| 111. |
- Kumar, Jitender, et al.
(författare)
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Associations of Body Mass Index and Obesity-Related Genetic Variants with Serum Metabolites
- 2014
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Ingår i: Current Metabolomics. - 2213-235X. ; 2:1, s. 27-36-
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Body mass index (BMI) is one of the most important risk factors for different metabolic and cardiovascular disorders. Previously, both genetic and environmental agents associated with BMI have been described. The main focus of this exploratory study was to find the circulating metabolites associated with BMI utilizing an untargeted metabolomics approach. Additionally, significant metabolites identified were studied for their relation with BMIassociated single nucleotide polymorphisms (SNPs). Materials and Methods: A total of 971 individuals from the Cancer of the Prostate in Sweden study (discovery sample- 275 prostate cancers patients and 182 controls; replication sample- 514 prostate cancer patients) were utilized. Blood samples were collected and serum metabolic profiling was obtained using ultra-performance liquid chromatography followed by mass spectrometry. Genotyping data was available for 26 out of 32 SNPs (21 genotyped and 5 proxies) previously robustly associated with BMI in individuals of European descent. Weighted genetic risk score was generated using these SNPs and studied for its association with metabolites. Results: A total of 6138 and 5209 metabolite features were detected in discovery and replication samples, respectively. Out of 6138 metabolite features in discovery sample, 201 were found to be significantly associated with BMI (p<8.15*10-6) after multiple testing correction. These 201 features were further investigated in the replication samples and 16 were found to be significantly associated with BMI (p<2.49*10-4). Seven of these significant features were isotopes for four of the primary metabolites. Four metabolites were putatively identified: monoacylglyceride (18:1), diacylglyrcerol (32:1) and two phosphatidylcholines (34:0 and 36:0). Weighted genetic score of BMI-associated SNPs was not associated with these four metabolites. Conclusion: Four identifiable metabolites (monoacylglyceride, diacyclglyrcerol and two phosphatidylcholines) were found to be significantly associated with BMI in both discovery and replication samples. Common variants associated with BMI did not show association with these four metabolites. - See more at: http://www.eurekaselect.com/120422/article#sthash.PgqffHqv.dpuf
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| 112. |
- Kumar, Jitender, et al.
(författare)
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Influence of Biological and Technical Covariates on Non-targeted Metabolite Profiling in a Large-scale Epidemiological Study
- 2013
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Ingår i: Current Metabolomics. - 2213-235X. ; 1:3, s. 220-226-
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Tidskriftsartikel (refereegranskat)abstract
- Non-targeted metabolite profiling using ultra performance liquid chromatography-mass spectrometry (UPLCMS) was performed as part of a large-scale epidemiological study involving biobanked serum samples. The influence of both biological (age and body mass index) and technical (season of sample collection, fasting time, handling time, and storage time) covariates on the analysis was assessed. Statistical models including different sets of these covariates were compared and the results illustrate that variation in which covariates were included did not have an appreciable effect on the number or composition of biologically significant metabolite features associated with body mass index or age. Furthermore, when all covariates were included in the model, there was little overlap of metabolite features significantly associated with the different covariates. Thus, the results of this study illustrate that while some of the observed quantitative variance of metabolite features can be explained by biological and technical covariates, the use of non-targeted metabolite profiling of serum by UPLC-MS is valid for studies of biological outcomes in biobanked clinical samples from large-scale studies. - See more at: http://www.eurekaselect.com/115259/article#sthash.BOvtwWe7.dpuf
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| 113. |
- Lango Allen, Hana, et al.
(författare)
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Hundreds of variants clustered in genomic loci and biological pathways affect human height.
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8
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Tidskriftsartikel (refereegranskat)abstract
- Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
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| 114. |
- Law, Philip J., et al.
(författare)
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Association analyses identify 31 new risk loci for colorectal cancer susceptibility
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 115. |
- Lennmyr, Fredrik, et al.
