| 1. |
- Marouli, Eirini, et al.
(författare)
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Rare and low-frequency coding variants alter human adult height
- 2017
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Tidskriftsartikel (refereegranskat)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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| 2. |
- Hart, James L., et al.
(författare)
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Electron-beam-induced ferroelectric domain behavior in the transmission electron microscope : Toward deterministic domain patterning
- 2016
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Ingår i: Physical Review B. - 2469-9950 .- 2469-9969. ; 94:17
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Tidskriftsartikel (refereegranskat)abstract
- We report on transmission electron microscope beam-induced ferroelectric domain nucleation and motion. While previous observations of this phenomenon have been reported, a consistent theory explaining induced domain response is lacking, and little control over domain behavior has been demonstrated. We identify positive sample charging, a result of Auger and secondary electron emission, as the underlying mechanism driving domain behavior. By converging the electron beam to a focused probe, we demonstrate controlled nucleation of nanoscale domains. Molecular dynamics simulations performed are consistent with experimental results, confirming positive sample charging and reproducing the result of controlled domain nucleation. Furthermore, we discuss the effects of sample geometry and electron irradiation conditions on induced domain response. These findings elucidate past reports of electron beam-induced domain behavior in the transmission electron microscope and provide a path towards more predictive, deterministic domain patterning through electron irradiation.
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| 3. |
- Khalili, Hamed, et al.
(författare)
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No Association Between Consumption of Sweetened Beverages and Later Risk of Crohn's Disease or Ulcerative Colitis
- 2019
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Ingår i: Clinical Gastroenterology and Hepatology. - : Elsevier. - 1542-3565 .- 1542-7714. ; 17:1, s. 123-129
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Consumption of sweetened beverages has been associated with inflammation, based on measurements of C-reactive protein and tumor necrosis factor, as well as immune-mediated disorders including rheumatoid arthritis. We investigated associations with Crohn's disease (CD) or ulcerative colitis (UC).METHODS: We conducted a prospective cohort study of 83,042 participants (44-83 years old) enrolled in the Cohort of Swedish Men or the Swedish Mammography Study. Dietary and lifestyle data were collected using a validated food frequency questionnaire at baseline in 1997. Diagnoses of CD and UC were ascertained from the Swedish Patient Register. We used Cox proportional hazards modeling to calculate hazard ratios (HR) and 95% CIs.RESULTS: Through December of 2014, we confirmed 143 incident cases of CD (incidence; rate = 11 cases/100,000 person-years) and 349 incident cases of UC (incidence rate = 28 cases/100,000 person-years) over 1,264,345 person-years of follow up. Consumption of sweetened beverages was not associated with increased risk of CD (Ptrend = 0.34) or UC (Ptrend = 0.40). Compared to participants who reported no consumption of sweetened beverages, the multivariable-adjusted HRs for 1 or more servings per day were 1.02 for CD (95% CI, 0.60-1.73) and 1.14 for UC (95% CI, 0.83-1.57). The association between consumption of sugar-sweetened beverages and risk of CD or UC were not modified by age, sex (cohort), body mass index, or smoking (all Pinteraction ≥ 0.12).CONCLUSION: In analyses of data from 2 large prospective cohort studies from Sweden, we observed no evidence for associations between consumption of sweetened beverages and later risk of CD or UC.
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| 4. |
- Khalili, Hamed, et al.
(författare)
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No Association Between Consumption of Sweetened Beverages and Risk of Later-Onset Crohn's Disease or Ulcerative Colitis.
