共查询到20条相似文献,搜索用时 15 毫秒
1.
Jari E. Kaikkonen Petri Kresanov Markku Ahotupa Antti Jula Vera Mikkilä Jorma S. A. Viikari 《Free radical research》2016,50(4):396-404
Oxidative reactions are thought to play a role in the inflammatory condition called fatty liver. It is unclear whether oxidized lipoprotein lipids or proteins are associated with future fatty liver. In the Cardiovascular Risk in Young Finns Study, we determined the circulating levels of LDL and HDL oxidized lipids and studied their associations with fatty liver assessed by ultrasonography. There were 1286 middle-aged subjects with normal liver and 288 subjects with fatty liver. Analysis of oxidized lipids consisted of conjugated dienes in isolated HDL (oxHDLlipids) and LDL (oxLDLlipids). Oxidized LDL was also measured with a method based on antibodies against oxidized apolipoprotein B (oxLDLprot). After adjustment for age, sex, leisure-time physical activity, body mass index, alcohol intake, smoking, serum LDL and HDL cholesterol as well as particle concentrations, participants with elevated oxLDLlipids (odds ratio for 1-SD change in oxLDLlipids?=?1.27, p?=?0.011) had an increased risk for fatty liver. Similarly, a high oxidation score (oxLDLlipids?+?oxLDLprot) was directly associated with fatty liver (odds ratio=1.34, p?=?0.012). The strongest direct association was seen with a high oxLDLlipids/oxHDLlipids ratio (odds ratio=1.49, p?=?0.001). These data suggest that oxidized lipoprotein lipids are linked with the risk of fatty liver in middle-aged adults. 相似文献
2.
Froguel P Ndiaye NC Bonnefond A Bouatia-Naji N Dechaume A Siest G Herbeth B Falchi M Bottolo L Guéant-Rodriguez RM Lecoeur C Langlois MR Labrune Y Ruokonen A El Shamieh S Stathopoulou MG Morandi A Maffeis C Meyre D Delanghe JR Jacobson P Sjöström L Carlsson LM Walley A Elliott P Jarvelin MR Dedoussis GV Visvikis-Siest S 《PloS one》2012,7(3):e32327
Haptoglobin is an acute phase inflammatory marker. Its main function is to bind hemoglobin released from erythrocytes to aid its elimination, and thereby haptoglobin prevents the generation of reactive oxygen species in the blood. Haptoglobin levels have been repeatedly associated with a variety of inflammation-linked infectious and non-infectious diseases, including malaria, tuberculosis, human immunodeficiency virus, hepatitis C, diabetes, carotid atherosclerosis, and acute myocardial infarction. However, a comprehensive genetic assessment of the inter-individual variability of circulating haptoglobin levels has not been conducted so far.We used a genome-wide association study initially conducted in 631 French children followed by a replication in three additional European sample sets and we identified a common single nucleotide polymorphism (SNP), rs2000999 located in the Haptoglobin gene (HP) as a strong genetic predictor of circulating Haptoglobin levels (P(overall) = 8.1 × 10(-59)), explaining 45.4% of its genetic variability (11.8% of Hp global variance). The functional relevance of rs2000999 was further demonstrated by its specific association with HP mRNA levels (β = 0.23 ± 0.08, P = 0.007). Finally, SNP rs2000999 was associated with decreased total and low-density lipoprotein cholesterol in 8,789 European children (P(total cholesterol) = 0.002 and P(LDL) = 0.0008).Given the central position of haptoglobin in many inflammation-related metabolic pathways, the relevance of rs2000999 genotyping when evaluating haptoglobin concentration should be further investigated in order to improve its diagnostic/therapeutic and/or prevention impact. 相似文献
3.
4.
