scholarly journals Adiposity and Genetic Factors in Relation to Triglycerides and Triglyceride-Rich Lipoproteins in the Women's Genome Health Study

2018 ◽  
Vol 64 (1) ◽  
pp. 231-241 ◽  
Author(s):  
Shafqat Ahmad ◽  
Samia Mora ◽  
Paul W Franks ◽  
Marju Orho-Melander ◽  
Paul M Ridker ◽  
...  
Keyword(s):  
Genetic Risk ◽  
Genetic Risk Score ◽  
Normal Weight ◽  
Differential Association ◽  
European Ancestry ◽  
Health Study ◽  
Resonance Spectroscopy ◽  
Lipoprotein Subfractions ◽  
Total N ◽  
Weighted Genetic Risk Score

Abstract BACKGROUND Previous results from Scandinavian cohorts have shown that obesity accentuates the effects of common genetic susceptibility variants on increased triglycerides (TG). Whether such interactions are present in the US population and further selective for particular TG-rich lipoprotein subfractions is unknown. METHODS We examined these questions using body mass index (BMI) and waist circumference (WC) among women of European ancestry from the Women's Genome Health Study (WGHS) (n = 21840 for BMI; n = 19313 for WC). A weighted genetic risk score (TG-wGRS) based on 40 published TG-associated single-nucleotide polymorphisms was calculated using published effect estimates. RESULTS Comparing overweight (BMI ≥ 25 kg/m2) and normal weight (BMI < 25 kg/m2) WGHS women, each unit increase of TG-wGRS was associated with TG increases of 1.013% and 1.011%, respectively, and this differential association was significant (Pinteraction = 0.014). Metaanalyses combining results for WGHS BMI with the 4 Scandinavian cohorts (INTER99, HEALTH2006, GLACIER, MDC) (total n = 40026) yielded a more significant interaction (Pinteraction = 0.001). Similarly, we observed differential association of the TG-wGRS with TG (Pinteraction = 0.006) in strata of WC (<80 cm vs ≥80 cm). Metaanalysis with 2 additional cohorts reporting WC (INTER99 and HEALTH2006) (total n = 27834) was significant with consistent effects (Pinteraction = 0.006). We also observed highly significant interactions of the TG-wGRS across the strata of BMI with very large, medium, and small TG-rich lipoprotein subfractions measured by nuclear magnetic resonance spectroscopy (all Pinteractions < 0.0001). The differential effects were strongest for very large TG-rich lipoprotein. CONCLUSIONS Our results support the original findings and suggest that obese individuals may be more susceptible to aggregated genetic risk associated with common TG-raising alleles, with effects accentuated in the large TG-rich lipoprotein subfraction.

scholarly journals Additive and Multiplicative Interactions Between Genetic Risk Score and Family History and Lifestyle in Relation to Risk of Type 2 Diabetes

2019 ◽  
Vol 189 (5) ◽  
pp. 445-460 ◽  
Author(s):  
Ming Ding ◽  
Shafqat Ahmad ◽  
Lu Qi ◽  
Yang Hu ◽  
Shilpa N Bhupathiraju ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Family History ◽  
Risk Score ◽  
Genetic Risk ◽  
Healthy Lifestyle ◽  
Genetic Risk Score ◽  
European Ancestry ◽  
Health Study ◽  
Public Health Implication

