Genetic epidemiology: Psoriatic arthritis

The existence of psoriatic arthritis as a distinct clinical entity remains a topic of debate; some authors propose that it is simply the co-occurrence of psoriasis and inflammatory arthritis. However, a distinct entity is likely to have distinct susceptibility factors in addition to those that contribute to psoriasis and inflammatory arthritis alone. These aetiological factors may be genetic and/or environmental, and in this review, the evidence for distinct psoriatic arthritis genetic susceptibility factors is considered

Tuning the DNA Reactivity of cis-Platinum: Conjugation to a Mismatch-Specific Metallointercalator

A novel bimetallic conjugate combining a rhodium intercalator that selectively binds DNA mismatches and a reactive cis-platinum analogue that targets DNA by coordination has been prepared. The site-selectivity of the bimetallic complex in forming coordination adducts is examined using mismatched and well-matched oligonucleotides of different sequences. The results indicate that through the bifunctional complex, the platinum center can be targeted near mismatched sites. Interestingly, with mismatched, DNA both intrastrand and the less common interstrand cross-linked adducts are formed. The recognition of a DNA mismatch by the bulky Rh intercalator appears to direct the Pt unit, depending upon steric constraints, to react preferentially with mismatched DNA at a site that may or may not be the preferred site of Pt coordination. Thus, the presence of a permanent link to a site-specific intercalator is able to tune the reactivity of the cis-platinum analogue

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

ASSIMILATOR: A new tool to inform selection of associated genetic variants for functional studies

Motivation: Fine-mapping experiments from genome-wide association studies (GWAS) are underway for many complex diseases. These are likely to identify a number of putative causal variants, which cannot be separated further in terms of strength of genetic association due to linkage disequilibrium. The challenge will be selecting which variant to prioritize for subsequent expensive functional studies. A wealth of functional information generated from wet lab experiments now exists but cannot be easily interrogated by the user. Here, we describe a program designed to quickly assimilate this data called ASSIMILATOR and validate the method by interrogating two regions to show its effectiveness. Availability: http://www.medicine.manchester.ac.uk/musculoskeletal/research/arc/genetics/bioinformatics/assimilator/. Contact: [email protected]

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

Overcoming provider barriers to therapeutic drug monitoring of tumour necrosis factor inhibitors for rheumatoid arthritis:a qualitative analysis

ObjectiveTherapeutic drug monitoring (TDM) of tumour necrosis factor-α inhibitors (TNFi), by measuring drug levels and/or anti-drug antibodies, is being considered by various international bodies to improve patient health outcomes and the value of care for people with rheumatoid arthritis. Rheumatology care providers may perceive barriers to adopting TNFi TDM within their own clinical practice, limiting the potential for patients and health care systems to benefit. This study aimed to explore the barriers perceived by rheumatologists that may reduce their uptake of TNFi TDM for rheumatoid arthritis.MethodSemi-structured one-to-one telephone interviews were performed with a convenience sample of senior rheumatologists with experience of managing people with rheumatoid arthritis. The interviews explored the rheumatologists’ understanding of TDM and their beliefs about how it can be integrated into their own routine practice. Interviews were audio recorded, transcribed verbatim and anonymized. Transcripts were coded inductively and barriers to using TNFi TDM were identified by thematic framework analysis.ResultA sample of eleven senior rheumatologists were interviewed. The rheumatologists described five barriers to adopting TNFi TDM in routine practice: (i) observing clinical need; (ii) understanding how testing can improve practice; (iii) insufficient clinical evidence; (iv) insufficient resources to pay for testing; and (v) insufficient capability to deliver testing.ConclusionBarriers to adopting TNFi TDM in routine care settings will restrict the ability for patients to benefit from effective monitoring strategies as they begin to emerge. Strategies to overcome these barriers are suggested which will require a coordinated response from stakeholders across health care systems

What can secondary data tell us about household food insecurity in a high-income country context?

In the absence of routinely collected household food insecurity data, this study investigated what could be determined about the nature and prevalence of household food insecurity in Scotland from secondary data. Secondary analysis of the Living Costs and Food Survey (2007–2012) was conducted to calculate weekly food expenditure and its ratio to equivalised income for households below average income (HBAI) and above average income (non-HBAI). Diet Quality Index (DQI) scores were calculated for this survey and the Scottish Health Survey (SHeS, 2008 and 2012). Secondary data provided a partial picture of food insecurity prevalence in Scotland, and a limited picture of differences in diet quality. In 2012, HBAI spent significantly less in absolute terms per week on food and non-alcoholic drinks (£53.85) compared to non-HBAI (£86.73), but proportionately more of their income (29% and 15% respectively). Poorer households were less likely to achieve recommended fruit and vegetable intakes than were more affluent households. The mean DQI score (SHeS data) of HBAI fell between 2008 and 2012, and was significantly lower than the mean score for non-HBAI in 2012. Secondary data are insufficient to generate the robust and comprehensive picture needed to monitor the incidence and prevalence of food insecurity in Scotland.</p