Sex-Specific Associations of Testosterone and Genetic Factors With Health Span

BackgroundPrevious studies have suggested associations between testosterone, genetic factors, and a series of complex diseases, but the associations with the lifespan phenotype, such as health span, remain unclear.MethodsIn this prospective cohort study, we analyzed 145,481 men and 147,733 women aged 38–73 years old from UK Biobank (UKB) to investigate the sex-specific associations of total testosterone (TT), free testosterone (FT), or polygenic risk score (PRS) with health span termination (HST) risk. At baseline, serum testosterone levels were measured. HST was defined by eight events strongly associated with longevity. PRS, an efficient tool combining the effect of common genetic variants to discriminate genetic risk of complex phenotypes, was constructed by 12 single-nucleotide polymorphisms related to health span from UKB (P ≤ 5.0 × 10−8). We used multivariable Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsWith a median follow-up time of 7.70 years, 26,748 (18.39%) men and 18,963 (12.84%) women had HST. TT was negatively associated with HST in men [HR per standard deviation (SD) increment of log-TT: 0.92, 95% CI: 0.88–0.97]. Inversely, both TT (HR per SD increment of log-TT: 1.05, 95% CI: 1.02–1.08) and FT (HR per SD increment of log-FT: 1.08, 95% CI: 1.05–1.11) presented an increased risk of HST in women. PRS was positively associated with HST risk (quintile 5 versus quintile 1, men, HR: 1.19, 95% CI: 1.15–1.24; women, HR: 1.21, 95% CI: 1.16–1.27). Moreover, men with high TT and low genetic risk showed the lowest HST risk (HR: 0.80, 95% CI: 0.73–0.88), whereas HST risk for women with both high TT and genetic risk increased obviously (HR: 1.32, 95% CI: 1.19–1.46). Similar joint effects were observed for FT in both genders.ConclusionsWe observed sex-specific associations that testosterone was negatively associated with HST risk in men and positively associated with HST risk in women. Genetic factors increased the HST risk, suggesting that participants with both high genetic risk and abnormal testosterone levels (high level in women or low level in men) should be the target for early intervention. Although our findings highlight the associations between testosterone and health span, further mechanistic studies and prospective trials are warranted to explore the causation behind.

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Prediction of primary venous thromboembolism based on clinical and genetic factors within the U.K. Biobank

Scientific Reports ◽

10.1038/s41598-021-00796-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

David A. Kolin ◽

Scott Kulm ◽

Olivier Elemento

Keyword(s):

Risk Factors ◽

Venous Thromboembolism ◽

Risk Score ◽

Genetic Risk ◽

Genetic Factors ◽

External Validation ◽

Predictive Score ◽

Polygenic Risk Score ◽

Genetic Components ◽

Increased Risk

AbstractBoth clinical and genetic factors drive the risk of venous thromboembolism. However, whether clinically recorded risk factors and genetic variants can be combined into a clinically applicable predictive score remains unknown. Using Cox proportional-hazard models, we analyzed the association of risk factors with the likelihood of venous thromboembolism in U.K. Biobank, a large prospective cohort. We then created a polygenic risk score of 36 single nucleotide polymorphisms and a clinical score determined by age, sex, body mass index, previous cancer diagnosis, smoking status, and fracture in the last 5 years. Participants were at significantly increased risk of venous thromboembolism if they were at high clinical risk (subhazard ratio, 4.37 [95% CI, 3.85–4.97]) or high genetic risk (subhazard ratio, 3.02 [95% CI, 2.63–3.47]) relative to participants at low clinical or genetic risk, respectively. The combined model, consisting of clinical and genetic components, was significantly better than either the clinical or the genetic model alone (P < 0.001). Participants at high risk in the combined score had nearly an eightfold increased risk of venous thromboembolism relative to participants at low risk (subhazard ratio, 7.51 [95% CI, 6.28–8.98]). This risk score can be used to guide decisions regarding venous thromboembolism prophylaxis, although external validation is needed.

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Genetic risk, incident stroke, and the benefits of adhering to a healthy lifestyle: cohort study of 306 473 UK Biobank participants

BMJ ◽

10.1136/bmj.k4168 ◽

2018 ◽

pp. k4168 ◽

Cited By ~ 32

Author(s):

Loes CA Rutten-Jacobs ◽

Susanna C Larsson ◽

Rainer Malik ◽

Kristiina Rannikmäe ◽

Cathie L Sudlow ◽

...