(författare)
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Cerebral effects of hyperglycemia in experimental cardiac arrest
- 2010
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Ingår i: Critical Care Medicine. - 0090-3493 .- 1530-0293. ; 38:8, s. 1726-1732
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate the effects of cardiac arrest on cerebral perfusion and oxidative stress during hyperglycemia and normoglycemia. Design: Experimental animal model. Setting: University laboratory. Subjects: Triple-breed pigs (weight, 22-27 kg). Interventions: Thirty-three pigs were randomized and clamped at blood glucose levels of 8.5-10 mM (high) or 4-5.5 mM (normal) and thereafter subjected to alternating current-induced 12-min cardiac arrest followed by 8 mins of cardiopulmonary resuscitation and direct-current shock to restore spontaneous circulation. Measurements and Main Results: Hemodynamics, regional near-infrared light spectroscopy, regional venous HbO(2), and biochemical markers (Protein S100 beta, troponin I, F-2-isoprostanes reflecting oxidative stress and inflammation) were monitored and/or sampled throughout an observation period of 4 hrs. No significant differences were seen in hemodynamics or biochemical profile. The cerebral oxygenation by means of regional near-infrared light spectroscopy was higher in the hyperglycemic (H) than in the normal (N) group after restoration of spontaneous circulation (p < .05). However, tendencies toward increased protein S100 beta and 15-keto-dihydro-prostaglandin F-2 alpha were observed in the H group but were not statistically significant. Conclusions: The responses to 12-min cardiac arrest and cardiopulmonary resuscitation share large similarities during hyperglycemia and normoglycemia. The higher cerebral tissue oxygenation observed in the hyperglycemia needs to be confirmed and the phenomenon needs to be addressed in future studies.
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| 116. |
- Lin, Daniel W., et al.
(författare)
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Genetic variants in the LEPR, CRY1, RNASEL, IL4, and ARVCF genes are prognostic markers of prostate cancer-specific mortality
- 2011
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - Philadelphia : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 20:9, s. 1928-1936
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Tidskriftsartikel (refereegranskat)abstract
- Background: Prostate cancer is the second leading cause of cancer-related deaths in men, accounting for more than 30,000 deaths annually. The purpose of this study was to test whether variation in selected candidate genes in biological pathways of interest for prostate cancer progression could help distinguish patients at higher risk for fatal prostate cancer. Methods: In this hypothesis-driven study, we genotyped 937 single nucleotide polymorphisms (SNPs) in 156 candidate genes in a population-based cohort of 1,309 prostate cancer patients. We identified 22 top-ranking SNPs (P <= 0.01, FDR <= 0.70) associated with prostate cancer-specific mortality (PCSM). A subsequent validation study was completed in an independent population-based cohort of 2,875 prostate cancer patients. Results: Five SNPs were validated (P <= 0.05) as being significantly associated with PCSM, one each in the LEPR, CRY1, RNASEL, IL4, and ARVCF genes. Compared with patients with 0 to 2 of the at-risk genotypes those with 4 to 5 at-risk genotypes had a 50% (95% CI, 1.2-1.9) higher risk of PCSM and risk increased with the number of at-risk genotypes carried (P(trend) = 0.001), adjusting for clinicopathologic factors known to influence prognosis. Conclusion: Five genetic markers were validated to be associated with lethal prostate cancer. Impact: This is the first population-based study to show that germline genetic variants provide prognostic information for prostate cancer-specific survival. The clinical utility of this five-SNP panel to stratify patients at higher risk for adverse outcomes should be evaluated. Cancer Epidemiol Biomarkers Prev; 20(9); 1928-36. (C)2011 AACR.
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| 117. |
- Lindblom, Rickard P F, 1981-, et al.
