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Common variation at the 11p11.2 locus, encompassing MADD, ACP2, NR1H3, MYBPC3, and SPI1, has been associated in genome-wide association studies with fasting glucose and insulin (FI). In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study, we sequenced 5 gene regions at 11p11.2 to identify rare, potentially functional variants influencing fasting glucose or FI levels.Sequencing (mean depth, 38×) across 16.1 kb in 3566 individuals without diabetes mellitus identified 653 variants, 79.9% of which were rare (minor allele frequency <1%) and novel. We analyzed rare variants in 5 gene regions with FI or fasting glucose using the sequence kernel association test. At NR1H3, 53 rare variants were jointly associated with FI (P=2.73×10-3); of these, 7 were predicted to have regulatory function and showed association with FI (P=1.28×10-3). Conditioning on 2 previously associated variants at MADD (rs7944584, rs10838687) did not attenuate this association, suggesting that there are >2 independent signals at 11p11.2. One predicted regulatory variant, chr11:47227430 (hg18; minor allele frequency=0.00068), contributed 20.6% to the overall sequence kernel association test score at NR1H3, lies in intron 2 of NR1H3, and is a predicted binding site for forkhead box A1 (FOXA1), a transcription factor associated with insulin regulation. In human HepG2 hepatoma cells, the rare chr11:47227430 A allele disrupted FOXA1 binding and reduced FOXA1-dependent transcriptional activity.Sequencing at 11p11.2-NR1H3 identified rare variation associated with FI. One variant, chr11:47227430, seems to be functional, with the rare A allele reducing transcription factor FOXA1 binding and FOXA1-dependent transcriptional activity. [ABSTRACT FROM AUTHOR]

Examination of employers' liability (workers' compensation) claims files confirms that accidents at work, resulting in major injury, continue to present a significant challenge to rehabilitation. This review of 209 patients who have pursued such claims describes them from relevant socio-economic, clinical and occupational perspectives; records their return to work; examines medical opinion on their residual disabilities and potential occupational handicap and traces their involvement with rehabilitation and resettlement services. A major finding is an interval of almost two years, on average, between patients' discharge from medical treatment and settlement of their claims. Given the severity of injuries, length of absences from work and the relatively high proportions who either lost their jobs or who were advised to seek less physically demanding alternative occupations, the rate of referral to specialist vocational rehabilitation services during this period was very low. Timely and effective delivery of relevant rehabilitation and resettlement services to such patients should be made a priority for future policy and practice. One half of the sample returned to work before settlement, with more who were unsuccessful in their attempts to do so. The adversarial climate of personal injury claims negotiation in Great Britain therefore may be a less formidable barrier to return to work than is sometimes supposed. Nevertheless, conventional practices and procedures in medicine, law and insurance may still delay or prevent resettlement in some cases. Any attempt to enhance the effectiveness of the present medicolegal system should pay at least as much attention to these iatrogenic factors as to the psychological explanations that have dominated previous thinking on this subject.