- 2019
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Ingår i: Clinical Gastroenterology and Hepatology. - : Elsevier BV. - 1542-3565 .- 1542-7714. ; 17:1, s. 123-129
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Consumption of sweetened beverages has been associated with inflammation based on measurements of C-reactive protein and tumor necrosis factor, as well as immune-mediated disorders including rheumatoid arthritis. We investigated associations with Crohn's disease (CD) or ulcerative colitis (UC).METHODS: We conducted a prospective cohort study of 83,042 participants (age, 44-83 y) enrolled in the Cohort of Swedish Men or the Swedish Mammography Study. Dietary and lifestyle data were collected using a validated food frequency questionnaire at baseline in 1997. Diagnoses of CD and UC were ascertained from the Swedish Patient Register. We used Cox proportional hazards modeling to calculate hazard ratios and 95% CIs.RESULTS: Through December of 2014, we confirmed 143 incident cases of CD (incidence rate, 11 cases/100,000 person-years) and 349 incident cases of UC (incidence rate, 28 cases/100,000 person-years) over 1,264,345 person-years of follow-up evaluation. Consumption of sweetened beverages was not associated with increased risk of CD (Ptrend = .34) or UC (Ptrend = .40). Compared with participants who reported no consumption of sweetened beverages, the multivariable-adjusted hazard ratios for 1 or more servings per day were 1.02 for CD (95% CI, 0.60-1.73) and 1.14 for UC (95% CI, 0.83-1.57). The association between consumption of sugar-sweetened beverages and risk of CD or UC were not modified by age, sex (cohort), body mass index, or smoking (all Pinteraction ≥ .12).CONCLUSIONS: In analyses of data from 2 large prospective cohort studies from Sweden, we observed no evidence for associations between consumption of sweetened beverages and later risk of CD or UC.
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| 5. |
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| 6. |
- Andersen, Vibeke, et al.
(författare)
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Fibre intake and the development of inflammatory bowel disease : A European prospective multi-centre cohort study (EPIC-IBD)
- 2018
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Ingår i: Journal of Crohn's & Colitis. - : OXFORD UNIV PRESS. - 1873-9946 .- 1876-4479. ; 12:2, s. 129-136
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims: Population-based prospective cohort studies investigating fibre intake and development of inflammatory bowel disease are lacking. Our aim was to investigate the association between fibre intake and the development of Crohn's disease [CD] and ulcerative colitis [UC] in a large European population.Methods: In total, 401 326 participants, aged 20-80 years, were recruited in eight countries in Europe between 1991 and 1998. At baseline, fibre intake [total fibres, fibres from fruit, vegetables and cereals] was recorded using food frequency questionnaires. The cohort was monitored for the development of inflammatory bowel disease. Each case was matched with four controls and odds ratios [ORs] for the exposures were calculated using conditional logistic regression. Sensitivity analyses according to smoking status were computed.Results: In total, 104 and 221 participants developed incident CD and UC, respectively. For both CD and UC, there were no statistically significant associations with either quartiles, or trends across quartiles, for total fibre or any of the individual sources. The associations were not affected by adjusting for smoking and energy intake. Stratification according to smoking status showed null findings apart from an inverse association with cereal fibre and CD in non-smokers [Quartile 4 vs 1 OR = 0.12, 95% confidence interval = 0.02-0.75, p = 0.023, OR trend across quartiles = 0.50, 95% confidence interval = 0.29-0.86, p = 0.017].Conclusion: The results do not support the hypothesis that dietary fibre is involved in the aetiology of UC, although future work should investigate whether there may be a protective effect of specific types of fibre according to smoking status in CD.
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| 7. |
- Couch, Fergus J., et al.
(författare)
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Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer
- 2016
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 7:11375, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 x 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for similar to 11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
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| 8. |
- Hamdi, Yosr, et al.
(författare)
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Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression : identification of a modifier of breast cancer risk at locus 11q22.3
- 2017
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Ingår i: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 0167-6806 .- 1573-7217. ; 161:1, s. 117-134
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. Methods: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. Results: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10−6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. Conclusion: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.
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| 9. |
- He, Xingcheng, et al.