(författare)
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Hyperglycemia Alters Expression of Cerebral Metabolic Genes after Cardiac Arrest
- 2018
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Ingår i: Journal of Stroke & Cerebrovascular Diseases. - : Elsevier BV. - 1052-3057 .- 1532-8511. ; 27:5, s. 1200-1211
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Tidskriftsartikel (refereegranskat)abstract
- Background: Survivors of cardiac arrest often experience neurologic deficits. To date, treatment options are limited. Associated hyperglycemia is believed to further worsen the neurologic outcome. The aim with this study was to characterize expression pathways induced by hyperglycemia in conjunction with global brain ischemia.Methods: Pigs were randomized to high or normal glucose levels, as regulated by glucose and insulin infusions with target levels of 8.5-10 mM and 4-5.5 mM, respectively. The animals were subjected to 5-minute cardiac arrest followed by 8 minutes of cardiopulmonary resuscitation and direct-current shock to restore spontaneous circulation. Global expression profiling of the cortex using microarrays was performed in both groups.Results: A total of 102 genes differed in expression at P<.001 between the hyperglycemic and the normoglycemic pigs. Several of the most strongly differentially regulated genes were involved in transport and metabolism of glucose. Functional clustering using bioinformatics tools revealed enrichment of multiple biological processes, including membrane processes, ion transport, and glycoproteins.Conclusions: Hyperglycemia during cardiac arrest leads to differential early gene expression compared with normoglycemia. The functional relevance of these expressional changes cannot be deduced from the current study; however, the identified candidates have been linked to neuroprotective mechanisms and constitute interesting targets for further studies.
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| 118. |
- Lindman, Henrik, et al.
(författare)
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Long-term treatment patterns and survival in metastatic breast cancer by intrinsic subtypes - an observational cohort study in Sweden
- 2022
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Ingår i: BMC Cancer. - : Springer Nature. - 1471-2407. ; 22
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Tidskriftsartikel (refereegranskat)abstract
- Background: Longitudinal, real-world data on the management of metastatic breast cancer is increasingly relevant to understand breast cancer care in routine clinical practice. Yet such data are scarce, particularly beyond second- and third-line treatment strategies. This study, therefore, examined both the long-term treatment patterns and overall survival (OS) in a regional Swedish cohort of female patients with metastatic breast cancer stratified by subtype in routine clinical practice during a recent eight-year period and correlation to current treatment guidelines.Methods: Consecutive female patients with metastatic breast cancer clinically managed at Uppsala University Hospital, Uppsala, Sweden, during 2009-2016 and followed until the end of September, 2017 (n = 370) were included and, where possible, classified as having one of five, intrinsic subtypes: Luminal A; Luminal B; human epidermal growth factor receptor 2-positive (HER2+)/ estrogen receptor-positive (ER+); HER2+/estrogen receptor-negative (ER-); or triple negative breast cancer (TNBC). Treatment patterns and OS were estimated by subtype using time-to-event methods.Results: A total of 352/370 patients with metastatic breast cancer (mean age 67.6 years) could be subtyped: 118 (34%) were Luminal A, 119 (34%) Luminal B, 31 (8%) HER2+/ER-, 38 (11%) HER2+/Luminal, and 46 (13%) TNBC. The median number of metastatic treatment lines was 3. Most patients were on active treatment during follow-up (80% of the observation period), except for patients with TNBC who were on treatment for 60% of the observation time. Overall, 67% of patients died whilst on treatment. Among all patients (n = 370), median OS was 32.5 months (95% CI = 28.2-35.7). The 5-year survival rate was highest for HER2+/Luminal (46%) patients, followed by Luminal B (29%), Luminal A (28%), HER2+/ER- (21%), and TNBC (7%). Increasing age and number of metastatic sites also predicted worse survival.Conclusions: Metastatic breast cancer patients in Sweden, irrespective of subtype, generally receive active treatment until time of death. Survival varies considerably across subtypes and is also associated with patient characteristics. Regardless of differences in treatment patterns for Luminal A and B patients, long-term OS was the same.
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| 119. |
- Lindstrom, Sara, et al.
