Browsing by Subject "Genetic Heterogeneity"

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    Association between p21 Ser31Arg polymorphism and cancer risk: a meta-analysis.
    (Chinese journal of cancer, 2011-04) Ma, Hongxia; Zhou, Ziyuan; Wei, Sheng; Wei, Qingyi
    P21 (CDKN1A), a key cell cycle regulatory protein that governs cell cycle progression from G1 to S phase, can regulate cell proliferation, growth arrest, and apoptosis. The Ser31Arg polymorphism is located in the highly conserved region of p21 and may encode functionally distinct proteins. Although many epidemiological studies have been conducted to evaluate the association between the p21 Ser31Arg polymorphism and cancer risk, the findings remain conflicting. This meta-analysis with 33 077 cases and 45 013 controls from 44 published case-control studies showed that the variant homozygous 31Arg/Arg genotype was associated with an increased risk of numerous types of cancers in a random-effect model (homozygote comparison: OR = 1.17, 95% CI = 0.99 to 1.37, P = 0.0002 for the heterogeneity test; recessive model comparison: OR = 1.16, 95% CI = 1.01 to 1.33, P = 0.0001 for the heterogeneity test). Stratified analysis revealed that increased cancer risk associated with the 31Arg/Arg genotype remained significant in subgroups of colorectal cancer, estrogen-related cancer, Caucasians, population-based studies, studies with matching information or a larger sample size. Heterogeneity analysis showed that tumor type contributed to substantial between-study heterogeneity (recessive model comparison: Χ(2) = 21.83, df = 7, P = 0.003). The results from this large-sample sized meta-analysis suggest that the p21 31Arg/Arg genotype may serve as a potential marker for increased cancer risk.
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    Evidence for GC-biased gene conversion as a driver of between-lineage differences in avian base composition.
    (Genome Biol, 2014) Weber, Claudia C; Boussau, Bastien; Romiguier, Jonathan; Jarvis, Erich D; Ellegren, Hans
    BACKGROUND: While effective population size (Ne) and life history traits such as generation time are known to impact substitution rates, their potential effects on base composition evolution are less well understood. GC content increases with decreasing body mass in mammals, consistent with recombination-associated GC biased gene conversion (gBGC) more strongly impacting these lineages. However, shifts in chromosomal architecture and recombination landscapes between species may complicate the interpretation of these results. In birds, interchromosomal rearrangements are rare and the recombination landscape is conserved, suggesting that this group is well suited to assess the impact of life history on base composition. RESULTS: Employing data from 45 newly and 3 previously sequenced avian genomes covering a broad range of taxa, we found that lineages with large populations and short generations exhibit higher GC content. The effect extends to both coding and non-coding sites, indicating that it is not due to selection on codon usage. Consistent with recombination driving base composition, GC content and heterogeneity were positively correlated with the rate of recombination. Moreover, we observed ongoing increases in GC in the majority of lineages. CONCLUSIONS: Our results provide evidence that gBGC may drive patterns of nucleotide composition in avian genomes and are consistent with more effective gBGC in large populations and a greater number of meioses per unit time; that is, a shorter generation time. Thus, in accord with theoretical predictions, base composition evolution is substantially modulated by species life history.
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    Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis.
    (PLoS Genet, 2016-10) Castaño-Betancourt, Martha C; Evans, Dan S; Ramos, Yolande FM; Boer, Cindy G; Metrustry, Sarah; Liu, Youfang; den Hollander, Wouter; van Rooij, Jeroen; Kraus, Virginia B; Yau, Michelle S; Mitchell, Braxton D; Muir, Kenneth; Hofman, Albert; Doherty, Michael; Doherty, Sally; Zhang, Weiya; Kraaij, Robert; Rivadeneira, Fernando; Barrett-Connor, Elizabeth; Maciewicz, Rose A; Arden, Nigel; Nelissen, Rob GHH; Kloppenburg, Margreet; Jordan, Joanne M; Nevitt, Michael C; Slagboom, Eline P; Hart, Deborah J; Lafeber, Floris; Styrkarsdottir, Unnur; Zeggini, Eleftheria; Evangelou, Evangelos; Spector, Tim D; Uitterlinden, Andre G; Lane, Nancy E; Meulenbelt, Ingrid; Valdes, Ana M; van Meurs, Joyce BJ
    Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10-8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies.