Large Scale Evaluation of Genetic Variation and the Risk of Multiple Myeloma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1679-1679
Author(s):  
Sonja I Berndt ◽  
David C Johnson ◽  
John Crowley ◽  
Brian G Durie ◽  
Robert Hoover ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dna Damage ◽  
Genetic Variation ◽  
Statistical Power ◽  
Large Scale ◽  
Cell Cycle Checkpoint ◽  
Health Study ◽  
Candidate Gene Approach ◽  
Ovarian Cancer Screening ◽  
Increased Risk

Abstract Genetic factors are thought to influence susceptibility to multiple myeloma, but most published studies to date have been small and limited in scope. To identify genetic polymorphisms associated with myeloma risk, we conducted a case-control study of 976 Caucasian myeloma cases enrolled from clinical trials as part of the International Myeloma Foundation’s Bank On A Cure® initiative and 3692 Caucasian controls from the three cohorts [Nurses’ Health Study (NHS), Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), and 1958 British Birth Cohort (BC58)] with genome-wide scan data. A candidate gene approach was taken with a preference given to single nucleotide polymorphisms (SNPs) in coding or regulatory regions. A total of 1097 SNPs with a minor allele frequency ≥1% were genotyped in the cases and at least one control population. In order to increase our statistical power, SNPs not genotyped in NHS and PLCO were imputed from the genome scan with MACH using the HapMap CEU population as a referent and included in the analysis if the quality control r2 was high (r2 ≥0.9). Logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (95% CIs) adjusting for age, sex, and country as appropriate. We found 26 loci to be associated with myeloma risk with P < 0.01. Of particular interest, we observed an increased risk of myeloma with variants in two genes involved in the metabolism of pyrimidines, DPYD and MTHFR. An increased risk of myeloma was found with two independent SNPs, rs1023244 and rs1399291, in DPYD (ORperGallele = 1.43, 95% CI: 1.16–1.76, P = 0.0008 and ORperTallele = 1.18, 95% CI: 1.06–1.31, P = 0.003, respectively) and with the MTHFR high activity 677C allele (rs1801133, ORperC allele = 1.18, 95% CI: 1.05–1.33, P = 0.006). We also observed significant associations for nonsynonymous SNPs in genes involved in cell cycle checkpoint regulation (ATR, P = 0.009; ZAK, P = 0.007) and the DNA damage bypass pathway (REV3L, P = 0.008), suggesting that alterations in DNA damage mediation may modulate myeloma susceptibility. In conclusion, this large study found SNPs in several pathways, including pyrimidine metabolism and DNA damage mediation, to be associated with myeloma risk. Additional studies are needed to replicate these findings and to further explore genetic variation in these regions.

Polymorphisms in Regulators of Xenobiotic Transport and Metabolism Genes NR1I2 and NR1I3 and Multiple Myeloma Risk: A Case-Control Study in the Context of IMMEnSE Consortium

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5014-5014
Author(s):  
Gabriele Buda ◽  
Alessandro Martino ◽  
Daniele Campa ◽  
Juan Sainz ◽  
Rui Manuel Vieira Reis ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Genetic Variation ◽  
Conflicts Of Interest ◽  
Individual Variability ◽  
P Value ◽  
Genotype Distribution ◽  
Nucleotide Polymorphisms ◽  
Elimination Process ◽  
Increased Risk ◽  
The Impact

