Commentary on "Genetic linkage and transmission disequilibrium of marker haplotypes at chromosome 1q41 in human systemic lupus erythematosus", by RR Graham et al.

Genome-wide linkage analysis studies in families with systemic lupus erythematosus (SLE) have revealed consistent evidence of linkage to several regions of the genome. In a previous issue of this journal, Graham and colleagues described their approach to following up the linkage data for one of these regions, 1q41–42. Using methods based on the transmission disequilibrium test, the region likely to harbour a SLE disease gene was refined to 2.3 Mb. This commentary discusses their approach and identifies lessons that may be applicable to the investigation of other complex diseases

Characterisation of the genomic architecture of human chromosome 17q and evaluation of different methods for haplotype block definition

BACKGROUND: The selection of markers in association studies can be informed through the use of haplotype blocks. Recent reports have determined the genomic architecture of chromosomal segments through different haplotype block definitions based on linkage disequilibrium (LD) measures or haplotype diversity criteria. The relative applicability of distinct block definitions to association studies, however, remains unclear. We compared different block definitions in 6.1 Mb of chromosome 17q in 189 unrelated healthy individuals. Using 137 single nucleotide polymorphisms (SNPs), at a median spacing of 15.5 kb, we constructed haplotype block maps using published methods and additional methods we have developed. Haplotype tagging SNPs (htSNPs) were identified for each map. RESULTS: Blocks were found to be shorter and coverage of the region limited with methods based on LD measures, compared to the method based on haplotype diversity. Although the distribution of blocks was highly variable, the number of SNPs that needed to be typed in order to capture the maximum number of haplotypes was consistent. CONCLUSION: For the marker spacing used in this study, choice of block definition is not important when used as an initial screen of the region to identify htSNPs. However, choice of block definition has consequences for the downstream interpretation of association study results

Fine mapping of genes within the IDDM8 region in rheumatoid arthritis

The IDDM8 region on chromosome 6q27, first identified as a susceptibility locus for type 1 diabetes, has previously been linked and associated with rheumatoid arthritis (RA). The region contains a number of potential candidate genes, including programmed cell death 2 (PDCD2), the proteosome subunit beta type 1 (PSMB1), delta-like ligand 1 (DLL-1) and TATA box-binding protein (TBP) amongst others. The aim of this study was to fine map the IDDM8 region on chromosome 6q27, focusing on the genes in the region, to identify polymorphisms that may contribute to susceptibility to RA and potentially to other autoimmune diseases. Validated single nucleotide polymorphisms (SNPs; n = 65) were selected from public databases from the 330 kb region of IDDM8. These were genotyped using Sequenom MassArray genotyping technology in two datasets; the test dataset comprised 180 RA cases and 180 controls. We tested 50 SNPs for association with RA and any significant associations were genotyped in a second dataset of 174 RA cases and 192 controls, and the datasets were combined before analysis. Association analysis was performed by chi-square test implemented in Stata software and linkage disequilibrium and haplotype analysis was performed using Helix tree version 4.1. There was initial weak evidence of association, with RA, of a number of SNPs around the loc154449 putative gene and within the KIAA1838 gene; however, these associations were not significant in the combined dataset. Our study has failed to detect evidence of association with any of the known genes mapping to the IDDM8 locus with RA

Interventions for preventing oral mucositis for patients with cancer receiving treatment