Abstract We examined interactions between lifestyle factors and genetic risk of type 2 diabetes (T2D-GR), captured by genetic risk score (GRS) and family history (FH). Our initial study cohort included 20,524 European-ancestry participants, of whom 1,897 developed incident T2D, in the Nurses’ Health Study (1984–2016), Nurses’ Health Study II (1989–2016), and Health Professionals Follow-up Study (1986–2016). The analyses were replicated in 19,183 European-ancestry controls and 2,850 incident T2D cases in the Women’s Genome Health Study (1992–2016). We defined 2 categories of T2D-GR: high GRS (upper one-third) with FH and low GRS or without FH. Compared with participants with the healthiest lifestyle and low T2D-GR, the relative risk of T2D for participants with the healthiest lifestyle and high T2D-GR was 2.24 (95% confidence interval (CI): 1.76, 2.86); for participants with the least healthy lifestyle and low T2D-GR, it was 4.05 (95% CI: 3.56, 4.62); and for participants with the least healthy lifestyle and high T2D-GR, it was 8.72 (95% CI: 7.46, 10.19). We found a significant departure from an additive risk difference model in both the initial and replication cohorts, suggesting that adherence to a healthy lifestyle could lead to greater absolute risk reduction among those with high T2D-GR. The public health implication is that a healthy lifestyle is important for diabetes prevention, especially for individuals with high GRS and FH of T2D.

Phenotypic and Genotypic Associations Between Migraine and Lipoprotein Subtractions

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012919
Author(s):  
Yanjun Guo ◽  
Iyas Daghlas ◽  
Padhraig Gormley ◽  
Franco Giulianini ◽  
Paul M Ridker ◽  
...  
Keyword(s):  
Genetic Correlation ◽  
Genetic Relationships ◽  
Meta Analysis ◽  
European Ancestry ◽  
Health Study ◽  
Lipoprotein Subfractions ◽  
Genetic Components ◽  
The Uk ◽  
Summary Data

Background and Objective:To evaluate phenotypic and genetic relationships between migraine and lipoprotein subfractions.Methods:We evaluated phenotypic associations between migraine and 19 lipoprotein subfractions measures in the Women’s Genome Health Study (WGHS, N=22,788). We then investigated genetic relationships between these traits using summary statistics from the International Headache Genetics Consortium (IHGC) for migraine (Ncase=54,552, Ncontrol=297,970) and combined summary data for lipoprotein subfractions (N up to 47,713).Results:There was a significant phenotypic association (odds ratio=1.27 [95% confidence interval:1.12-1.44]) and a significant genetic correlation at 0.18 (P=0.001) between migraine and triglyceride-rich lipoproteins (TRLP) concentration but not for LDL or HDL subfractions. Mendelian randomization (MR) estimates were largely null implying that pleiotropy rather than causality underlies the genetic correlation between migraine and lipoprotein subfractions. Pleiotropy was further supported in cross-trait meta-analysis revealing significant shared signals at four loci (chr2p21 harboring THADA, chr5q13.3 harboring HMGCR, chr6q22.31 harboring HEY2, and chr7q11.23 harboring MLXIPL) between migraine and lipoprotein subfractions. Three of these loci were replicated for migraine (P<0.05) in a smaller sample from the UK Biobank. The shared signal at chr5q13.3 colocalized with expression of HMGCR, ANKDD1B, and COL4A3BP in multiple tissues.Conclusions:The current study supports the association between certain lipoprotein subfractions, especially for TRLP, and migraine in populations of European ancestry. The corresponding shared genetic components may be help identify potential targets for future migraine therapeutics.Classification of Evidence:This study provides Class I evidence that migraine is significantly associated with some lipoprotein subfractions.

scholarly journals Mitigation of Venous Thromboembolism Risk through Favorable Lifestyle: The ARIC Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1151-1151
Author(s):  
Christina Evans ◽  
Ching-Png Hong ◽  
Aaron R Folsom ◽  
Susan Heckbert ◽  
Nicholas Smith ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Lifestyle Factors ◽  
Normal Weight ◽  
Common Disease ◽  
High Genetic Risk ◽  
Optimal Health ◽  
Aric Study ◽  
The Impact