Abstract Abstract 5014 Exposure to toxic compounds and pesticides leads to an increased risk to develop Multiple Myeloma (MM). The metabolism and the excretion of xenobiotics are mediated by the enzymes and transporters acting in the detoxifying/elimination process. The nuclear receptors NR1I2 (or PXR) and NR1I3 (or CAR) act as xenosensor activating the detoxifying/elimination process in response to the intracellular levels of xenobiotics. It has been hypothesized that part of the individual variability in drug metabolism efficiency could be due to the genetic variations within these regulator genes affecting their expression and/or function. To investigate the impact of genetic variation within these genes on MM susceptibility, we selected and genotyped 10 tag Single Nucleotide Polymorphisms (SNPs) in the PXR gene and 7 tag SNPs in the CAR gene in 627 MM cases (320 males and 307 females) and 883 (459 males and 424 females) controls from different European populations. All the SNPs were in Hardy-Weinberg equilibrium (p>0.001), with the exception of the PXR SNP rs2461818 that was therefore excluded from the analysis. We found no association of any of the genotyped SNPs with MM risk. In the same way, haplotype distribution showed no differences between cases and controls. This was the first comprehensive investigation of genetic variation in xenobiotic regulators genes PXR and CAR in relation to MM risk and our data suggest that common variants in these genes have no impact in modifying MM risk. Table I. Genotype distribution of the PXR and CAR SNPs among MM cases and controls. SNP (rs) Cases (%) Controls (%) OR* 95%C.I. p-value p-trend PXR C/C 429 (69.5) 623 (70.7) 1.00 Ref 0.423 rs10511395 A/C 160 (25.9) 228 (25.9) 1.02 0.81 – 1.30 0.851 A/A 28 (4.6) 30 (3.4) 1.38 0.81 – 2.35 0.232 PXR C/C 452 (74.0) 656 (74.8) 1.00 Ref 0.451 rs1054190 C/T 137 (22.4) 200 (22.8) 1.00 0.78 – 1.28 0.993 T/T 22 (3.6) 21 (2.4) 1.56 0.84 – 2.88 0.155 PXR C/C 412 (65.9) 591 (67.2) 1.00 Ref 0.819 rs11917714 C/T 190 (30.4) 250 (28.5) 1.07 0.85 – 1.35 0.535 T/T 23 (3.7) 38 (4.3) 0.84 0.49 – 1.44 0.536 PXR C/C 223 (36.3) 296 (33.7) 1.00 Ref 0.126 rs12488820 C/T 289 (47.0) 407 (46.4) 0.93 0.74 – 1.18 0.574 T/T 103 (16.7) 175 (19.9) 0.79 0.58 – 1.06 0.119 PXR G/G 430 (69.6) 593 (67.4) 1.00 Ref 0.807 rs13071341 A/G 166 (26.9) 269 (30.6) 0.85 0.67 – 1.07 0.158 A/A 22 (3.5) 18 (2.0) 1.70 0.90 – 3.22 0.102 PXR A/A 352 (58.7) 516 (39.4) 1.00 Ref 0.981 rs3237359 A/G 209 (34.8) 291 (33.5) 1.04 0.83 – 1.30 0.720 G/G 39 (6.5) 62 (7.1) 0.90 0.59 – 1.37 0.619 PXR C/C 255 (41.2) 383 (43.6) 1.00 Ref 0.815 rs13059232 C/T 299 (48.3) 390 (44.4) 1.16 0.93 – 1.44 0.192 T/T 65 (10.5) 106 (12.0) 0.94 0.66 – 1.33 0.711 PXR A/A 300 (48.7) 437 (49.7) 1.00 Ref 0.258 rs3732357 A/G 240 (39.0) 361 (41.0) 0.94 0.75 – 1.17 0.589 G/G 76 (12.3) 82 (9.3) 1.31 0.92 – 1.85 0.130 PXR T/T 328 (53.6) 463 (52.9) 1.00 Ref 0.424 rs1357459 C/T 249 (40.7) 345 (39.4) 1.02 0.82 – 1.27 0.850 C/C 35 (5.7) 67 (7.7) 0.75 0.49 – 1.17 0.206 CAR A/A 218 (35.4) 335 (38.1) 1.00 Ref 0.571 rs3003596 A/G 296 (48.0) 393 (44.7) 1.16 0.93 – 1.46 0.191 G/G 102 (16.6) 151 (17.2) 1.04 0.77 – 1.41 0.799 CAR G/G 264 (42.7) 371 (42.0) 1.00 Ref 0.642 rs3813627 G/T 276 (44.7) 392 (44.4) 0.98 0.79 – 1.23 0.882 T/T 78 (12.6) 120 (13.6) 0.91 0.66 – 1.26 0.581 CAR A/A 441 (73.1) 635 (73.5) 1.00 Ref 0.911 rs11265571 A/T 147 (24.4) 207 (24.0) 1.01 0.79 – 1.29 0.911 T/T 15 (2.5) 22 (2.5) 0.97 0.49 – 1.89 0.921 CAR T/T 404 (64.2) 575 (65.7) 1.00 Ref 0.836 rs2307418 G/T 193 (31.1) 268 (30.6) 1.02 0.81 – 1.27 0.879 G/G 23 (3.7) 32 (3.7) 1.05 0.60 – 1.83 0.863 CAR C/C 348 (56.6) 508 (57.7) 1.00 Ref 0.527 rs2502805 C/T 220 (35.8) 313 (35.6) 1.05 0.84 – 1.30 0.693 T/T 47 (7.6) 59 (6.7) 1.16 0.77 – 1.74 0.484 CAR A/A 245 (39.8) 346 (39.4) 1.00 Ref 0.770 rs4073054 A/C 291 (47.2) 412 (46.9) 0.98 0.78 – 1.22 0.855 C/C 80 (13.0) 120 (13.7) 0.94 0.68 – 1.31 0.720 CAR C/C 360 (57.6) 524 (59.8) 1.00 Ref 0.391 rs4233368 A/C 225 (36.0) 302 (34.4) 1.09 0.88 – 1.36 0.439 A/A 40 (6.4) 51 (5.8) 1.15 0.74 – 1.78 0.538 Genotype distribution among MM cases and controls in the overall population. * OR are adjusted for age, gender and region of origin. Differences in samples numbers are due to failures in genotyping. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Uterus Hyperplasia and Increased Carcinogen-Induced Tumorigenesis in Mice Carrying a Targeted Mutation of the Chk2 Phosphorylation Site in Brca1

