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1.
  • Bentham, James, et al. (creator_code:aut_t)
  • A century of trends in adult human height
  • 2016
  • record:In_t: eLIFE. - 2050-084X. ; 5
  • swepub:Mat_article_t (swepub:level_refereed_t)abstract
    • Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.522.7) and 16.5 cm (13.319.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.
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2.
  • Bentham, James, et al. (creator_code:aut_t)
  • A century of trends in adult human height
  • 2016
  • record:In_t: eLIFE. - : eLife Sciences Publications Ltd. - 2050-084X. ; 5
  • swepub:Mat_article_t (swepub:level_refereed_t)abstract
    • Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5–22.7) and 16.5 cm (13.3– 19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8– 144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.
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3.
  • Birney, Ewan, et al. (creator_code:aut_t)
  • Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
  • 2007
  • record:In_t: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 447:7146, s. 799-816
  • swepub:Mat_article_t (swepub:level_refereed_t)abstract
    • We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
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4.
  • Nelson, Laura, et al. (creator_code:aut_t)
  • FKBPL: a marker of good prognosis in breast cancer.
  • 2015
  • record:In_t: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 6:14, s. 12209-12223
  • swepub:Mat_article_t (swepub:level_refereed_t)abstract
    • FK506-binding protein-like (FKBPL) has established roles as an anti-tumor protein, with a therapeutic peptide based on this protein, ALM201, shortly entering phase I/II clinical trials. Here, we evaluated FKBPL's prognostic ability in primary breast cancer tissue, represented on tissue microarrays (TMA) from 3277 women recruited into five independent retrospective studies, using immunohistochemistry (IHC). In a meta-analysis, FKBPL levels were a significant predictor of BCSS; low FKBPL levels indicated poorer breast cancer specific survival (BCSS) (hazard ratio (HR) = 1.30, 95% confidence interval (CI) 1.14-1.49, p < 0.001). The prognostic impact of FKBPL remained significant after adjusting for other known prognostic factors (HR = 1.25, 95% CI 1.07-1.45, p = 0.004). For the sub-groups of 2365 estrogen receptor (ER) positive patients and 1649 tamoxifen treated patients, FKBPL was significantly associated with BCSS (HR = 1.34, 95% CI 1.13-1.58, p < 0.001, and HR = 1.25, 95% CI 1.04-1.49, p = 0.02, respectively). A univariate analysis revealed that FKBPL was also a significant predictor of relapse free interval (RFI) within the ER positive patient group, but it was only borderline significant within the smaller tamoxifen treated patient group (HR = 1.32 95% CI 1.05-1.65, p = 0.02 and HR = 1.23 95% CI 0.99-1.54, p = 0.06, respectively). The data suggests a role for FKBPL as a prognostic factor for BCSS, with the potential to be routinely evaluated within the clinic.
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5.
  • Campbell, Christine, et al. (creator_code:aut_t)
  • Markers of steroid receptor, kinase signalling pathways and Ki-67 expression in relation to tamoxifen sensitivity and resistance
  • 2020
  • record:In_t: Translational Breast Cancer Research. - : AME Publishing Company. - 2218-6778. ; 1
  • swepub:Mat_article_t (swepub:level_refereed_t)abstract
    • Background: It remains clinically important to identify ER positive breast cancers likely to respond to tamoxifen (TAM) and so we aimed to select a group of biomarkers able to predict response. We also assessed whether data from different sample types [tumor microarrays (TMAs) and core biopsies] or tumor sites could be combined for biomarker studies.Methods: A total of 123 endocrine treatment naïve patients with known ER and HER2 status treated with TAM had paraffin-embedded tumor tissue available either as TMAs (n=102) or core biopsies (n=21). TMA cores were collected from three different tumor sites, two central and one peripheral. Ten biomarkers were evaluated by immunohistochemistry, for % positivity and/or H-Score, comprising: ER, HER2, Ki-67, phosphorylated forms of ER (Ser118), IGF1R, PRAS40, Akt & MAPK (ERK1/2), and PTEN & androgen receptor expression (AR). Each tumor was analysed for Akt1 E17K somatic mutation using BEAMing technology. Patient outcome was assessed by clinical benefit (CB) rate & survival analyses [time to progression (TTP) and time to death (TTD)].Results: There was no significant difference in % positivity or H-Score between central & peripheral tumor sites for all biomarkers examined. After False Discovery Rate (FDR) correction differences (P<0.05) were observed between the two central samples only for HER2 & pER118 and pPRAS40. However, differences in biomarker expression were common between core biopsies and TMAs. Only 2/123 (1.6%) tumors had Akt1 E17K mutations. Univariate and multivariate analyses identified that lower levels of PTEN and higher levels of Ki-67 (% positivity) were predictive of poor outcome (TTP & TTD) following TAM. Higher ER. lower Ki-67 and AR/ER ratio <2 predicted increased CB rate.Conclusions: There were few differences in marker expression between TMAs from different intra-tumoral sites. More marked differences between TMAs and core biopsies suggest caution if combining such datasets. Loss of PTEN, a key regulator of the PI3K/Akt pathway, was the only RTK/kinase signaling biomarker related to poorer clinical outcome. PTEN along with ER & lower Ki-67 proved the most predictive markers for better outcome (TTP & TTD and/or CBR) following TAM treatment.Keywords: ER+ breast cancer; Akt pathway; tamoxifen
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6.