Harri Helaj?rvi Tom Rosenstr?m Katja Pahkala Mika K?h?nen Terho Lehtim?ki Olli J. Heinonen Mervi Oikonen Tuija Tammelin Jorma S. A. Viikari Olli T. Raitakari 《PloS one》2014,9(7)
Background
Television viewing time (TV time) is associated with increased weight and obesity, but it is unclear whether this relation is causal.Methods and Results
We evaluated changes in TV time, waist circumference (waist) and body mass index (BMI) in participants of the population-based Cardiovascular Risk in Young Finns study (761 women, 626 men aged 33–50 years in 2011). Waist and BMI were measured, and TV time was self-reported in 2001, 2007, and 2011. Changes in waist and BMI between 2001 and 2011 were studied a) for the whole group, b) in groups with constantly low (≤1 h/d), moderate (1–3 h/d), or high (≥3 h/d) TV time, and c) in groups with ≥1 hour in-/decrease in daily TV time between 2001 and 2011. BMIs in 1986 were also evaluated. We explored the causal relationship of TV time with waist and BMI by classical temporality criterion and recently introduced causal-discovery algorithms (pairwise causality measures). Both methods supported the hypothesis that TV time is causative to weight gain, and no evidence was found for reverse or bidirectional causality. Constantly low TV time was associated with less pronounced increase in waist and BMI, and waist and BMI increase was lower with decreased TV time (P<0.05). The increase in waist and BMI was at least 2-fold in the high TV time group compared to the low TV time group (P<0.05). Adjustment for age, sex, BMI/waist in 2001, physical activity, energy intake, or smoking did not change the results.Conclusions
In young and middle-aged adults, constantly high TV time is temporally antecedent to BMI and waist increase. 相似文献5.
Sebastian Okser Terho Lehtim?ki Laura L. Elo Nina Mononen Nina Peltonen Mika K?h?nen Markus Juonala Yue-Mei Fan Jussi A. Hernesniemi Tomi Laitinen Leo-Pekka Lyytik?inen Riikka Rontu Carita Eklund Nina Hutri-K?h?nen Leena Taittonen Mikko Hurme Jorma S. A. Viikari Olli T. Raitakari Tero Aittokallio 《PLoS genetics》2010,6(9)
The relative contribution of genetic risk factors to the progression of subclinical atherosclerosis is poorly understood. It is likely that multiple variants are implicated in the development of atherosclerosis, but the subtle genotypic and phenotypic differences are beyond the reach of the conventional case-control designs and the statistical significance testing procedures being used in most association studies. Our objective here was to investigate whether an alternative approach—in which common disorders are treated as quantitative phenotypes that are continuously distributed over a population—can reveal predictive insights into the early atherosclerosis, as assessed using ultrasound imaging-based quantitative measurement of carotid artery intima-media thickness (IMT). Using our population-based follow-up study of atherosclerosis precursors as a basis for sampling subjects with gradually increasing IMT levels, we searched for such subsets of genetic variants and their interactions that are the most predictive of the various risk classes, rather than using exclusively those variants meeting a stringent level of statistical significance. The area under the receiver operating characteristic curve (AUC) was used to evaluate the predictive value of the variants, and cross-validation was used to assess how well the predictive models will generalize to other subsets of subjects. By means of our predictive modeling framework with machine learning-based SNP selection, we could improve the prediction of the extreme classes of atherosclerosis risk and progression over a 6-year period (average AUC 0.844 and 0.761), compared to that of using conventional cardiovascular risk factors alone (average AUC 0.741 and 0.629), or when combined with the statistically significant variants (average AUC 0.762 and 0.651). The predictive accuracy remained relatively high in an independent validation set of subjects (average decrease of 0.043). These results demonstrate that the modeling framework can utilize the “gray zone” of genetic variation in the classification of subjects with different degrees of risk of developing atherosclerosis. 相似文献
6.
