Genome-wide association study and meta-analysis in Northern European populations replicate multiple colorectal cancer risk loci

Genome-wide association studies have been successful in elucidating the genetic basis of colorectal cancer (CRC), but there remains unexplained variability in genetic risk. To identify new risk variants and to confirm reported associations, we conducted a genome-wide association study in 1,701 CRC cases and 14,082 cancer-free controls from the Finnish population. A total of 9,068,015 genetic variants were imputed and tested, and 30 promising variants were studied in additional 11,647 cases and 12,356 controls of European ancestry. The previously reported association between the single-nucleotide polymorphism (SNP) rs992157 (2q35) and CRC was independently replicated (p=2.08 x 10(-4); OR, 1.14; 95% CI, 1.06-1.23), and it was genome-wide significant in combined analysis (p=1.50 x 10(-9); OR, 1.12; 95% CI, 1.08-1.16). Variants at 2q35, 6p21.2, 8q23.3, 8q24.21, 10q22.3, 10q24.2, 11q13.4, 11q23.1, 14q22.2, 15q13.3, 18q21.1, 20p12.3 and 20q13.33 were associated with CRC in the Finnish population (false discovery ratePeer reviewe

Association analyses identify 31 new risk loci for colorectal cancer susceptibility

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.Peer reviewe

Natalizumab plus interferon beta-1a for relapsing multiple sclerosis

.AbstractBackgroundInterferon beta is used to modify the course of relapsing multiple sclerosis. Despiteinterferon beta therapy, many patients have relapses. Natalizumab, an α4 integrinantagonist, appeared to be safe and effective alone and when added to interferonbeta-1a in preliminary studies.MethodsWe randomly assigned 1171 patients who, despite interferon beta-1a therapy, hadhad at least one relapse during the 12-month period before randomization to receivecontinued interferon beta-1a in combination with 300 mg of natalizumab (589patients) or placebo (582 patients) intravenously every 4 weeks for up to 116 weeks.The primary end points were the rate of clinical relapse at 1 year and the cumulativeprobability of disability progression sustained for 12 weeks, as measured by theExpanded Disability Status Scale, at 2 years.ResultsCombination therapy resulted in a 24 percent reduction in the relative risk of sustaineddisability progression (hazard ratio, 0.76; 95 percent confidence interval, 0.61to 0.96; P = 0.02). Kaplan–Meier estimates of the cumulative probability of progressionat two years were 23 percent with combination therapy and 29 percent withinterferon beta-1a alone. Combination therapy was associated with a lower annualizedrate of relapse over a two-year period than was interferon beta-1a alone (0.34vs. 0.75, P<0.001) and with fewer new or enlarging lesions on T2-weighted magneticresonance imaging (0.9 vs. 5.4, P<0.001). Adverse events associated with combinationtherapy were anxiety, pharyngitis, sinus congestion, and peripheral edema.Two cases of progressive multifocal leukoencephalopathy, one of which was fatal,were diagnosed in natalizumab-treated patients.ConclusionsNatalizumab added to interferon beta-1a was significantly more effective than interferonbeta-1a alone in patients with relapsing multiple sclerosis. Additional researchis needed to elucidate the benefits and risks of this combination treatment.(ClinicalTrials.gov number, NCT00030966.

The incidence and significance of anti-natalizumab antibodies - Results from AFFIRM and SENTINEL

Objective: To determine the incidence and clinical effects of antibodies that develop during treatment with natalizumab