  • Hollestelle, Antoinette, et al. (creator_code:aut_t)
  • No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
  • 2016
  • record:In_t: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 141:2, s. 386-401
  • swepub:Mat_article_t (swepub:level_refereed_t)abstract
    • Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
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7.
  • Joshi, Peter K, et al. (creator_code:aut_t)
  • Directional dominance on stature and cognition in diverse human populations
  • 2015
  • record:In_t: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
  • swepub:Mat_article_t (swepub:level_refereed_t)abstract
    • Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
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8.
  • Lawrenson, Kate, et al. (creator_code:aut_t)
  • Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
  • 2016
  • record:In_t: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
  • swepub:Mat_article_t (swepub:level_refereed_t)abstract
    • A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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9.
  • Zhou, Bin, et al. (creator_code:aut_t)
  • Worldwide trends in diabetes since 1980: A pooled analysis of 751 population-based studies with 4.4 million participants
  • 2016
  • record:In_t: The Lancet. - : Elsevier B.V.. - 0140-6736 .- 1474-547X. ; 387:10027, s. 1513-1530
  • swepub:Mat_article_t (swepub:level_refereed_t)abstract
    • Background: One of the global targets for non-communicable diseases is to halt, by 2025, the rise in the age standardised adult prevalence of diabetes at its 2010 levels. We aimed to estimate worldwide trends in diabetes, how likely it is for countries to achieve the global target, and how changes in prevalence, together with population growth and ageing, are aff ecting the number of adults with diabetes.Methods: We pooled data from population-based studies that had collected data on diabetes through measurement of its biomarkers. We used a Bayesian hierarchical model to estimate trends in diabetes prevalence-defined as fasting plasma glucose of 7.0 mmol/L or higher, or history of diagnosis with diabetes, or use of insulin or oral hypoglycaemic drugs-in 200 countries and territories in 21 regions, by sex and from 1980 to 2014. We also calculated the posterior probability of meeting the global diabetes target if post-2000 trends continue.Findings: We used data from 751 studies including 4372000 adults from 146 of the 200 countries we make estimates for. Global age-standardised diabetes prevalence increased from 4.3% (95% credible interval 2.4-17.0) in 1980 to 9.0% (7.2-11.1) in 2014 in men, and from 5.0% (2.9-7.9) to 7.9% (6.4-9.7) in women. The number of adults with diabetes in the world increased from 108 million in 1980 to 422 million in 2014 (28.5% due to the rise in prevalence, 39.7% due to population growth and ageing, and 31.8% due to interaction of these two factors). Age-standardised adult diabetes prevalence in 2014 was lowest in northwestern Europe, and highest in Polynesia and Micronesia, at nearly 25%, followed by Melanesia and the Middle East and north Africa. Between 1980 and 2014 there was little change in age-standardised diabetes prevalence in adult women in continental western Europe, although crude prevalence rose because of ageing of the population. By contrast, age-standardised adult prevalence rose by 15 percentage points in men and women in Polynesia and Micronesia. In 2014, American Samoa had the highest national prevalence of diabetes (>30% in both sexes), with age-standardised adult prevalence also higher than 25% in some other islands in Polynesia and Micronesia. If post-2000 trends continue, the probability of meeting the global target of halting the rise in the prevalence of diabetes by 2025 at the 2010 level worldwide is lower than 1% for men and is 1% for women. Only nine countries for men and 29 countries for women, mostly in western Europe, have a 50% or higher probability of meeting the global target.Interpretation: Since 1980, age-standardised diabetes prevalence in adults has increased, or at best remained unchanged, in every country. Together with population growth and ageing, this rise has led to a near quadrupling of the number of adults with diabetes worldwide. The burden of diabetes, both in terms of prevalence and number of adults aff ected, has increased faster in low-income and middle-income countries than in high-income countries.
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10.
  • Beral, Valerie, et al. (creator_code:aut_t)
  • The number of women who would need to be screened regularly by mammography to prevent one death from breast cancer
  • 2011
  • record:In_t: Journal of medical screening. - : SAGE Publications. - 1475-5793 .- 0969-1413. ; 18:4, s. 210-212
  • swepub:Mat_article_t (swepub:level_refereed_t)abstract
    • The number of women who would need to be screened regularly by mammography to prevent one death from breast cancer depends strongly on several factors, including the age at which regular screening starts, the period over which it continues, and the duration of follow-up after screening. Furthermore, more women would need to be INVITED for screening than would need to be SCREENED to prevent one death, since not all women invited attend for screening or are screened regularly. Failure to consider these important factors accounts for many of the major discrepancies between different published estimates. The randomised evidence indicates that, in high income countries, around one breast cancer death would be prevented in the long term for every 400 women aged 50-70 years regularly screened over a ten-year period.
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