Background: Venous thromboembolism (VTE) is a common disease with a strong genetic basis. Unhealthy lifestyle factors contribute to risk, but it is unknown whether healthier lifestyle can mitigate the risk for VTE in those at high genetic risk. We studied whether greater adherence to the American Heart Association's (AHA's) cardiovascular health metric called Life's Simple 7 (LS7) is associated with a lower rate of VTE in individuals with high genetic risk score (GRS) for VTE. Methods: We followed 9,026 middle-aged white participants from the Atherosclerosis Risk in Communities (ARIC) Study, a prospective cohort of 15,792 individuals enrolled in 1987-89. A validated GRS was used, comprising 5 well known genetic conditions associated with VTE (factor V Leiden, prothrombin 20210A, non-O blood group, factor XI rs4241824, and fibrinogen gamma FGG rs2066865). Only white participants were included, as the GRS did not predict VTE in others. AHA's LS7 categories of inadequate, average, and optimal health were determined based on smoking status, body mass index, physical activity, diet, total cholesterol, blood pressure, and fasting glucose. VTE events were adjudicated by expert medical record review. We calculated hazard ratios (HRs) and 95% confidence intervals (CI) of incident VTE by LS7 categories, stratified by GRS (low, intermediate, high), adjusting for age, sex, and education. HRs were also calculated for individual LS7 components stratified by GRS. Results: There were 466 incident VTE over 22.8 years of follow-up. Compared to those with optimal health, those with inadequate LS7 score had higher rates of VTE (5.7% vs. 3.9%). In Figure 1, compared to the high GRS / inadequate LS7 group, the HR of VTE in the low GRS group with optimal health was lowest at 0.39 (95% CI 0.25-0.61), but moreover, the HR in the high GRS group with optimal health was also attenuated to 0.65 (95% CI 0.48-0.89). The pattern of association was similar for provoked and unprovoked VTE. Of the LS7 components, obesity was most strongly related to VTE. In Figure 2, compared to obese / high GRS participants, the HR of VTE with normal weight / low GRS was 0.36 (95% CI 0.23-0.57), while the HR in high GRS / normal weight participants was reduced by 45%, at 0.55 (95% CI 0.4-0.76). Conclusion: Among all participants, even those at high genetic risk, healthier lifestyle factors, particularly obesity, were associated with decreased incidence of VTE. Further studies should determine the impact of lifestyle change among patients at high genetic risk of VTE, such as in thrombophilic families. Disclosures Heckbert: National Institutes of Health: Other: Grants.

scholarly journals A Weighted Genetic Risk Score Predicts Surgical Recurrence Independent of High-Risk Clinical Features in Dupuytren’s Disease

2019 ◽  
Vol 143 (2) ◽  
pp. 512-518 ◽  
Author(s):  
Sophie A. Riesmeijer ◽  
Oliver W. G. Manley ◽  
Michael Ng ◽  
Ilja M. Nolte ◽  
Dieuwke C. Broekstra ◽  
...  
Keyword(s):  
High Risk ◽  
Clinical Features ◽  
Risk Score ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Dupuytren’S Disease ◽  
Dupuytren's Disease ◽  
Surgical Recurrence ◽  
Weighted Genetic Risk Score

scholarly journals 1152 Genetic Risk Of Alzheimer’S Disease Is Linked To Short Sleep Duration

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A439-A439
Author(s):  
Y Leng ◽  
K Yaffe ◽  
S Ackley ◽  
M Glymour ◽  
W Brenowitz
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Sleep Duration ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Genetic Ancestry ◽  
European Ancestry ◽  
Short Sleep Duration ◽  
Short Sleep