Mathieu Lemire Conghui Qu Lenora W. M. Loo Syed H. E. Zaidi Hansong Wang Sonja I. Berndt Stéphane Bézieau Hermann Brenner Peter T. Campbell Andrew T. Chan Jenny Chang-Claude Mengmeng Du Christopher K. Edlund Steven Gallinger Robert W. Haile Tabitha A. Harrison Michael Hoffmeister John L. Hopper Lifang Hou Li Hsu Eric J. Jacobs Mark A. Jenkins Jihyoun Jeon Sébastien Küry Li Li Noralane M. Lindor Polly A. Newcomb John D. Potter Gad Rennert Anja Rudolph Robert E. Schoen Fredrick R. Schumacher Daniela Seminara Gianluca Severi Martha L. Slattery Emily White Michael O. Woods Michelle Cotterchio Loïc Le Marchand Graham Casey Stephen B. Gruber Ulrike Peters Thomas J. Hudson 《Human genetics》2015,134(11-12):1249-1262
7.
Yin Huang Dan Li Lu Qiao Yu Liu Qianqian Peng Sijie Wu Manfei Zhang Yajun Yang Jingze Tan Shuhua Xu Li Jin Sijia Wang Kun Tang Stefan Grünewald 《遗传学报》2021,48(3):198-207
The human face is a heritable surface with many complex sensory organs. In recent years, many genetic loci associated with facial features have been reported in different populations, yet there is a lack of studies on the Han Chinese population. Here, we report a genome-wide association study of 3 D normal human faces of 2,659 Han Chinese with autosegment phenotypes of facial morphology. We identify singlenucleotide polymorphisms(SNPs) encompassing four genomic regions showing significant associations with different facial regions, including SNPs in DENND1 B associated with the chin, SNPs among PISRT1 associated with eyes, SNPs between DCHS2 and SFRP2 associated with the nose, and SNPs in VPS13 B associated with the nose. We replicate 24 SNPs from previously reported genetic loci in different populations, whose candidate genes are DCHS2, SUPT3 H, HOXD1, SOX9, PAX3, and EDAR. These results provide a more comprehensive understanding of the genetic basis of variation in human facial morphology. 相似文献
8.
Harry D. Green Alistair Jones Jonathan P. Evans Andrew R. Wood Robin N. Beaumont Jessica Tyrrell Timothy M. Frayling Christopher Smith Michael N. Weedon 《PLoS genetics》2021,17(6)
Frozen shoulder is a painful condition that often requires surgery and affects up to 5% of individuals aged 40–60 years. Little is known about the causes of the condition, but diabetes is a strong risk factor. To begin to understand the biological mechanisms involved, we aimed to identify genetic variants associated with frozen shoulder and to use Mendelian randomization to test the causal role of diabetes. We performed a genome-wide association study (GWAS) of frozen shoulder in the UK Biobank using data from 10,104 cases identified from inpatient, surgical and primary care codes. We used data from FinnGen for replication and meta-analysis. We used one-sample and two-sample Mendelian randomization approaches to test for a causal association of diabetes with frozen shoulder. We identified five genome-wide significant loci. The most significant locus (lead SNP rs28971325; OR = 1.20, [95% CI: 1.16–1.24], p = 5x10-29) contained WNT7B. This variant was also associated with Dupuytren’s disease (OR = 2.31 [2.24, 2.39], p<1x10-300) as were a further two of the frozen shoulder associated variants. The Mendelian randomization results provided evidence that type 1 diabetes is a causal risk factor for frozen shoulder (OR = 1.03 [1.02–1.05], p = 3x10-6). There was no evidence that obesity was causally associated with frozen shoulder, suggesting that diabetes influences risk of the condition through glycemic rather than mechanical effects. We have identified genetic loci associated with frozen shoulder. There is a large overlap with Dupuytren’s disease associated loci. Diabetes is a likely causal risk factor. Our results provide evidence of biological mechanisms involved in this common painful condition. 相似文献
9.
