scholarly journals Gene variations of ROCKs and risk of ischaemic stroke: the Women's Genome Health Study

2014 ◽  
Vol 126 (12) ◽  
pp. 829-835 ◽  
Author(s):  
Robert Y. L. Zee ◽  
Qing-Mei Wang ◽  
Daniel I. Chasman ◽  
Paul M Ridker ◽  
James K. Liao
Keyword(s):  
Genetic Variation ◽  
Ischaemic Stroke ◽  
Health Study ◽  
Cellular Functions ◽  
Gene Variation ◽  
Kinase Pathway ◽  
Rock1 Gene

The present study has shown that genetic variation within the ROCK (RhoA/Rho-associated kinase) pathway (which is involved in regulating diverse cellular functions) gene loci examined, in particular ROCK1 gene variation, may influence the risk of ischaemic stroke.

scholarly journals Islet amyloid polypeptide gene variation (IAPP) and the risk of incident type 2 diabetes mellitus: The women's genome health study

2011 ◽  
Vol 412 (9-10) ◽  
pp. 785-787 ◽  
Author(s):  
Robert Y.L. Zee ◽  
Patricia Pulido-Perez ◽  
Ricardo Perez-Fuentes ◽  
Paul M Ridker ◽  
Daniel I. Chasman ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Islet Amyloid Polypeptide ◽  
Health Study ◽  
Islet Amyloid ◽  
Incident Type ◽  
Gene Variation ◽  
Incident Type 2 Diabetes

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.

scholarly journals COMT and Alpha-Tocopherol Effects in Cancer Prevention: Gene-Supplement Interactions in Two Randomized Clinical Trials

2019 ◽  
Vol 111 (7) ◽  
pp. 684-694 ◽  
Author(s):  
Kathryn T Hall ◽  
Julie E Buring ◽  
Kenneth J Mukamal ◽  
M Vinayaga Moorthy ◽  
Peter M Wayne ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Cancer Prevention ◽  
Randomized Trials ◽  
Randomized Clinical Trials ◽  
Statistical Tests ◽  
Meta Analysis ◽  
Alpha Tocopherol ◽  
Health Study ◽  
Post Trial

AbstractBackgroundVitamins are among the most frequently used supplements (48% of US adults). However, little is known about contributions of genetic variation to their efficacy and safety. Multiple pathways link catechol-O-methyltransferase (COMT) to the vitamin E supplement, alpha-tocopherol, and cancer.MethodsHere we determined if COMT exerted pharmacogenetic effects on cancer prevention in two randomized trials of alpha-tocopherol supplementation. Pharmacogenetic effects of common COMT rs4680 (val158met), which encodes a nonsynonymous valine-to-methionine substitution, were examined in the trial plus a 10-year post-trial follow-up (overall) period of The Women’s Genome Health Study (WGHS, N = 23 294), a 10-year alpha-tocopherol and aspirin trial with 10 years post-trial follow-up. Results were validated in a case/control (N = 2396/2235) subset of the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (ATBC, N = 29 133). The primary outcome was total cancers. Rates of cancer types prevalent in women (colorectal, breast, lung, uterine, and lymphoma/leukemia) were also examined. All statistical tests were two-sided.ResultsRandom-effects meta-analysis of rs4680 genotype strata, in WGHS and ATBC overall periods, revealed differential alpha-tocopherol effects compared with placebo: met/met (hazard ratio [HR] = 0.88; 95% confidence interval [CI] = 0.80 to 0.97; P = .01), val/met (HR = 0.99; 95% CI = 0.92 to 1.06; P = .74), and val/val (HR = 1.18; 95% CI = 1.06 to 1.31; P = .002) with a statistically significant COMT by alpha-tocopherol interaction (Pinteraction <.001). Timing of effects differed, with stronger effects in WGHS trial and ATBC post-trial.ConclusionPharmacogenetic analysis of COMT and cancer prevention in two large randomized trials revealed statistically significant COMT by alpha-tocopherol interaction, such that alpha-tocopherol was beneficial among rs4680 met-allele (28.0%), but not val-allele (22.8%) homozygotes. These effects indicate the need for additional studies of genetic variation as a determinant of the benefits and possible harms of over-the-counter supplements, like alpha-tocopherol, used for health promotion.