Abstract Introduction Sleep disturbances including short sleep duration are common in older adults, especially in those with Alzheimer’s disease (AD). However, it is unclear to what extent sleep duration is a manifestation of AD disease process. We examined whether genetic variants related to AD influence sleep duration in middle-aged and older adults and estimated the causal effects of AD on sleep duration using a mendelian randomization (MR) analysis. Methods We examined 406,687 UK Biobank participants with Caucasian genetic ancestry who self-reported sleep duration at baseline (2006-2010). Sleep duration was assessed by asking: “About how many hours sleep do you get in every 24 hours? (please include naps).” A genetic risk score for AD (AD-GRS) was calculated as a weighted sum of 23 previously identified AD-related single nucleotide polymorphisms in individuals of European ancestry. We evaluated whether AD-GRS predicted sleep duration using linear regression, adjusting for age, sex and principle components for genetic ancestry. We also stratified the analysis by age at baseline (≤55y or &gt;55y) and conducted a MR analysis to estimate the effect of AD (ICD-9/10 codes for AD/dementia diagnosis) on sleep duration. Results The participants (aged 56.91±8.00y) had an average sleep duration of 7.2 (Standard deviation [SD]=1.1) hours and AD-GRS of 0.11 (SD=0.40) (range: -1.15~1.85). Higher AD-GRS score predicted shorter sleep duration (b= -0.013, 95%CI:-0.022,-0.005), mainly among those aged over 55y (b= -0.023, 95%CI:-0.034,-0.012) and not in those 55y or younger (b= 0.006, 95%CI:-0.012,0.013); p for interaction by age=0.02. MR analysis using AD-GRS as an instrumental variable suggested that AD was associated with 1.76 hrs (b=-1.76, -2.62~ -0.90) shorter sleep duration in those aged &gt;55y. Conclusion Using a novel analytical approach, we found that higher genetic risk for AD predicted shorter sleep duration among older adults. This suggests shared genetic pathways; the biologic processes that lead to AD may also affect sleep duration. Support Dr. Leng received support from the National Institute on Aging (NIA) 1K99AG056598, and from GBHI, Alzheimer’s Association, and Alzheimer’s Society (GBHI ALZ UK-19-591141).

scholarly journals Combined Effects of MMP-7, MMP-8 and MMP-26 on the Risk of Ischemic Stroke

2019 ◽  
Vol 8 (11) ◽  
pp. 2011
Author(s):  
Fang-I Hsieh ◽  
Hung-Yi Chiou ◽  
Chaur-Jong Hu ◽  
Jiann-Shing Jeng ◽  
Huey-Juan Lin ◽  
...  
Keyword(s):  
Risk Factors ◽  
Ischemic Stroke ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Weighted Average ◽  
Combined Effects ◽  
Cvd Risk Factors ◽  
Cvd Risk ◽  
Increased Risk ◽  
Weighted Genetic Risk Score

Ischemic stroke (IS) is multifactorial causation combining with traditional cardiovascular disease (CVD) and genetic risk factors. Combined effects of MMP-7, MMP-8 and MMP-26 on the risk of IS remain incompletely understood. We aimed to assess individual and joint effects for IS risk by weighted genetic risk score (wGRS) from these three genes and traditional CVD risk factors. A case-control study including 500 cases with IS and 500 stroke-free healthy controls frequency-matched with cases by age and sex was conducted. The wGRS was a weighted average of the number of risk genotype across selected SNPs from MMP-7, MMP-8 and MMP-26. Multivariate logistic regression models were used to analyze the relationship between wGRS and risk of IS. A wGRS in the second tertile was associated with a 1.5-fold increased risk of IS compared with the lowest tertile after adjusting for traditional CVD risk factors. Compared to subjects with low genetic and low modifiable CVD risk, those with high genetic and high modifiable CVD risk had the highest risk of IS (adjusted-OR = 5.75). In conclusion, higher wGRS was significantly associated with an increased risk for IS. A significant interaction between genetic and traditional CVD risk factors was also found on the risk of IS.

scholarly journals Evaluation of a weighted genetic risk score for the prediction of biomarkers of CYP2A6 activity

2019 ◽  
Vol 25 (1) ◽  
Author(s):  
Ahmed El‐Boraie ◽  
Taraneh Taghavi ◽  
Meghan J. Chenoweth ◽  
Koya Fukunaga ◽  
Taisei Mushiroda ◽  
...  
Keyword(s):  
Risk Score ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Weighted Genetic Risk Score

scholarly journals Do genetic risk scores for body mass index predict risk of phobic anxiety? Evidence for a shared genetic risk factor