2004 ◽  
Vol 24 (21) ◽  
pp. 9498-9507 ◽  
Author(s):  
Sang Soo Kim ◽  
Liu Cao ◽  
Cuiling Li ◽  
Xiaoling Xu ◽  
L. Julie Huber ◽  
...  
Keyword(s):  
Dna Damage ◽  
Phosphorylation Site ◽  
Tumor Formation ◽  
Cell Cycle Checkpoint ◽  
Mutant Mice ◽  
Developmental Defect ◽  
M Cell ◽  
Γ Irradiation ◽  
Intracellular Location ◽  
Increased Risk

ABSTRACT The tumor suppressor BRCA1 contains multiple functional domains that interact with many proteins. After DNA damage, BRCA1 is phosphorylated by CHK2 at serine 988, followed by a change in its intracellular location. To study the functions of CHK2-dependent phosphorylation of BRCA1, we generated a mouse model carrying the mutation S971A (S971 in mouse Brca1 corresponds to S988 in human BRCA1) by gene targeting. Brca1S971A/S971A mice were born at the expected ratio without a developmental defect, unlike previously reported Brca1 mutant mice. However, Brca1S971A/S971A mice suffered a moderately increased risk of spontaneous tumor formation, with a majority of females developing uterus hyperplasia and ovarian abnormalities by 2 years of age. After treatment with DNA-damaging agents, Brca1S971A/S971A mice exhibited several abnormalities, including increased body weight, abnormal hair growth pattern, lymphoma, mammary tumors, and endometrial tumors. In addition, the onset of tumor formation became accelerated, and 80% of the mutant mice had developed tumors by 1 year of age. We demonstrated that the Brca1S971A/S971A cells displayed reduced ability to activate the G2/M cell cycle checkpoint upon γ-irradiation and to stabilize p53 following N-methyl-N′-nitro-N-nitrosoguanidine treatment. These observations suggest that Chk2 phosphorylation of S971 is involved in Brca1 function in modulating the DNA damage response and repressing tumor formation.

scholarly journals Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Amand F. Schmidt ◽  
◽  
Michael V. Holmes ◽  
David Preiss ◽  
Daniel I. Swerdlow ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Large Scale ◽  
Plasma Lipid ◽  
Blood Lipid ◽  
Chronic Obstructive ◽  
Genetic Associations ◽  
Obstructive Pulmonary Disease ◽  
Pcsk9 Inhibitor ◽  
Increased Risk ◽  
Individual Participant

Abstract Background We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable. Conclusions Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