scholarly journals Migraine and cardiovascular disease in women and the role of aspirin: Subgroup analyses in the Women’s Health Study

Cephalalgia ◽  
2011 ◽  
Vol 31 (10) ◽  
pp. 1106-1115 ◽  
Author(s):  
Tobias Kurth ◽  
Hans-Christoph Diener ◽  
Julie E Buring
Keyword(s):  
Cardiovascular Disease ◽  
Ischaemic Stroke ◽  
Women’S Health ◽  
Women's Health ◽  
Health Study ◽  
Protective Effects ◽  
Increased Risk ◽  
Subgroup Analyses ◽  
Post Hoc

Background: Migraine with aura (MA) has been associated with increased risk of cardiovascular disease (CVD). The role of aspirin on this association remains unclear. Methods: Post-hoc subgroup analyses of the Women’s Health Study, a randomized trial testing 100 mg aspirin on alternate days in primary prevention of CVD among 39,876 women aged ≥45. Results: During 10 years, 998 major CVD events were confirmed in 39,757 women with complete migraine information. Aspirin reduced risk of ischaemic stroke (relative risk, RR, 0.76, 95% CI 0.63–0.93) but not other CVD. Migraine or MA did not modify the effect of aspirin on CVD except for myocardial infarction (MI) ( p for interaction = 0.01). Women with MA on aspirin had increased risk of MI (RR 3.72, 95% CI 1.39–9.95). Further exploratory analyses indicate that this increased risk is only apparent among women with MA on aspirin who ever smoked or had history of hypertension ( p for interaction<0.01). Conclusions: In post-hoc subgroup analyses, aspirin had similar protective effects on ischaemic stroke for women with or without migraine. By contrast, our data suggest that women with MA on aspirin had increased risk of MI. The small number of outcome events in subgroups, the exploratory nature of our analyses, and lack of plausible mechanisms raise the possibility of a chance finding, which must caution the interpretation.

scholarly journals Gene Variation of Endoplasmic Reticulum Aminopeptidases 1 and 2, and Risk of Blood Pressure Progression and Incident Hypertension among 17,255 Initially Healthy Women

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Robert Y. L. Zee ◽  
Alicia Rivera ◽  
Yaritza Inostroza ◽  
Paul M. Ridker ◽  
Daniel I. Chasman ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Endoplasmic Reticulum ◽  
Regression Analysis ◽  
Cox Regression ◽  
Health Study ◽  
Multivariable Logistic Regression Analysis ◽  
Regression Analyses ◽  
Cox Regression Analysis ◽  
Incident Hypertension ◽  
Gene Variation

Recent studies have demonstrated the importance of endoplasmic reticulum aminopeptidase (ERAP) in blood pressure (BP) homeostasis. To date, no large prospective, genetic–epidemiological data are available on genetic variation within ERAP and hypertension risk. The association of 45 genetic variants of ERAP1 and ERAP2 was investigated in 17,255 Caucasian female participants from the Women’s Genome Health Study. All subjects were free of hypertension at baseline. During an 18-year follow-up period, 10,216 incident hypertensive cases were identified. Multivariable linear, logistic, and Cox regression analyses were performed to assess the relationship of genotypes with baseline BP levels, BP progression at 48 months, and incident hypertension assuming an additive genetic model. Linear regression analyses showed associations of four tSNPs (ERAP1: rs27524; ERAP2: rs3733904, rs4869315, and rs2549782; all p<0.05) with baseline systolic BP levels. Three tSNPs (ERAP1: rs27851, rs27429, and rs34736, all p<0.05) were associated with baseline diastolic BP levels. Multivariable logistic regression analysis showed that ERAP1 rs27772 was associated with BP progression at 48 months (p=0.0366). Multivariable Cox regression analysis showed an association of three tSNPs (ERAP1: rs469783 and rs10050860; ERAP2: rs2927615; all p<0.05) with risk of incident hypertension. Analyses of dbGaP for genotype–phenotype association and GTEx Portal for gene expression quantitative trait loci revealed five tSNPs with differential association of BP and nine tSNPs with lower ERAP1 and ERAP2 mRNA expression levels, respectively. The present study suggests that ERAP1 and ERAP2 gene variation may be useful for risk assessment of BP progression and the development of hypertension.