Keyword(s):

Cohort Study ◽

Risk Score ◽

Genetic Risk ◽

Cox Regression ◽

Healthy Lifestyle ◽

Lifestyle Factors ◽

Polygenic Risk Score ◽

Uk Biobank ◽

Polygenic Risk ◽

Increased Risk

AbstractObjectiveTo evaluate the associations of a polygenic risk score and healthy lifestyle with incident stroke.DesignProspective population based cohort study.SettingUK Biobank Study, UK.Participants306 473 men and women, aged 40-73 years, recruited between 2006 and 2010.Main outcome measureHazard ratios for a first stroke, estimated using Cox regression. A polygenic risk score of 90 single nucleotide polymorphisms previously associated with stroke was constructed at P<1×10−5to test for an association with incident stroke. Adherence to a healthy lifestyle was determined on the basis of four factors: non-smoker, healthy diet, body mass index <30 kg/m2, and regular physical exercise.ResultsDuring a median follow-up of 7.1 years (2 138 443 person years), 2077 incident strokes (1541 ischaemic stroke, 287 intracerebral haemorrhage, and 249 subarachnoid haemorrhage) were ascertained. The risk of incident stroke was 35% higher among those at high genetic risk (top third of polygenic score) compared with those at low genetic risk (bottom third): hazard ratio 1.35 (95% confidence interval 1.21 to 1.50), P=3.9×10−8. Unfavourable lifestyle (0 or 1 healthy lifestyle factors) was associated with a 66% increased risk of stroke compared with a favourable lifestyle (3 or 4 healthy lifestyle factors): 1.66 (1.45 to 1.89), P=1.19×10−13. The association with lifestyle was independent of genetic risk stratums.ConclusionIn this cohort study, genetic and lifestyle factors were independently associated with incident stroke. These results emphasise the benefit of entire populations adhering to a healthy lifestyle, independent of genetic risk.

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Higher sRAGE Levels Predict Mortality in Frail Older Adults with Cardiovascular Disease

Gerontology ◽

10.1159/000512287 ◽

2021 ◽

pp. 1-9

Author(s):

Lee Butcher ◽

Jose Antonio Carnicero ◽

Karine Pérès ◽

Marco Colpo ◽

David Gomez Cabrero ◽

...

Keyword(s):

Older Adults ◽

Cox Regression ◽

Population Based ◽

Blood Levels ◽

Roc Curve Analysis ◽

Baseline Serum ◽

Frailty Status ◽

Risk Of Death ◽

Survival Difference ◽

Increased Risk

Introduction: The evidence that blood levels of the soluble receptor for advanced glycation end products (sRAGE) predict mortality in people with cardiovascular diseases (CVD) is inconsistent. To clarify this matter, we investigated if frailty status influences this association. Methods: We analysed data of 1,016 individuals (median age, 75 years) from 3 population-based European cohorts, enrolled in the FRAILOMIC project. Participants were stratified by history of CVD and frailty status. Mortality was recorded during 8 years of follow-up. Results: In adjusted Cox regression models, baseline serum sRAGE was positively associated with an increased risk of mortality in participants with CVD (HR 1.64, 95% CI 1.09–2.49, p = 0.019) but not in non-CVD. Within the CVD group, the risk of death was markedly enhanced in the frail subgroup (CVD-F, HR 1.97, 95% CI 1.18–3.29, p = 0.009), compared to the non-frail subgroup (CVD-NF, HR 1.50, 95% CI 0.71–3.15, p = 0.287). Kaplan-Meier analysis showed that the median survival time of CVD-F with high sRAGE (>1,554 pg/mL) was 2.9 years shorter than that of CVD-F with low sRAGE, whereas no survival difference was seen for CVD-NF. Area under the ROC curve analysis demonstrated that for CVD-F, addition of sRAGE to the prediction model increased its prognostic value. Conclusions: Frailty status influences the relationship between sRAGE and mortality in older adults with CVD. sRAGE could be used as a prognostic marker of mortality for these individuals, particularly if they are also frail.