A Large-Scale Mutagenesis and Strain Characterization Project To Identify Genetic Variability in Mice: Resources Available from the Jackson Laboratory Program for Genomic Applications (JAX PGA).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1578-1578
Author(s):  
Luanne L. Peters ◽  
Orah S. Platt ◽  
Karen L. Svenson ◽  
Beverly J. Paigen ◽  
Gary A. Churchill ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Animal Models ◽  
Hypothesis Testing ◽  
Statistical Power ◽  
Large Scale ◽  
Inbred Strains ◽  
Chromosome 1 ◽  
Mouse Strains ◽  
Strain Characterization ◽  
Jackson Laboratory

Abstract Identifying the genes and gene products relevant to physiological systems and creating opportunities to elucidate their function are essential first steps in understanding the pathophysiology of disease. To dissect the genetic variation underlying hematopoietic, cardiovascular, lung, and sleep dysfunction, we established a Center for Mouse Models of Heart, Lung, Blood and Sleep (HLBS) Disorders at The Jackson Laboratory as part of the NHLBI Program for Genomic Applications (PGA). The major goal of the JAX PGA is to enable researchers to link both single-gene mutations and quantitative trait loci (QTL) to gene function and disease. To achieve this goal, we are generating new mutations in mice by chemical (ENU) mutagenesis, and characterizing the common inbred mouse strains to detect existing genetic variation. Here, we report an extensive body of hematologically relevant strain characterization data and the establishment of new animal models. All strain characterization data is deposited into the Mouse Phenome Database (MPD, http://www.jax.org/phenome), also accessible via the JAX PGA website (http://pga.jax.org). Data for up to 48 inbred strains are currently available and include complete blood counts and coagulation profiles (PT, aPTT, fibrinogen). These data allow investigators to identify the most appropriate strains for (a) physiological testing; (b) drug development; (c) progenitors in QTL crosses; (d) sensitized mutagenesis screens; and (e) direct hypothesis testing. For example, to maximize the potential for successful QTL identification, parental strains that differ substantially in the phenotype of interest, at least 2 standard deviations (SD), should be selected. We used our strain survey data to select parental strains for identification of QTL for baseline WBC count, an important risk factor for sickle cell disease severity. The strains C57BLKS/J and SM/J have WBC counts of 12.6 ± 1.6 and 3.3 ± 0.8 x 103/μL, respectively, a difference much greater the 2 SD, indicating a high statistical power. We identified a highly significant QTL (LOD = 7) on chromosome 1 in an initial genome wide scan of 279 F2 animals. Moreover, the availability of extensive phenotypic data across the inbred strains in conjunction with the availability of saturated sslp and SNP maps has allowed us to identify QTL in silico. As an example of the utility of the MPD in hypothesis testing, a modifier gene associated with decreased VWF levels is present in 5 of the 6 MPD strains showing the highest aPTT levels (see abstract by Johnsen et al). In total, 44 different phenotypic projects, each consisting of large datasets, can be freely accessed through the MPD. The JAX PGA mutagenesis effort in C57BL/6J mice has likewise yielded valuable resources. Nearly 100 new mutant strains are in various stages of development, including strains with phenotypes of interest to the hematology community (e. g., anemia, thrombocytopenia, leukopenia, leukocytosis). These animal models and all other JAX PGA resources (protocols, software, QTL locations) are freely available to the scientific community.

scholarly journals Association between the estrogen receptor α gene polymorphisms rs2234693 and rs9340799 and severe and mild pre-eclampsia: a meta-analysis

2019 ◽  
Vol 39 (2) ◽  
Author(s):  
Ge Zhao ◽  
Yunfei Cai ◽  
Jing Liu ◽  
Tao Meng
Keyword(s):  
Estrogen Receptor ◽  
Statistical Power ◽  
Large Scale ◽  
Meta Analysis ◽  
Estrogen Receptor Α ◽  
China National Knowledge Infrastructure ◽  
Knowledge Infrastructure ◽  
Esr1 Gene ◽  
Increased Risk ◽  
Estrogen Receptor Α Gene