(författare)
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Genetic variation in the upstream region of ERG and prostate cancer
- 2009
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Ingår i: Cancer Causes and Control. - : SPRINGER. - 0957-5243 .- 1573-7225. ; 20:7, s. 1173-1180
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Tidskriftsartikel (refereegranskat)abstract
- A considerable fraction of prostate cancers harbor a gene fusion between the androgen-regulated TMPRSS2 and ERG, one of the most frequently over-expressed proto-oncogenes in prostate cancer. Here, we investigated if inherited genetic variation upstream of ERG alters prostate cancer risk and survival. We genotyped 21 haplotype tagging SNPs (htSNPs) covering 123 kb of 5'UTR DNA including exon 3 of ERG in 2,760 incident prostate cancer cases and 1,647 controls from a population-based Swedish case-control study (CAPS). Individual SNPs and haplotypes were tested for association with prostate cancer risk and survival. One haplotype-'CTCGTATG' located 100 kb upstream of ERG-was associated with lethal prostate cancer (HR, 1.36; 95% CI, 1.2-1.9, p = 0.006). Carriers of the variant 'T' allele of rs2836626 were diagnosed with higher TNM-stage (p = 0.009) and had an increased risk of prostate cancer-specific death (HR = 1.3; 95% CI, 1.1-1.7, p = 0.009). However, this association did not remain statistically significant after adjusting for multiple testing. We found overall no association between ERG variation and prostate cancer risk. Genetic variation upstream of ERG may alter prostate cancer stage and ultimately prostate cancer-specific death but it is unlikely that it plays a role in prostate cancer development.
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| 120. |
- Lindstrom, Sara, et al.
(författare)
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Germ-line genetic variation in the key androgen-regulating genes androgen receptor, cytochrome P450, and steroid-5-alpha-reductase type 2 is important for prostate cancer development
- 2006
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Ingår i: Cancer Research. - Umea Univ, Dept Radiat Sci Oncol, SE-90185 Umea, Sweden. Karolinska Inst, Dept Med Epidemiol & Biostat, CLINTEC, S-10401 Stockholm, Sweden. Karolinska Inst, Oncol Ctr, CLINTEC, S-10401 Stockholm, Sweden. : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 66:22, s. 11077-11083
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer risk may be influenced by single genetic variants in the hormone-regulating genes androgen receptor (AR), cytochrome P450 (CYP17), and steroid-5-alpha-reductase type 2 (SRD5A2). In this study, we comprehensively investigated polymorphisms in these three loci and their joint effect in a large population-based study. We selected 23 haplotype-tagging single-nucleotide polymorphisms (htSNP) that could uniquely describe > 95% of the haplotypes (6 in AR, 6 in CYP17, and 11 in SRD5A2). These htSNPs were then genotyped in the Cancer Prostate in Sweden population (2,826 case subjects and 1,705 controls). We observed significant association for several SNPs in the AR gene (P = 0.004-0.02) and CYP17 (P = 0.009-0.05) and one SNP in SRD5A2 (P = 0.02). Carriers of the most common AR haplotype had a significant excess risk to develop prostate cancer [odds ratio (OR), 1.25; 95% confidence interval (95% CI), 1.1-1.5; P = 0.002], yielding an estimated population attributable risk of 16% (95% CI, 0.06-0.25). Combining risk alleles from these genes yielded a 12% risk increase for each additional high-risk allele carried (95% CI, 1.1-1.2; P for trend = 9.2 x 10(-5)), with an overall OR of 1.87 (95% CI, 1.0-3.4) for carriers of all five included risk alleles, an OR of 2.13 (P for trend = 8 x 10(-4)) for advanced disease, and an OR of 4.35 (P for trend = 7 x 10(-5)) for disease onset before age 65 years. Genetic variation in key genes in the androgen pathway is important for development of prostate cancer and may account for a considerable proportion of all prostate cancers. Carriers of rive high-risk alleles in the AR, CYP17, and SRD5A2 genes are at similar to 2-fold excess risk to develop prostate cancer.
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