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Translating Genomic Advances to Physical Therapist Practice: A Closer Look at the Nature and Nurture of Common Diseases

Physical Therapy ◽

10.2522/ptj.20150112 ◽

2016 ◽

Vol 96 (4) ◽

pp. 570-580 ◽

Cited By ~ 4

Author(s):

Catherine L. Curtis ◽

Allon Goldberg ◽

Jeffrey A. Kleim ◽

Steven L. Wolf

Keyword(s):

Cardiovascular Disease ◽

Human Genome ◽

Genetic Variants ◽

Genetic Factors ◽

Social Issues ◽

Common Diseases ◽

Common Genetic Variants ◽

Increased Risk ◽

Exercise Response ◽

Health And Disease

The Human Genome Project and the International HapMap Project have yielded new understanding of the influence of the human genome on health and disease, advancing health care in significant ways. In personalized medicine, genetic factors are used to identify disease risk and tailor preventive and therapeutic regimens. Insight into the genetic bases of cellular processes is revealing the causes of disease and effects of exercise. Many diseases known to have a major lifestyle contribution are highly influenced by common genetic variants. Genetic variants are associated with increased risk for common diseases such as cardiovascular disease and osteoarthritis. Exercise response also is influenced by genetic factors. Knowledge of genetic factors can help clinicians better understand interindividual differences in disease presentation, pain experience, and exercise response. Family health history is an important genetic tool and encourages clinicians to consider the wider client-family unit. Clinicians in this new era need to be prepared to guide patients and their families on a variety of genomics-related concerns, including genetic testing and other ethical, legal, or social issues. Thus, it is essential that clinicians reconsider the role of genetics in the preservation of wellness and risk for disease to identify ways to best optimize fitness, health, or recovery. Clinicians with knowledge of the influence of genetic variants on health and disease will be uniquely positioned to institute individualized lifestyle interventions, thereby fulfilling roles in prevention and wellness. This article describes how discoveries in genomics are rapidly evolving the understanding of health and disease by highlighting 2 conditions: cardiovascular disease and osteoarthritis. Genetic factors related to exercise effects also are considered.

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Genetic risk for coronary heart disease alters the influence of Alzheimer’s genetic risk on mild cognitive impairment

10.1101/432443 ◽

2018 ◽

Author(s):

Jeremy A. Elman ◽

Matthew S. Panizzon ◽

Mark W. Logue ◽

Nathan A. Gillespie ◽

Michael C. Neale ◽

...

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Genetic Risk ◽

Early Stage ◽

Case Fatality ◽

Polygenic Risk Score ◽

Protective Effects ◽

Increased Risk ◽

Incident Cases ◽

The Impact

ABSTRACTBACKGROUNDAlzheimer’s disease (AD) is under considerable genetic influence. However, known susceptibility loci only explain a modest proportion of variance in disease outcomes. This small proportion could occur if the etiology of AD is heterogeneous. We previously found that an AD polygenic risk score (PRS) was significantly associated with mild cognitive impairment (MCI), an early stage of AD. Poor cardiovascular health is also associated with increased risk for AD and has been found to interact with AD pathology. Conditions such as coronary artery disease (CAD) are also heritable, and may contribute to heterogeneity if there are interactions of genetic risk for these conditions as there is phenotypically. However, case-control designs based on prevalent cases of a disease with relatively high case-fatality rate such as CAD may be biased toward individuals who have long post-event survival times and may therefore also identify loci with protective effects.METHODSWe compared interactions between an AD-PRS and two CAD-PRSs, one based on a GWAS of incident cases and one on prevalent cases, on MCI status in 1,209 individuals.RESULTSAs expected, the incidence-based CAD-PRS interacts with the AD-PRS to further increase MCI risk. Conversely, higher prevalence-based CAD-PRSs reduced the effect of AD genetic risk on MCI status.CONCLUSIONSThese results demonstrate: i) the utility of including multiple PRSs and their interaction effects; ii) how genetic risk for one disease may modify the impact of genetic risk for another; and iii) the importance of considering ascertainment procedures of GWAS being used for genetic risk prediction.

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1389Do associations between a healthy lifestyle and incidence of cancer differ by genetic risk?

International Journal of Epidemiology ◽

10.1093/ije/dyab168.105 ◽

2021 ◽

Vol 50 (Supplement_1) ◽

Author(s):

Stephanie Byrne ◽

Terry Boyle ◽

Beben Benyamin ◽

Sang Hong Lee ◽

Muktar Ahmed ◽

...

Keyword(s):