Zhengjun Wang Shunan Zhao Liming Zhang Qing Yang Chen Cheng Ning Ding Zijian Zhu Hua Shu Chunyu Liu Jingjing Zhao 《Genes, Brain & Behavior》2023,22(1):e12833
Reading disability exhibited defects in different cognitive domains, including word reading fluency, word reading accuracy, phonological awareness, rapid automatized naming and morphological awareness. To identify the genetic basis of Chinese reading disability, we conducted a genome-wide association study (GWAS) of the cognitive traits related to Chinese reading disability in 2284 unrelated Chinese children. Among the traits analyzed in the present GWAS, we detected one genome-wide significant association (p < 5 × 10−8) on word reading fluency for one SNP on 4p16.2, within EVC genes (rs6446395, p = 7.33 × 10−10). Rs6446395 also showed significant association with Chinese character reading accuracy (p = 2.95 × 10−4), phonological awareness (p = 7.11 × 10−3) and rapid automatized naming (p = 4.71 × 10−3), implying multiple effects of this variant. The eQTL data showed that rs6446395 affected EVC expression in the cerebellum. Gene-based analyses identified a gene (PRDM10) to be associated with word reading fluency at the genome-wide level. Our study discovered a new candidate susceptibility variant for reading ability and provided new insights into the genetics of developmental dyslexia in Chinese children. 相似文献
10.
C. Fernandez-Rozadilla J. B. Cazier I. Tomlinson A. Brea-Fernández M. J. Lamas M. Baiget L. A. López-Fernández J. Clofent L. Bujanda D. Gonzalez L. de Castro K. Hemminki X. Bessa M. Andreu R. Jover R. Xicola X. Llor V. Moreno A. Castells S. Castellví-Bel A. Carracedo C. Ruiz-Ponte 《Human genetics》2014,133(5):525-534
Colorectal cancer (CRC) is a complex disease, and therefore its development is determined by the combination of both environmental factors and genetic variants. Although genome-wide association studies (GWAS) of SNP variation have conveniently identified 20 genetic variants so far, a significant proportion of the observed heritability is yet to be explained. Common copy-number variants (CNVs) are one of the most important genomic sources of variability, and hence a potential source to explain part of this missing genetic fraction. Therefore, we have performed a GWAS on CNVs to explore the relationship between common structural variation and CRC development. Phase 1 of the GWAS consisted of 881 cases and 667 controls from a Spanish cohort. Copy-number status was validated by quantitative PCR for each of those common CNVs potentially associated with CRC in phase I. Subsequently, SNPs were chosen as proxies for the validated CNVs for phase II replication (1,342 Spanish cases and 1,874 Spanish controls). Four common CNVs were found to be associated with CRC and were further replicated in Phase II. Finally, we found that SNP rs1944682, tagging a 11q11 CNV, was nominally associated with CRC susceptibility (p value = 0.039; OR = 1.122). This locus has been previously related to extreme obesity phenotypes, which could suggest a relationship between body weight and CRC susceptibility. 相似文献
11.
Okada Y Shimane K Kochi Y Tahira T Suzuki A Higasa K Takahashi A Horita T Atsumi T Ishii T Okamoto A Fujio K Hirakata M Amano H Kondo Y Ito S Takada K Mimori A Saito K Kamachi M Kawaguchi Y Ikari K Mohammed OW Matsuda K Terao C Ohmura K Myouzen K Hosono N Tsunoda T Nishimoto N Mimori T Matsuda F Tanaka Y Sumida T Yamanaka H Takasaki Y Koike T Horiuchi T Hayashi K Kubo M Kamatani N Yamada R Nakamura Y Yamamoto K 《PLoS genetics》2012,8(1):e1002455
12.