2014 ◽  
Vol 45 (1) ◽  
pp. 181-191 ◽  
Author(s):  
S. Walter ◽  
M. M. Glymour ◽  
K. Koenen ◽  
L. Liang ◽  
E. J. Tchetgen Tchetgen ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Body Mass ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Conclusive Evidence ◽  
Anxiety Symptoms ◽  
Risk Scores ◽  
Health Study ◽  
Nucleotide Polymorphisms ◽  
Phobic Anxiety

BackgroundObesity and anxiety are often linked but the direction of effects is not clear.MethodUsing genetic instrumental variable (IV) analyses in 5911 female participants from the Nurses' Health Study (NHS, initiated 1976) and 3697 male participants from the Health Professional Follow-up Study (HPFS, initiated 1986), we aimed to determine whether obesity increases symptoms of phobic anxiety. As instrumental variables we used the fat mass and obesity-associated (FTO) gene, the melanocortin 4 receptor (MC4R) gene and a genetic risk score (GRS) based on 32 single nucleotide polymorphisms (SNPs) that significantly predict body mass index (BMI). ‘Functional’ GRSs corresponding with specific biological pathways that shape BMI (adipogenesis, appetite and cardiopulmonary) were considered. The main outcome was phobic anxiety measured by the Crown Crisp Index (CCI) in 2004 in the NHS and in 2000 in the HPFS.ResultsIn observational analysis, a 1-unit higher BMI was associated with higher phobic anxiety symptoms [women:β = 0.05, 95% confidence interval (CI) 0.030–0.068; men:β = 0.04, 95% CI 0.016–0.071). IV analyses showed that BMI was associated with higher phobic anxiety symptoms in theFTO-instrumented analysis (p = 0.005) but not in the GRS-instrumented analysis (p = 0.256). Functional GRSs showed heterogeneous, non-significant effects of BMI on phobic anxiety symptoms.ConclusionsOur findings do not provide conclusive evidence in favor of the hypothesis that higher BMI leads to higher levels of phobic anxiety, but rather suggest that genes that influence obesity, in particularFTO, may have direct effects on phobic anxiety, and hence that obesity and phobic anxiety may share common genetic determinants.

scholarly journals Pregnancy does not modify the risk of MS in genetically susceptible women

2020 ◽  
Vol 7 (6) ◽  
pp. e898
Author(s):  
Cameron J. Adams ◽  
Sean L. Wu ◽  
Xiaorong Shao ◽  
Patrick T. Bradshaw ◽  
Edlin Gonzales ◽  
...  
Keyword(s):  
Risk Score ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
The United States ◽  
Sensitivity Analyses ◽  
Risk Variants ◽  
Inverse Variance ◽  
Weighted Genetic Risk Score ◽  
Meta Analyses ◽  
Genetic Risk Variants

ObjectiveTo use the case-only gene-environment (G E) interaction study design to estimate interaction between pregnancy before onset of MS symptoms and established genetic risk factors for MS among White adult females.MethodsWe studied 2,497 female MS cases from 4 cohorts in the United States, Sweden, and Norway with clinical, reproductive, and genetic data. Pregnancy exposure was defined in 2 ways: (1) live birth pregnancy before onset of MS symptoms and (2) parity before onset of MS symptoms. We estimated interaction between pregnancy exposure and established genetic risk variants, including a weighted genetic risk score and both HLA and non-HLA variants, using logistic regression and proportional odds regression within each cohort. Within-cohort associations were combined using inverse variance meta-analyses with random effects. The case-only G × E independence assumption was tested in 7,067 individuals without MS.ResultsEvidence for interaction between pregnancy exposure and established genetic risk variants, including the strongly associated HLA-DRB1*15:01 allele and a weighted genetic risk score, was not observed. Results from sensitivity analyses were consistent with observed results.ConclusionOur findings indicate that pregnancy before symptom onset does not modify the risk of MS in genetically susceptible White females.

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