Background: Treatment of cancer with chemotherapy is becoming increasingly more effective but is associated with short and long-term side effects. Oral side effects remain a major source of illness despite the use of a variety of agents to prevent them. Objectives: To evaluate the effectiveness of oral (and topical) prophylactic agents for oral mucositis and oral candidiasis in patients with cancer (excluding head and neck cancer), compared with placebo or no treatment. Search Strategy: Computerised MEDLINE, EMBASE, CINAHL, CANCERLIT, the Cochrane Controlled Trials Register and the Cochrane Oral Health Group Specialist Register search up to July 1999. Reference lists from relevant articles were scanned and the authors of eligible studies were contacted to identify trials and obtain additional information. Selection Criteria: Studies were selected if they met the following criteria: design - random or quasi-random allocation of participants; participants - anyone with cancer receiving chemotherapy (excluding head and neck cancer); interventions - prophylactic agents prescribed to reduce oral conditions arising from cancer or its treatment; outcomes - mucositis and oral candidiasis. Data Collection and Analysis: Information regarding methods, participants, interventions and outcome measures and results were independently extracted, in duplicate, by two reviewers (JC &amp; HW). Specialist advice was sought to categorise interventions. Authors were contacted for details of randomisation and withdrawals and a quality assessment was carried out using the Jadad criteria (Jadad 1998). The Cochrane Oral Health Group statistical guidelines were followed and relative risk values calculated using random effects models where significant heterogeneity was detected (P &lt; 0.1). Main Results: Thirty-eight reports of trials were initially included. Two were duplicate reports and nine were excluded as there was no useable information. Of the 27 useable studies 14 had data for mucositis comprising 945 randomised patients and 15 included data for oral candidiasis with 1164 randomised patients. Of the eight prophylactic agents used for mucositis only one, ice chips, was effective (Relative risk 0.57, 95% CI 0.43 to 0.77, chi-square for heterogeneity = 0.26 (df = 1), p = 0.61). The NNT to prevent one extra case of mucositis over the baseline incidence using ice chips was 4 (95%CI: 3 to 7). The NNT for when the baseline incidence of mucositis in the population ranges from 50% to 80% are 5 to 4 respectively. There is evidence that antifungal agents which are partially or fully absorbed from the gastrointestinal tract prevent oral candidiasis and that the partially absorbed agents may be more effective than the fully absorbed agents. The RR for partially absorbed agents was 0.13 (95% CI 0.06 to 0.27, chi-square for heterogeneity = 5.3 (df = 3), P = 0. 15). The NNT to prevent one extra case of oral candidiasis over the baseline incidence using partially absorbed drugs was 3 (95% CI: 3 to 5). The NNT for when the baseline incidence of oral candidiasis in the population ranges from 30% to 70% are 4 to 2 respectively. The general reporting of RCT's was poor however the median Jadad score was acceptable and improved further when the authors provided additional information. The sensitivity analysis confirmed the findings for oral candidiasis. Reviewer's Conclusions: There is some evidence that ice chips prevent mucositis. None of the other prophylactic agents included in this review prevented mucositis. There is evidence that prophylactic use of antifungal agents which are absorbed or partially absorbed from the gastrointestinal tract reduce the clinical signs of oral candidiasis, and the partially absorbed drugs may be more effective. Future trials in this area should address the link between oral and general health including outcomes relevant to the patient. Collaboration between medical and dental teams is indicated.</p

Association of the FCRL3 gene with rheumatoid arthritis: a further example of population specificity?

Association of a functional promoter polymorphism mapping to the Fc receptor-like 3 (FCRL3) gene has recently been reported and replicated with rheumatoid arthritis (RA) in Japanese populations. The aim of this study was to investigate association of the FCRL3 gene with RA in UK subjects. DNA was available from 1065 patients with RA and 2073 population controls from the UK. Four single nucleotide polymorphism (SNP) markers (FCRL3-169*C/T (fclr3_3, rs7528684), fclr3_4 (rs11264799), fclr3_5 (rs945635), fclr3_6 (rs3761959)) all previously associated with RA in a Japanese population were genotyped in 761 RA samples and 484 controls. In the remaining samples, only the putative disease causal polymorphism, FCRL3-169*C/T, was tested. Genotyping was performed using either the Sequenom MassArray iPlex platform or a 5' Allelic discrimination assay (Taqman, ABI). Extensive linkage disequilibrium was present across the promoter SNPs genotyped (r(2) values = 0.60-0.98). Allele frequencies did not differ between RA cases and controls either for the putative disease causal polymorphism (odds ratio FCRL3-169*C allele = 0.97 (0.87-1.07), p = 0.51) or for the other SNPs tested. Similarly, no association was detected with RA using haplotype analysis or when stratification by shared epitope carriage or by presence of rheumatoid factor was undertaken. This study was powered to detect an effect size of 1.24 or greater for the FCRL3-169*C/T functional promoter polymorphism but no evidence for association was detected, suggesting that this gene will not have a substantial effect in determining susceptibility to RA in populations of Northern European descent