Background: studies investigating the associations between UDP-glucuronosyltransferase 1A7 (UGT1A7) gene polymorphisms and various carcinomas risk reported conflicting results. To derive a more precise estimation of the association, we have conducted a meta-analysis. Methods: data were collected from the following electronic databases: PubMed, Medline and Chinese Biomedical Literature Database, with the last report up to September 2011. Case–control studies containing available genotype frequencies of UGT1A7 were chose. The odds ratio (OR) and its 95% confidence interval (95%CI) were used to assess the strength of association. Results: a total of 22 separate case–control studies including 3852 cases and 5604 controls based on the search criteria were involved in this meta-analysis. The combined results based on all studies showed that there was a statistically significant link between UGT1A7*3 allele and cancer risk (OR = 1.31, 95%CI = 1.14–1.50, P = 0.0001). In the stratified analysis by racial descent, significant increased risk was found in Asian population for UGT1A7*3 allele (OR = 1.41, 95%CI = 1.22–1.63, P < 0.00001). No significant associations were found between the UGT1A7 polymorphism and cancer susceptibility among Caucasians and African-Americans. In the subgroup analysis by cancer types, significant associations were found in UGT1A7*2 allele (OR = 1.23, 95%CI = 1.06–1.43, P = 0.006) and *3 allele (OR = 1.51, 95%CI = 1.11–2.06, P = 0.009) for hepatocellular carcinoma, *3 allele for lung cancer (OR = 1.36, 95%CI = 1.11–1.68, P = 0.004) and for bladder cancer (OR = 1.50, 95%CI = 1.09–2.07, P = 0.01). Conclusions: This meta-analysis suggests that the UGT1A7*3 allele is a risk factor for cancer among Asians, especially for hepatocellular carcinoma. 相似文献
13.
AW Lee H Hengstler K Schwald M Berriel-Diaz D Loreth M Kirsch O Kretz CA Haas MH de Angelis S Herzig T Brümmendorf M Klingenspor FG Rathjen J Rozman G Nicholson RD Cox MK Schäfer 《PloS one》2012,7(7):e41537
To date, genome-wide association studies (GWAS) have identified at least 32 novel loci for obesity and body mass-related traits. However, the causal genetic variant and molecular mechanisms of specific susceptibility genes in relation to obesity are yet to be fully confirmed and characterised. Here, we examined whether the candidate gene NEGR1 encoding the neuronal growth regulator 1, also termed neurotractin or Kilon, accounts for the obesity association. To characterise the function of NEGR1 for body weight control in vivo, we generated two novel mutant mouse lines, including a constitutive NEGR1-deficient mouse line as well as an ENU-mutagenised line carrying a loss-of-function mutation (Negr1-I87N) and performed metabolic phenotypic analyses. Ablation of NEGR1 results in a small but steady reduction of body mass in both mutant lines, accompanied with a small reduction in body length in the Negr1-I87N mutants. Magnetic resonance scanning reveals that the reduction of body mass in Negr1-I87N mice is due to a reduced proportion of lean mass. Negr1-I87N mutants display reduced food intake and physical activity while normalised energy expenditure remains unchanged. Expression analyses confirmed the brain-specific distribution of NEGR1 including strong expression in the hypothalamus. In vitro assays show that NEGR1 promotes cell-cell adhesion and neurite growth of hypothalamic neurons. Our results indicate a role of NEGR1 in the control of body weight and food intake. This study provides evidence that supports the link of the GWAS candidate gene NEGR1 with body weight control. 相似文献
14.