Abstract This meta-analysis was performed in order to determine the associations between the estrogen receptor α (ESR1) gene PvuII site (-397T/C, rs2234693) and XbaI site (-351A/G, rs9340799) polymorphisms with severe and mild pre-eclampsia. Eligible studies were identified by searching PubMed, Medline, Embase, China National Knowledge Infrastructure (CNKI), and WanFang databases until May 2018. The pooled odds ratio (OR) and 95% confidence interval (CI) were used to calculate the associations. Six articles (consisting of seven studies; one article was considered as two separate studies with two different subpopulations) investigated the ESR1 gene PvuII -397T/C and XbaI -351A/G polymorphisms in severe and mild pre-eclampsia patients and included controls. The pooled results indicated an increased risk of severe pre-eclampsia for the XbaI -351A/G polymorphism (OR = 1.67, 95% CI = 1.10–2.25, P=0.017 for GG compared with AA+GA; OR = 1.81, 95% CI = 1.17–2.82, P=0.008 for GG compared with GA). The GG genotype of the ESR1 XbaI polymorphism could be a genetic risk factor for severe pre-eclampsia susceptibility. However, the ESR1 gene PvuII -397T/C polymorphism was not significantly associated with the risk of severe pre-eclampsia, and there was no association between mild pre-eclampsia and the ESR1 gene PvuII -397T/C and XbaI -351A/G polymorphisms separately. The current meta-analysis indicates that the ESR1 XbaI genetic polymorphism may be associated with severe pre-eclampsia. However, there was no association of the ESR1 gene PvuII and XbaI polymorphisms with the risk of mild pre-eclampsia. Owing to the low statistical power, the results may not be sufficiently robust and this conclusion should be interpreted cautiously, which highlights the requirement for large-scale and high-quality studies in this field.

Genetic variation in NFE2L2 and SEPS1S associated with increased risk of Hashimoto's thyroiditis

2017 ◽  
Author(s):  
Liliana R Santos ◽  
Cecila Duraes ◽  
Ana Pestana ◽  
Cesar Esteves ◽  
Celestino Neves ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Hashimoto’S Thyroiditis ◽  
Hashimoto's Thyroiditis ◽  
Increased Risk

Study of Biochemical and Clinical Markers in Steatohepatitis Related to Obesity

2018 ◽  
Vol 69 (6) ◽  
pp. 1501-1505
Author(s):  
Roxana Maria Livadariu ◽  
Radu Danila ◽  
Lidia Ionescu ◽  
Delia Ciobanu ◽  
Daniel Timofte
Keyword(s):  
Liver Disease ◽  
Liver Biopsy ◽  
Large Scale ◽  
Biological Data ◽  
Obese Patients ◽  
Clinical Markers ◽  
Mean Values ◽  
Nonalcoholic Fatty Liver ◽  
Obstructive Sleep ◽  
Increased Risk

Nonalcoholic fatty liver disease (NAFLD) is highly associated to obesity and comprises several liver diseases, from simple steatosis to steatohepatitis (NASH) with increased risk of developing progressive liver fibrosis, cirrhosis and hepatocellular carcinoma. Liver biopsy is the gold standard in diagnosing the disease, but it cannot be used in a large scale. The aim of the study was the assessment of some non-invasive clinical and biological markers in relation to the progressive forms of NAFLD. We performed a prospective study on 64 obese patients successively hospitalised for bariatric surgery in our Surgical Unit. Patients with history of alcohol consumption, chronic hepatitis B or C, other chronic liver disease or patients undergoing hepatotoxic drug use were excluded. All patients underwent liver biopsy during sleeve gastrectomy. NAFLD was present in 100% of the patients: hepatic steatosis (38%), NASH with the two forms: with fibrosis (31%) and without fibrosis (20%), cumulating 51%; 7 patients had NASH with vanished steatosis. NASH with fibrosis statistically correlated with metabolic syndrome (p = 0.036), DM II (p = 0.01) and obstructive sleep apnea (p = 0.02). Waist circumference was significantly higher in the steatohepatitis groups (both with and without fibrosis), each 10 cm increase increasing the risk of steatohepatitis (p = 0.007). The mean values of serum fibrinogen and CRP were significantly higher in patients having the progressive forms of NAFLD. Simple clinical and biological data available to the practitioner in medicine can be used to identify obese patients at high risk of NASH, aiming to direct them to specialized medical centers.

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