Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33

Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 x 10-39; Region 3: rs2853677, P = 3.30 x 10-36 and PConditional = 2.36 x 10-8; Region 4: rs2736098, P = 3.87 x 10-12 and PConditional = 5.19 x 10-6, Region 5: rs13172201, P = 0.041 and PConditional = 2.04 x 10-6; and Region 6: rs10069690, P = 7.49 x 10-15 and PConditional = 5.35 x 10-7) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 x 10-18 and PConditional = 7.06 x 10-16). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci

Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33

Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 x 10(-39); Region 3: rs2853677, P = 3.30 x 10(-36) and P-Conditional = 2.36 x 10(-8); Region 4: rs2736098, P = 3.87 x 10(-12) and P-Conditional = 5.19 x 10(-6), Region 5: rs13172201, P = 0.041 and P-Conditional = 2.04 x 10(-6); and Region 6: rs10069690, P = 7.49 x 10 215 and P-Conditional = 5.35 x 10(-7)) and one in the neighboring CLPTM1L gene(Region 2: rs451360; P = 1.90 x 10(-18) and P-Conditional = 7.06 x 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci

Neuroinflammation: beneficial and detrimental effects after traumatic brain injury

Traumatic brain injury (TBI) is the major cause of death and severe disability in young adults and infants worldwide and many survivors also have mild to moderate neurological deficits which impair their lives. This review highlights the primary and secondary lesions constituting craniocerebral trauma and the main elements of neuroinflammation, one of the most important secondary events evolving after the initial traumatic insult. Neuroinflammation has dual and opposing roles in outcome after TBI, being both beneficial and harmful, its effects often differing between the acute and more delayed phases after injury. Since each patient with TBI has a unique and complex pattern of cerebral damage, developing pharmacological intervention strategies targeted at the multiple cellular and molecular events in the neuroinflammatory cascade is difficult. While there have been very few successful outcomes to date in human clinical trials of drugs developed to treat TBI in general, those that have been devised to modulate neuroinflammation are discussed.J. W. Finni