M. J. V?lim?ki M. K?rkk?inen C. Lamberg-Allardt K. Laitinen E. Alhava J. Heikkinen O. Impivaara P. M?kel? J. Palmgren R. Sepp?nen et al. 《BMJ (Clinical research ed.)》1994,309(6949):230-235
OBJECTIVE--To evaluate the contribution to peak bone mass of exercise, smoking, and calcium intake in adolescents and young adults. DESIGN--Prospective cohort study with end point measurement (bone mineral density) after 11 years'' follow up for lifestyle. SETTING--Five university hospital clinics. SUBJECTS--264 (153 females, 111 males) subjects aged 9 to 18 years at the beginning of the follow up and 20 to 29 years at the time of measurement of bone mineral density. MAIN OUTCOME MEASURE--Bone mineral density of lumbar spine and femoral neck by dual energy x ray absorptiometry; measures of physical activity and smoking and estimates of calcium intake repeated three times during follow up. RESULTS--In the groups with the lowest and highest levels of exercise the femoral bone mineral densities (adjusted for age and weight) were 0.918 and 0.988 g/cm2 for women (P = 0.015, analysis of covariance) and 0.943 and 1.042 g/cm2 for men (P = 0.005), respectively; at the lumbar spine the respective values were 1.045 and 1.131 (P = 0.005) for men. In men the femoral bone mineral densities (adjusted for age, weight, and exercise) were 1.022 and 0.923 g/cm2 for the groups with the lowest and highest values of smoking index (P = 0.054, analysis of covariance). In women the adjusted femoral bone mineral density increased by 4.7% together with increasing calcium intake (P = 0.089, analysis of covariance). In multiple regression analysis on bone mineral density of the femoral neck, weight, exercise, age, and smoking were independent predictors for men; with weight, exercise, and age for women. These predictors together explained 38% of the variance in bone mineral density in women and 46% in men. At the lumbar spine, weight, smoking, and exercise were predictors for men; and only weight for women. CONCLUSIONS--Regular exercise and not smoking is important in achieving maximal peak bone mass in adolescents and young adults. 相似文献
15.
Meredith A. Bostrom Lingyi Lu Jeff Chou Pamela J. Hicks Jianzhao Xu Carl D. Langefeld Donald W. Bowden Barry I. Freedman 《Human genetics》2010,128(2):195-204
African Americans have increased susceptibility to non-diabetic (non-DM) forms of end-stage renal disease (ESRD) and extensive
evidence supports a genetic contribution. A genome-wide association study (GWAS) using pooled DNA was performed in 1,000 African
Americans to detect associated genes. DNA from 500 non-DM ESRD cases and 500 non-nephropathy controls was quantified using
gel electrophoresis and spectrophotometric analysis and pools of 50 case and 50 control DNA samples were created. DNA pools
were genotyped in duplicate on the Illumina HumanHap550-Duo BeadChip. Normalization methods were developed and applied to
array intensity values to reduce inter-array variance. Allele frequencies were calculated from normalized channel intensities
and compared between case and control pools. Three SNPs had p values of <1.0E−6: rs4462445 (ch 13), rs4821469 (ch 22) and rs8077346 (ch 17). After normalization, top scoring SNPs (n = 65) were genotyped individually in 464 of the original cases and 478 of the controls, with replication in 336 non-DM ESRD
cases and 363 non-nephropathy controls. Sixteen SNPs were associated with non-DM ESRD (p < 7.7E−4, Bonferroni corrected). Twelve of these SNPs are in or near the MYH9 gene. The four non-MYH9 SNPs that were associated with non-DM ESRD in the pooled samples were not associated in the replication set. Five SNPs that
were modestly associated in the pooled samples were more strongly associated in the replication and/or combined samples. This
is the first GWAS for non-DM ESRD in African Americans using pooled DNA. We demonstrate strong association between non-DM
ESRD in African Americans with MYH9, and have identified additional candidate loci. 相似文献
16.