(författare)
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Elevational patterns of bird species richness on the eastern slope of Mt. Gongga, Sichuan Province, China
- 2019
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Ingår i: Avian Research. - : BMC. - 2053-7166. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: In biological systems, biological diversity often displays a rapid turn-over across elevations. This defining feature has made mountains classic systems for studying the spatial variation in diversity. Because patterns of elevational diversity can vary among lineages and mountain systems it remains difficult to extrapolate findings from one montane region to another, or among lineages. In this study, we assessed patterns and drivers of avian diversity along an elevational gradient on the eastern slope of Mt. Gongga, the highest peak in the Hengduan Mountain Range in central China, and a mountain where comprehensive studies of avian diversity are still lacking.Methods: We surveyed bird species in eight 400-m elevational bands from 1200 to 4400m a.s.l. between 2012 and 2017. To test the relationship between bird species richness and environmental factors, we examined the relative importance of seven ecological variables on breeding season distribution patterns: land area (LA), mean daily temperature (MDT), seasonal temperature range (STR), the mid-domain effect (MDE), seasonal precipitation (SP), invertebrate biomass (IB) and enhanced vegetation index (EVI). Climate data were obtained from five local meteorological stations and three temperature/relative humidity smart sensors in 2016.Results: A total of 219 bird species were recorded in the field, of which 204 were recorded during the breeding season (April-August). Species richness curves (calculated separately for total species, large-ranged species, and small-ranged species) were all hump-shaped. Large-ranged species contributed more to the total species richness pattern than small-ranged species. EVI and IB were positively correlated with total species richness and small-ranged species richness. LA and MDT were positively correlated with small-ranged species richness, while STR and SP were negatively correlated with small-ranged species richness. MDE was positively correlated with large-ranged species richness. When we considered the combination of candidate factors using multiple regression models and model-averaging, total species richness and large-ranged species richness were correlated with STR (negative) and MDE (positive), while small-ranged species richness was correlated with STR (negative) and IB (positive).Conclusions: Although no single key factor or suite of factors could explain patterns of diversity, we found that MDE, IB and STR play important but varying roles in shaping the elevational richness patterns of different bird species categories. Model-averaging indicates that small-ranged species appear to be mostly influenced by IB, as opposed to large-ranged species, which exhibit patterns more consistent with the MDE model. Our data also indicate that the species richness varied between seasons, offering a promising direction for future work.
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| 10. |
- Jonsson, Knud Andreas, et al.
(författare)
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Unrecognised (species) diversity in New Guinean passerine birds
- 2019
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Ingår i: Emu (Print). - : TAYLOR & FRANCIS AUSTRALASIA. - 0158-4197 .- 1448-5540. ; 119:3, SI, s. 233-241
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Tidskriftsartikel (refereegranskat)abstract
- Species represent an important unit for the study of diversity, but may not always be delimited consistently across regions and clades. Many of these taxonomic inconsistencies are due to the variable views of taxonomists. In recent years, however, new methodologies have attempted to circumvent this problem by assigning more objective criteria for the delimitation of species, drawing on a wide range of data such as DNA, morphology, vocalisation and ecology. Here, we apply a genetic screening approach in which we sequence the mitochondrial gene ND2 for all recognised subspecies of 16 species in eight genera (a mix of lowland and montane species) from the geologically complex tropical island of New Guinea. We show that populations within some species are genetically highly divergent despite little morphological differentiation, but we also find an example in which populations from five morphologically distinct species are genetically very similar. Overall, our data show higher levels of genetic differentiation than expected, but also highlight the difficulty of predicting which groups contain unrecognised diversity. These results are interesting in their own right, but also have implications for further analyses that focus on increasing our understanding of how diversity builds up over time.
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| 11. |
- Lu, Yunxia, et al.
(författare)
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Dietary Polyphenols in the Aetiology of Crohn's Disease and Ulcerative Colitis-A Multicenter European Prospective Cohort Study (EPIC)
- 2017
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Ingår i: Inflammatory Bowel Diseases. - : Lippincott Williams & Wilkins. - 1078-0998 .- 1536-4844. ; 23:12, s. 2072-2082
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Tidskriftsartikel (refereegranskat)abstract
- Background: Oxidative stress may be involved in the aetiology of inflammatory bowel disease and whether dietary polyphenols, which possess antioxidants properties, prevent its development is unknown.Methods: A total of 401,326 men and women aged 20 to 80 years from 8 countries were recruited between 1991 and 1998 and at baseline completed validated food frequency questionnaires. Dietary polyphenol intake was measured using Phenol-Explorer, a database with information on the content of 502 polyphenols. Incident cases of Crohn's diseases (CD) and ulcerative colitis (UC) were identified during the follow-up period of up to December 2010. A nested case–control study using conditional logistic regression estimated the odds ratios (ORs), and 95% confidence intervals, for polyphenol intake (categories based on quartiles) and developing CD or UC.Results: In total, 110 CD (73% women) and 244 UC (57% women) cases were identified and matched to 440 and 976 controls, respectively. Total polyphenol intake was not associated with CD ( P trend = 0.17) or UC ( P trend = 0.16). For flavones and CD, there were reduced odds for all quartiles, which were statistically significant for the third (OR 3rd versus 1st quartile = 0.33; 95% confidence interval, 0.15–0.69) and there was an inverse trend across quartiles ( P = 0.03). Similarly, for resveratrol, there was an inverse association with CD (OR 4th versus 1st quartile = 0.40; 95% confidence interval, 0.20–0.82) with an inverse trend across quartiles ( P = 0.02). No significant associations between subtypes of polyphenols and UC were found. Effect modification by smoking in CD was documented with borderline statistical significance.Conclusions: The data supports a potential role of flavones and resveratrol in the risk of developing CD; future aetiological studies should investigate these dietary components and further examine the potential for residual confounding.
