Mutation altering the miR-184 seed region causes keratoconus with cataract

MicroRNAs (miRNAs) bind to complementary sequences within the 3? untranslated region (UTR) of mRNAs from hundreds of target genes, leading either to mRNA degradation or suppression of translation. We found that a mutation in the seed region of miR-184 (MIR184) is responsible for familial severe keratoconus combined with early-onset anterior polar cataract, by deep sequencing of a linkage region known to contain the mutation. The mutant form fails to compete with miR-205 (MIR205) for overlapping target sites on the 3? UTRs of INPPL1 and ITGB4. Although these target genes and miR-205 are expressed widely, the phenotype is restricted to the cornea and lens because of the very high expression of miR-184 in these tissues. Our finding highlights the tissue-specificity of a gene network regulated by a miRNA. Awareness of the important function of miRNAs may aid identification of susceptibility genes and new therapeutic targets for treatment of both rare and common diseases.

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10 -5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10 -5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10 -10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression.

Proton pump inhibitors and histamine-2-receptor antagonists and pancreatic cancer risk: a nested case-control study

Background: The relationship between use of proton pump inhibitors (PPIs) and histamine-2-receptor antagonists (H₂RAs) and pancreatic cancer risk has yet to be examined. Data from a range of studies suggest biologically plausible mechanisms, whereby these drugs (or the conditions for which they are prescribed) may affect pancreatic cancer risk. The objective of this study was to investigate the relationship between use of PPIs/H₂RAs and pancreatic cancer risk.

Methods: A nested case – control study was conducted within the UK general practice research database (GPRD). Cases had a diagnosis of exocrine pancreatic cancer and controls were matched to cases on general practice site, sex and year of birth. Exposure to PPIs and to H₂RAs since entry into GPRD until 2 years before the diagnosis date (corresponding date in controls) and in the 5 years before the diagnosis date were separately assessed. Conditional logistic regression analyses were used to generate odds ratios (ORs) and 95% confidence intervals (CIs) associated with PPI or H₂RA use compared with nonuse.

Results: Ever use of PPIs since entry into the GPRD (excluding the 2 years prior to diagnosis) was not associated with risk of pancreatic cancer; OR (95% CI) 1.02 (0.85 – 1.22). Neither the dose nor the duration of PPI or H₂RA use was associated with pancreatic cancer risk. No consistent patterns of association were seen when cumulative exposure (dose and duration) to these drugs was examined separately or together.

Conclusion: PPI/H₂RA use, in a UK population, was not associated with pancreatic cancer risk.

Genetic susceptibility to invasive meningococcal disease: MBL2 structural polymorphisms revisited in a large case–control study and a systematic review

Invasive infection caused by Neisseria meningitidis is a worldwide public health problem. Previous reports have indicated that carriage of common ‘defective’ structural polymorphisms of the host mannose-binding lectin gene (MBL2) greatly increases an individual’s risk of developing the disease. We report the largest case–control study so far to investigate the effect of these polymorphisms in meningococcal disease (296 PCR-positive cases and 5196 population controls, all of European ancestry) and demonstrate that no change in risk is associated with the polymorphisms overall or in any age-defined subgroup. This finding contrasts with two smaller studies that reported an increase in risk. A systematic review of all studies of MBL2 polymorphisms in people of European ancestry published since 1999, including 24 693 individuals, revealed a population frequency of the combined ‘defective’MBL2 allele of 0.230 (95% confidence limits: 0.226–0.234). The past reported associations of increased risk of meningococcal disease were because of low ‘defective’ allele frequencies in their study control populations (0.13 and 0.04) that indicate systematic problems with the studies. The data from our study and all other available evidence indicate that MBL2 structural polymorphisms do not predispose children or adults to invasive meningococcal disease.

Infection-control strategies for preventing the transmission of meticillin-resistant Staphylococcus aureus (MRSA) in nursing homes for older people (Review)

Background: Nursing homes for older people provide an environment likely to promote the acquisition and spread of meticillin-resistant Staphylococcus aureus (MRSA), putting residents at increased risk of colonisation and infection. It is recognised that infection control strategies are important in preventing and controlling MRSA transmission.

Objectives: The objective of this review was to determine the effects of infection control strategies for preventing the transmission of MRSA in nursing homes for older people.

Search strategy: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2009, Issue 2), the Cochrane Wounds Group Specialised Register (searched May 29th, 2009). We also searched MEDLINE (from 1950 to May Week 4 2009), Ovid EMBASE (1980 to 2009 Week 21), EBSCO CINAHL (1982 to May Week 4 2009), British Nursing Index (1985 to May 2009), DARE (1992 to May 2009), Web of Science (1981 to May 2009), and the Health Technology Assessment (HTA) website (1988 to May 2009). Research in progress was sought through Current Clinical Trials (www.controlled-trials.com), Medical Research Council Research portfolio, and HSRPRoj (current USA projects). SIGLE was also searched in order to identify atypical material which was not accessible through more conventional sources.

Selection criteria: All randomised and controlled clinical trials, controlled before and after studies and interrupted time series studies of infection control interventions in nursing homes for older people were eligible for inclusion.

Data collection and analysis: Two authors independently reviewed the results of the searches.

Main results: Since no studies met the selection criteria, neither a meta-analysis nor a narrative description of studies was possible.

Authors' conclusions: The lack of studies in this field is surprising. Nursing homes for older people provide an environment likely to promote the acquisition and spread of infection, with observational studies repeatedly reporting that being a resident of a nursing home increases the risk of MRSA colonisation. Much of the evidence for recently-issued United Kingdom guidelines for the control and prevention of MRSA in health care facilities was generated in the acute care setting. It may not be possible to transfer such strategies directly to the nursing home environment, which serves as both a healthcare setting and a resident's home. Rigorous studies should be conducted in nursing homes, to test interventions that have been specifically designed for this unique environment.