Borrione P Spaccamiglio A Rizzo M Termine A Chierto E Campostrini N Quaranta F Di Gianfrancesco A Pigozzi F 《Journal of biological regulators and homeostatic agents》2011,25(3):427-434
The use of iron supplements should be a judicious choice, primarily when considering the possible risks deriving from an unjustified treatment. In trained athletes, levels of ferritin between 15 and 30 microg/L are frequently observed. Within this ferritin range, the usefulness of iron supplementation is still controversial. The aim of the present study is to evaluate the clinical usefulness of hepcidin assessment in the analysis of the iron status of young non-anemic athletes. Fifty young athletes were enrolled. The subjects were divided into 4 groups according to their ferritin levels. No statistically significant difference was found regarding hepcidin levels between athletes with ferritin lower than 15 microg/L and those in the 15-30 microg/L range. Similarly, no difference was found between athletes with ferritin higher than 50 microg/L and those in the 30-50 microg/L range. On the contrary, statistically significant differences were found between athletes with ferritin levels ranging from 15 to 30 microg/L and those in the 30-50 microg/L range. The present study suggests that serum ferritin levels below 30 microg/L indicate an asymptomatic iron deficiency status inhibiting hepcidin expression and that 30 microg/L should be considered the ferritin cut-off when considering an iron supplementation in young athletes. 相似文献
17.
Hernesniemi JA Seppälä I Lyytikäinen LP Mononen N Oksala N Hutri-Kähönen N Juonala M Taittonen L Smith EN Schork NJ Chen W Srinivasan SR Berenson GS Murray SS Laitinen T Jula A Kettunen J Ripatti S Laaksonen R Viikari J Kähönen M Raitakari OT Lehtimäki T 《PloS one》2012,7(1):e28931
Background
Genome-wide association studies (GWASs) have identified a large number of variants (SNPs) associating with an increased risk of coronary artery disease (CAD). Recently, the CARDIoGRAM consortium published a GWAS based on the largest study population so far. They successfully replicated twelve already known associations and discovered thirteen new SNPs associating with CAD. We examined whether the genetic profiling of these variants improves prediction of subclinical atherosclerosis – i.e., carotid intima-media thickness (CIMT) and carotid artery elasticity (CAE) – beyond classical risk factors.Subjects and Methods
We genotyped 24 variants found in a population of European ancestry and measured CIMT and CAE in 2001 and 2007 from 2,081, and 2,015 subjects (aged 30–45 years in 2007) respectively, participating in the Cardiovascular Risk in Young Finns Study (YFS). The Bogalusa Heart Study (BHS; n = 1179) was used as a replication cohort (mean age of 37.5). For additional replication, a sub-sample of 5 SNPs was genotyped for 1,291 individuals aged 46–76 years participating in the Health 2000 population survey. We tested the impact of genetic risk score (GRS24SNP/CAD) calculated as a weighted (by allelic odds ratios for CAD) sum of CAD risk alleles from the studied 24 variants on CIMT, CAE, the incidence of carotid atherosclerosis and the progression of CIMT and CAE during a 6-year follow-up.Results
CIMT or CAE did not significantly associate with GRS24SNP/CAD before or after adjusting for classical CAD risk factors (p>0.05 for all) in YFS or in the BHS. CIMT and CAE associated with only one SNP each in the YFS. The findings were not replicated in the replication cohorts. In the meta-analysis CIMT or CAE did not associate with any of the SNPs.Conclusion
Genetic profiling, by using known CAD risk variants, should not improve risk stratification for subclinical atherosclerosis beyond conventional risk factors among healthy young adults. 相似文献18.
Rheumatoid arthritis (RA) is a chronic inflammatory disorder with a polygenic mode of inheritance. This study examined the hypothesis that runs of homozygosity (ROHs) play a recessive-acting role in the underlying RA genetic mechanism and identified RA-associated ROHs. Ours is the first genome-wide homozygosity association study for RA and characterized the ROH patterns associated with RA in the genomes of 2,000 RA patients and 3,000 normal controls of the Wellcome Trust Case Control Consortium. Genome scans consistently pinpointed two regions within the human major histocompatibility complex region containing RA-associated ROHs. The first region is from 32,451,664 bp to 32,846,093 bp (-log10(p)>22.6591). RA-susceptibility genes, such as HLA-DRB1, are contained in this region. The second region ranges from 32,933,485 bp to 33,585,118 bp (-log10(p)>8.3644) and contains other HLA-DPA1 and HLA-DPB1 genes. These two regions are physically close but are located in different blocks of linkage disequilibrium, and ~40% of the RA patients' genomes carry these ROHs in the two regions. By analyzing homozygote intensities, an ROH that is anchored by the single nucleotide polymorphism rs2027852 and flanked by HLA-DRB6 and HLA-DRB1 was found associated with increased risk for RA. The presence of this risky ROH provides a 62% accuracy to predict RA disease status. An independent genomic dataset from 868 RA patients and 1,194 control subjects of the North American Rheumatoid Arthritis Consortium successfully validated the results obtained using the Wellcome Trust Case Control Consortium data. In conclusion, this genome-wide homozygosity association study provides an alternative to allelic association mapping for the identification of recessive variants responsible for RA. The identified RA-associated ROHs uncover recessive components and missing heritability associated with RA and other autoimmune diseases. 相似文献
19.