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| 12. |
- Opstelten, Jorrit L., et al.
(författare)
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Dairy products, dietary calcium, and risk of inflammatory bowel disease : Results from a European prospective cohort investigation
- 2016
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Ingår i: Inflammatory Bowel Diseases. - 1078-0998 .- 1536-4844. ; 22:6, s. 1403-1411
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Tidskriftsartikel (refereegranskat)abstract
- Background: Dairy products may be involved in the etiology of inflammatory bowel disease by modulating gut microbiota and immune responses, but data from epidemiological studies examining this relationship are limited. We investigated the association between prediagnostic intake of these foods and dietary calcium, and the subsequent development of Crohn's disease (CD) and ulcerative colitis (UC). Methods: In total, 401,326 participants were enrolled in the European Prospective Investigation into Cancer and Nutrition cohort. At recruitment, consumption of total and specific dairy products (milk, yogurt, and cheese) and dietary calcium was measured using validated food frequency questionnaires. Cases developing incident CD (n 110) or UC (n 244) during follow-up were matched with 4 controls. Conditional logistic regression analyses were used to calculate odds ratios (ORs) with 95% confidence intervals (CIs), adjusted for total energy intake and smoking. Results: Compared with the lowest quartile, the ORs for the highest quartile of total dairy products and dietary calcium intake were 0.61 (95% CI, 0.32-1.19, p trend 0.19) and 0.63 (95% CI, 0.28-1.42, p trend 0.23) for CD, and 0.80 (95% CI, 0.50-1.30, p trend 0.40) and 0.81 (95% CI, 0.49-1.34, p trend 0.60) for UC, respectively. Compared with nonconsumers, individuals consuming milk had significantly reduced odds of CD (OR 0.30, 95% CI, 0.13-0.65) and nonsignificantly reduced odds of UC (OR 0.85, 95% CI, 0.49-1.47). Conclusions: Milk consumption may be associated with a decreased risk of developing CD, although a clear dose-response relationship was not established. Further studies are warranted to confirm this possible protective effect.
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| 13. |
- Racine, Antoine, et al.
(författare)
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Dietary Patterns and Risk of Inflammatory Bowel Disease in Europe : Results from the EPIC Study
- 2016
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Ingår i: Inflammatory Bowel Diseases. - 1078-0998 .- 1536-4844. ; 22:2, s. 345-354
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Tidskriftsartikel (refereegranskat)abstract
- Background: Specific nutrients or foods have been inconsistently associated with ulcerative colitis (UC) or Crohn’s disease (CD) risks. Thus, we investigated associations between diet as a whole, as dietary patterns, and UC and CD risks.Methods: Within the prospective EPIC (European Prospective Investigation into Cancer) study, we set up a nested matched case–control study among 366,351 participants with inflammatory bowel disease data, including 256 incident cases of UC and 117 of CD, and 4 matched controls per case. Dietary intake was recorded at baseline from validated food frequency questionnaires. Incidence rate ratios of developing UC and CD were calculated for quintiles of the Mediterranean diet score and a posteriori dietary patterns produced by factor analysis.Results: No dietary pattern was associated with either UC or CD risks. However, when excluding cases occurring within the first 2 years after dietary assessment, there was a positive association between a “high sugar and soft drinks” pattern and UC risk (incidence rate ratios for the fifth versus first quintile, 1.68 [1.00–2.82]; Ptrend ¼ 0.02). When considering the foods most associated with the pattern, high consumers of sugar and soft drinks were at higher UC risk only if they had low vegetables intakes.
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| 14. |
- Reddy, Hemanth K. N., et al.