scholarly journals Associations of ‘Relative corticosterone deficiency’ with genetic variation in CYP17A1 and metabolic syndrome features

2019 ◽  
Author(s):  
Scott D Mackenzie ◽  
Andrew A Crawford ◽  
Daniel Ackermann ◽  
Katharina E Schraut ◽  
Caroline Hayward ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Metabolic Syndrome ◽  
Genetic Variation ◽  
Lipid Profile ◽  
Fasting Glucose ◽  
Health Study ◽  
Hydroxylase Activity ◽  
The Metabolic Syndrome ◽  
Common Genetic Variants ◽  
Dexamethasone Suppression

ABSTRACTContext and objectiveCommon genetic variants in CYP17A1 associate with higher blood pressure, putatively from impaired 17α-hydroxylase activity and mineralocorticoid excess. However, the same variants protect against obesity and insulin resistance. We tested whether CYP17A1 variants that enhance 17α-hydroxylase activity cause ‘relative corticosterone deficiency’. Since corticosterone is thought to contribute disproportionately to negative feedback in the hypothalamic-pituitary-adrenal axis, we also tested whether lower corticosterone associates with higher cortisol and hence with metabolic syndrome.DesignCross-sectional studies within the population-based Orkney Complex Disease Study (ORCADES; n=2018), VIKING Health Study Shetland (VIKING; n=2098), East Hertfordshire study (EHERTS; n=279), Edinburgh Type 2 Diabetes Study (ET2DS; n=903), and the Swiss Kidney Project on Genes in Hypertension (SKIPOGH; n=888).Outcome measuresCortisol and corticosterone in morning plasma samples in ORCADES, VIKING and ET2DS, and in EHERTS in plasma following overnight dexamethasone suppression (0.25mg) and 30 mins after ACTH1-24 (1µg); cortisol and corticosterone metabolites in day and night urine samples in SKIPOGH. Features of the metabolic syndrome including body mass index, systolic blood pressure, lipid profile, fasting glucose, fasting insulin and HOMA-IR.ResultsIn ORCADES, ET2DS and SKIPOGH, CYP17A1 variants were associated with corticosterone:cortisol ratio. In ORCADES, VIKING and ET2DS there were consistent associations of morning plasma cortisol and corticosterone with BMI, blood pressure, lipid profile, fasting glucose and HOMA-IR. In EHERTS, however, after dexamethasone suppression and ACTH1-24 stimulation, impaired glucose tolerance and insulin sensitivity were associated with higher cortisol but lower corticosterone. Similarly, in SKIPOGH, low corticosterone:cortisol metabolite ratios were associated with high BMI and dyslipidemia.Conclusions‘Relative corticosterone deficiency’, due to a primary alteration in adrenal steroidogenesis favouring cortisol over corticosterone, may mediate the associations of genetic variation in CYP17A1 with metabolic syndrome. However, additional determinants of variation in plasma corticosterone are likely to explain its generally positive associations with features of metabolic syndrome.

Genetic variation in the lymphotoxin alpha pathway and the risk of ischaemic stroke

2007 ◽  
Vol 34 (S 2) ◽  
Author(s):  
M Dichgans ◽  
A Gschwendtner ◽  
S Bevan ◽  
P Lichtner ◽  
S Ripke ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Ischaemic Stroke ◽  
Lymphotoxin Alpha
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