Joana R. Lérias Madalena C. Pinto Hugo M. Botelho Nikhil T. Awatade Margarida C. Quaresma Iris A.L. Silva Podchanart Wanitchakool Rainer Schreiber Rainer Pepperkok Karl Kunzelmann Margarida D. Amaral 《Biochimica et Biophysica Acta (BBA)/Molecular Cell Research》2018,1865(2):421-431
An attractive possibility to treat Cystic Fibrosis (CF), a severe condition caused by dysfunctional CFTR, an epithelial anion channel, is through the activation of alternative (non-CFTR) anion channels. Anoctamin 1 (ANO1) was demonstrated to be a Ca2+-activated chloride channel (CaCC) and thus of high potential to replace CFTR. Despite that ANO1 is expressed in human lung CF tissue, it is present at the cell surface at very low levels. In addition, little is known about regulation of ANO1 traffic, namely which factors promote its plasma membrane (PM) localization.Here, we generated a novel cellular model, expressing an inducible 3HA-ANO1-eGFP construct, and validated its usage as a microscopy tool to monitor for ANO1 traffic.We demonstrate the robustness and specificity of this cell-based assay, by the identification of siRNAs acting both as ANO1 traffic enhancer and inhibitor, targeting respectively COPB1 and ESYT1 (extended synaptotagmin-1), the latter involved in coupling of the endoplasmic reticulum to the PM at specific microdomains. We further show that knockdown of ESYT1 (and family members ESYT2 and ESYT3) significantly decreased ANO1 current density.This ANO1 cell-based assay constitutes an important tool to be further used in high-throughput screens and drug discovery of high relevance for CF and cancer. 相似文献
20.
Schwartzman J Mongoue-Tchokote S Gibbs A Gao L Corless CL Jin J Zarour L Higano C True LD Vessella RL Wilmot B Bottomly D McWeeney SK Bova GS Partin AW Mori M Alumkal J 《Epigenetics》2011,6(10):1248-1256
DNA methylation of promoter regions is a common event in prostate cancer, one of the most common cancers in men worldwide. Because prior reports demonstrating that DNA methylation is important in prostate cancer studied a limited number of genes, we systematically quantified the DNA methylation status of 1505 CpG dinucleotides for 807 genes in 78 paraffin-embedded prostate cancer samples and three normal prostate samples. The ERG gene, commonly repressed in prostate cells in the absence of an oncogenic fusion to the TMPRSS2 gene, was one of the most commonly methylated genes, occurring in 74% of prostate cancer specimens. In an independent group of patient samples, we confirmed that ERG DNA methylation was common, occurring in 57% of specimens, and cancer-specific. The ERG promoter is marked by repressive chromatin marks mediated by polycomb proteins in both normal prostate cells and prostate cancer cells, which may explain ERG's predisposition to DNA methylation and the fact that tumors with ERG DNA methylation were more methylated, in general. These results demonstrate that bead arrays offer a high-throughput method to discover novel genes with promoter DNA methylation such as ERG, whose measurement may improve our ability to more accurately detect prostate cancer. 相似文献