(författare)
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Coherent soft X-ray diffraction imaging of coliphage PR772 at the Linac coherent light source
- 2017
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Ingår i: Scientia Danica. Series H. Humanistica 4. - : Nature Publishing Group. - 1904-5506 .- 2052-4463. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Single-particle diffraction from X-ray Free Electron Lasers offers the potential for molecular structure determination without the need for crystallization. In an effort to further develop the technique, we present a dataset of coherent soft X-ray diffraction images of Coliphage PR772 virus, collected at the Atomic Molecular Optics (AMO) beamline with pnCCD detectors in the LAMP instrument at the Linac Coherent Light Source. The diameter of PR772 ranges from 65-70 nm, which is considerably smaller than the previously reported similar to 600 nm diameter Mimivirus. This reflects continued progress in XFEL-based single-particle imaging towards the single molecular imaging regime. The data set contains significantly more single particle hits than collected in previous experiments, enabling the development of improved statistical analysis, reconstruction algorithms, and quantitative metrics to determine resolution and self-consistency.
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| 15. |
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| 16. |
- Thomson, Suzanne E., et al.
(författare)
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Bioengineered nerve conduits and wraps for peripheral nerve repair of the upper limb
- 2017
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Ingår i: Cochrane Database of Systematic Reviews. - 1361-6137. ; 2017:3
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Forskningsöversikt (refereegranskat)abstract
- This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess and compare the effects and complication rates of licensed bioengineered nerve conduits or wraps for surgical repair of traumatic peripheral nerve injuries of the upper limb. To compare effects and complications against the current gold surgical standard (nerve autograft).
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| 17. |
- Thomson, Suzanne E., et al.
(författare)
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Microtopographical cues promote peripheral nerve regeneration via transient mTORC2 activation
- 2017
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Ingår i: Acta Biomaterialia. - : Elsevier. - 1742-7061 .- 1878-7568. ; 60, s. 220-231
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Tidskriftsartikel (refereegranskat)abstract
- Despite microsurgical repair, recovery of function following peripheral nerve injury is slow and often incomplete. Outcomes could be improved by an increased understanding of the molecular biology of regeneration and by translation of experimental bioengineering strategies. Topographical cues have been shown to be powerful regulators of the rate and directionality of neurite regeneration, and in this study we investigated the downstream molecular effects of linear micropatterned structures in an organotypic explant model. Linear topographical cues enhanced neurite outgrowth and our results demonstrated that the mTOR pathway is important in regulating these responses. mTOR gene expression peaked between 48 and 72 h, coincident with the onset of rapid neurite outgrowth and glial migration, and correlated with neurite length at 48 h. mTOR protein was located to glia and in a punctate distribution along neurites. mTOR levels peaked at 72 h and were significantly increased by patterned topography (p < 0.05). Furthermore, the topographical cues could override pharmacological inhibition. Downstream phosphorylation assays and inhibition of mTORC1 using rapamycin highlighted mTORC2 as an important mediator, and more specific therapeutic target. Quantitative immunohistochemistry confirmed the presence of the mTORC2 component rictor at the regenerating front where it co-localised with F-actin and vinculin. Collectively, these results provide a deeper understanding of the mechanism of action of topography on neural regeneration, and support the incorporation of topographical patterning in combination with pharmacological mTORC2 potentiation within biomaterial constructs used to repair peripheral nerves.Statement of Significance: Peripheral nerve injury is common and functionally devastating. Despite microsurgical repair, healing is slow and incomplete, with lasting functional deficit. There is a clear need to translate bioengineering approaches and increase our knowledge of the molecular processes controlling nerve regeneration to improve the rate and success of healing. Topographical cues are powerful determinants of neurite outgrowth and represent a highly translatable engineering strategy. Here we demonstrate, for the first time, that microtopography potentiates neurite outgrowth via the mTOR pathway, with the mTORC2 subtype being of particular importance. These results give further evidence for the incorporation of microtopographical cues into peripheral nerve regeneration conduits and indicate that mTORC2 may be a suitable therapeutic target to potentiate nerve regeneration.
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| 18. |
- Zeng, Chenjie, et al.
(författare)
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Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus
- 2016
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 x 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 x 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 x 10(-4)) identified in the general populations, and rs113824616 (P = 7 x 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. Conclusion: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.
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