Cancer Risk ◽

Cancer Incidence ◽

Genetic Risk ◽

Cox Regression ◽

Healthy Lifestyle ◽

Lymphocytic Leukemia ◽

European Ancestry ◽

Risk Scores ◽

Increased Risk ◽

Cancer Types

Abstract Background It is unknown whether relationships between lifestyle and cancer differ by genetic risk. We investigated this for 13 cancer types using prospective data from the UK Biobank. Methods In 2006-2010, participants aged 37-73 years completed an assessment and provided biological samples. Those of European ancestry with no history of malignant cancer were included in our analysis (n = 196,485). For each individual, a healthy lifestyle index (HLI) was calculated based on recommendations, and polygenic risk scores (PRSs) were computed for 13 cancer types. Relationships with cancer incidence were assessed by cox regression, adjusting for age, sex, assessment centre, birth location, and measures of socioeconomic status. Interactions between the HLI and PRSs were explored. Results For all cancer outcomes, a high genetic risk was associated with an increased cancer risk, or there was a trend in that direction. Those in the top PRS tertile had a greater than 2-fold increased risk of colorectal cancer (HR[95%CI]=2.18[1.90,2.49]), pancreatic cancer (2.39[1.71,3.32]) and lymphocytic leukemia (2.45[1.67,3.59]). An unhealthy lifestyle was associated with a higher cancer risk for 8 cancer types, with strong relationships observed for lung (3.41[2.76,4.20]), pancreatic (2.06[1.47,2.91]), bladder (1.95[1.43,2.66]) and kidney cancers (1.90[1.43,2.54]). No interactions between HLI and PRSs were detected (all interaction p-values>0.10). Conclusions Associations between lifestyle and cancer incidence did not differ by genetic risk. Key messages A healthy lifestyle can reduce the risk of several cancers, even in those who are genetically predisposed to develop cancer.

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Genetic Sex Effects of Polycystic Ovary Syndrome Reveal Distinct Metabolic Etiology

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1558 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A766-A766

Author(s):

Ky’Era Actkins ◽

Digna R Velez Edwards ◽

Melinda Aldrich ◽

Lea K Davis

Keyword(s):

Polycystic Ovary Syndrome ◽

Genetic Risk ◽

Polycystic Ovary ◽

Medical Center ◽

Genetic Relationships ◽

African Descent ◽

Polygenic Risk Score ◽

Polycystic Ovaries ◽

Ovary Syndrome ◽

Increased Risk

Abstract Females with polycystic ovary syndrome (PCOS) have an increased risk of developing metabolic disorders such as insulin resistance, obesity, and type 2 diabetes (T2D). High-risk groups or individuals with a family history are more likely to have a greater genetic susceptibility to these diseases, which drastically increases their risk of developing other chronic health conditions. In this study, we systematically evaluated the bidirectional genetic burden of PCOS and its comorbidities among females and males. First, we analyzed the pleiotropic effects of the PCOS polygenic risk score (PRS), a measurement of genetic liability to PCOS, across 1,857 medical conditions recorded in the Vanderbilt University Medical Center electronic health record. We conducted a phenome-wide association study (PheWAS) adjusted for median age, sex, and genetic ancestry. In the European sex-combined model (n = 72,824), we observed that PCOS PRS was significantly (Bonferroni corrected p < 7.86e-06) associated with T2D (OR = 1.11, p = 8.75e-08) and hypertension (OR = 1.06, p = 1.13e-07) in addition to polycystic ovaries (OR = 1.11, p = 1.91e-07). In the sex-stratified model, we found that males (n = 32,022) with a higher PRS for PCOS were more likely to develop cardiovascular diseases (CVD) compared to females (n = 40,802) who had higher odds of developing T2D. Although we were underpowered to detect any phenome-wide significant effects in our African descent sample (n=15,283), uterine leiomyoma (OR = 1.24, p = 3.79e-03), osteoarthritis (OR = 1.21, p = 3.94e-03), and benign neoplasm of uterus (OR = 1.24, p = 4.00e-03) were the top three nominal significant results (p < 0.05) in females (n = 9,418). To understand the genetic relationships observed in the PheWAS, we used LD score regression to determine the genetic correlation between the phenotypes. We found that PCOS was positively correlated with T2D (rg = 31%), systolic blood pressure (rg = 12%), and pulse pressure (rg = 15%). However, we found no significant associations between the genetic risk of CVD and PCOS diagnosis in the European or African descent samples. Our findings show that the genetic architecture of PCOS has distinct metabolic sex differences, but the genetic risk of those comorbidities is not predictive of a PCOS diagnosis. This suggests that other drivers are contributing to the endocrine and cardiovascular comorbid signatures that underlie PCOS.

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Interactions between dietary patterns and genetic factors in relation to incident dementia among 70-year-olds

European Journal of Nutrition ◽

10.1007/s00394-021-02688-9 ◽

2021 ◽

Author(s):

Jessica Samuelsson ◽

Jenna Najar ◽

Ola Wallengren ◽

Silke Kern ◽

Hanna Wetterberg ◽

...

