
Background & Aims:
Common germline genetic variation in the 3′ region of myosin IXB (
MYO9B) has been associated recently with susceptibility to celiac disease, with a hypothesis that
MYO9B variants ...might influence intestinal permeability. These findings suggested the current study investigating a possible further role for
MYO9B variation in inflammatory bowel disease.
Methods:
Eight single-nucleotide polymorphisms (SNPs) were selected to tag common haplotypes from the 35-kb 3′ region of
MYO9B. These included the strongest celiac disease–associated variants reported in a Dutch cohort. These SNPs were studied in 3 independently collected and genotyped case-control cohorts of European descent (UK, Dutch, and Canadian/Italian), comprising in total 2717 inflammatory bowel disease patients (1197 with Crohn’s disease, 1520 with ulcerative colitis) and 4440 controls.
Results:
Common variation in
MYO9B was associated with susceptibility to inflammatory bowel disease in all 3 cohorts examined (most associated SNP, rs1545620; meta-analysis
P = 1.9 × 10
-6; odds ratio, 1.2), with the same alleles showing association as reported for celiac disease.
Conclusions:
MYO9B genetic variants predispose to inflammatory bowel disease. Interestingly, rs1545620 is a nonsynonymous variant leading to an amino acid change (Ala1011Ser) in the third calmodulin binding IQ domain of MYO9B. Unlike previous variants (in other genes) reported to predispose to inflammatory bowel disease, the association at
MYO9B was considerably stronger with ulcerative colitis, although weaker association with Crohn’s disease also was observed. These data imply shared causal mechanisms underlying intestinal inflammatory diseases.
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.
Autoimmune diseases are chronic disorders initiated by a loss of immunologic tolerance to self-antigens. They cluster within families, and patients may be diagnosed with more than one disease, ...suggesting pleiotropic genes are involved in the aetiology of different diseases. To identify potential loci, which confer susceptibility to autoimmunity independent of disease phenotype, we pooled results from genome-wide linkage studies, using the genome scan meta-analysis method (GSMA). The meta-analysis included 42 independent studies for 11 autoimmune diseases, using 7350 families with 18 291 affected individuals. In addition to the HLA region, which showed highly significant genome-wide evidence for linkage, we obtained suggestive evidence for linkage on chromosome 16, with peak evidence at 10.0-19.8 Mb. This region may harbour a pleiotropic gene (or genes) conferring risk for several diseases, although no such gene has been identified through association studies. We did not identify evidence for linkage at several genes known to confer increased risk to different autoimmune diseases (PTPN22, CTLA4), even in subgroups of diseases consistently found to be associated with these genes. The relative risks conferred by variants in these genes are modest (<1.5 in most cases), and even a large study like this meta-analysis lacks power to detect linkage. This study illustrates the concept that linkage and association studies have power to identify very different types of disease-predisposing variants.
A common haplotype spanning 250 kb in the cytokine gene cluster on chromosome 5q31 has recently been reported to be strongly associated with Crohn disease (CD) in Canadian families. We have ...replicated this finding by both the transmission-disequilibrium test (TDT) (P=.016) and in a case-control association study (P=.008) in a large European cohort of patients with CD, although the increase in disease risk was small (odds ratio 1.49 for homozygotes, 95% CI 1.11–2.0). No association was detected in families or individuals with ulcerative colitis (UC). Stratification of offspring with CD in the TDT sample by mutation status in the CD susceptibility gene CARD15 showed that the association with the 5q31 risk haplotype was present only in offspring with at least one of the known CARD15 disease susceptibility alleles (P=.044). The 5q31 risk haplotype frequency was 53.1% in unrelated individuals with CD who had one or two CARD15 mutations versus 43.7% in control subjects (P=.0001) but was not significantly elevated in individuals with CD who had no CARD15 mutations (45.4%, P=.41). Kaplan-Meier survival analysis of age at disease onset showed a significantly earlier onset in homozygotes for the 5q31 risk haplotype (P=.0019). These findings suggest that genetic variants at the 5q31 (IBD5) locus may hasten the onset of Crohn disease and cooperate with CARD15 in disease causation.
Background/aims: A strong association has been confirmed between age-related macular degeneration (AMD) and variants at two independent loci including Tyr402His in the complement factor H (CFH) on ...1q32 and Ser69Ala at LOC387715, a hypothetical gene on chromosome 10q26. The contribution of both loci to AMD was investigated in an isolated north-west Russian population. Methods: Together with a PLEKHA1 variant at 10q26, the CFH Tyr402His and LOC387715 Ser69Ala polymorphisms were genotyped in 155 patients with AMD and 151 age-matched controls. χ2 and Mantel–Haenszel (M–H) score tests were used to test for association. Sex-adjusted ORs were calculated. Results: The frequency of the Tyr402His C allele was significantly higher in patients with AMD compared with controls (pM–H = 0.0035). The increased risk observed in patients homozygous for the C allele (ORHOM = 2.71, 95% CI 1.25 to 5.90) in this indigenous Russian population was considerably lower than that observed in previous western Caucasian populations. A significant increase in the frequency of the LOC387715 variant was observed in patients with late-stage AMD compared with controls (pM–H = 0.007), with a homozygous OR of 3.47 (95% CI 1.01 to 11.9), although this association was not seen with early-stage AMD. Conclusion: The CFH gene contributes to AMD in this Russian population, although the risk conferred is considerably lower in this population than that found in other Western populations. A contribution of LOC387715 to disease in this population is also likely to be of weak effect.
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