Keyword(s):

Dietary Patterns ◽

Dietary Pattern ◽

Genetic Factors ◽

Cox Regression ◽

Population Based ◽

Risk Scores ◽

Reduced Rank Regression ◽

Apoe Ε4 ◽

Incident Dementia ◽

Increased Risk

Abstract Purpose To investigate potential interactions between dietary patterns and genetic factors modulating risk for Alzheimer’s disease (AD) in relation to incident dementia. Methods Data were derived from the population-based Gothenburg H70 Birth Cohort Studies in Sweden, including 602 dementia-free 70-year-olds (examined 1992–93, or 2000–02; 64% women) followed for incident dementia until 2016. Two factors from a reduced rank regression analysis were translated into dietary patterns, one healthy (e.g., vegetables, fruit, and fish) and one western (e.g., red meat, refined cereals, and full-fat dairy products). Genetic risk was determined by APOE ε4 status and non-APOE AD-polygenic risk scores (AD-PRSs). Gene–diet interactions in relation to incident dementia were analysed with Cox regression models. The interaction p value threshold was < 0.1. Results There were interactions between the dietary patterns and APOE ε4 status in relation to incident dementia (interaction p value threshold of < 0.1), while no evidence of interactions were found between the dietary patterns and the AD-PRSs. Those with higher adherence to a healthy dietary pattern had a reduced risk of dementia among ε4 non-carriers (HR: 0.77; 95% CI: 0.61; 0.98), but not among ε4 carriers (HR: 0.86; CI: 0.63; 1.18). Those with a higher adherence to the western dietary pattern had an increased risk of dementia among ε4 carriers (HR: 1.37; 95% CI: 1.05; 1.78), while no association was observed among ε4 non-carriers (HR: 0.99; CI: 0.81; 1.21). Conclusions The results of this study suggest that there is an interplay between dietary patterns and APOE ε4 status in relation to incident dementia.

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Abstract 572: Hyperglycemia and Poor Outcomes in Patients without Diabetes Mellitus in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS): A Propensity Matched Analysis

Circulation ◽

10.1161/circ.118.suppl_18.s_583-b ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Prakash C Deedwania ◽

Bertram Pitt ◽

Enrique V Carbajal ◽

Ali Ahmed

Keyword(s):

Diabetes Mellitus ◽

Myocardial Infarction ◽

Heart Failure ◽

Acute Myocardial Infarction ◽

Sudden Cardiac Death ◽

Cardiac Death ◽

Propensity Scores ◽

Cox Regression ◽

Baseline Serum ◽

Increased Risk

Background: The effect of hyperglycemia on outcomes in patients with acute MI (AMI) and low LVEF without diabetes mellitus is not well known. Methods: In the EPHESUS trial, of the 4411 non-DM patients, 554 had baseline hyperglycemia (≥140 mg/dL). Propensity scores for hyperglycemia were calculated for each of the 4411 patients based on 63 baseline covariates, and a greedy 1:8 matching protocol was used to match 400 and 2542 patients respectively with and without hyperglycemia. Matched Cox regression models were used to estimate associations between hyperglycemia and outcomes during 16 months of follow up. Results: Patients with hyperglycemia were more likely to be older, have higher heart rate, lower LVEF, and receive nitrates, statins, digoxin, loop diuretics, and PTCA during index admission. Unadjusted hazard ratios {HR} and 95% confidence intervals {CI} for hyperglycemia were: all-cause death (1.51; 1.22–1.87; P<0.001), cardiovascular (CV) death (1.52; 1.21–1.90; P<0.001), heart failure (HF) death (2.19, 1.46–3.29; P<0.001), all-cause hospitalization (1.23; 1.08–1.40; P=0.002), CV hospitalization (1.51, 1.24–1.84; P<0.001) and HF hospitalization (1.75; 1.37–2.25; P<0.001). In the matched cohort, hyperglycemia was significantly associated with CV death (HR=1.25, 95%CI=1.01–1.54; P=0.039), sudden cardiac death (HR=1.33; 95%CI=1.02–1.73, P=0.035) and fatal/nonfatal AMI (HR=1.53, 95%CI=1.07–2.19; P=0.04; Figure ). Conclusions: In non-diabetic post-AMI HF patients, hyperglycemia is a poor prognosticator and is associated with increased risk of fatal and non-fatal AMI, CV death, HF deaths, sudden cardiac death, and CV hospitalization. Figure Fatal or non fatal acute myocardial infarction (AMI) by baseline serum glucose in post-AMI patients with no known history of diabetes mellitus

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Comparison of Two Creatinine-Based Equations for Predicting Decline in Renal Function in Type 2 Diabetic Patients with Nephropathy in a Korean Population

International Journal of Endocrinology ◽

10.1155/2013/848963 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Eun Young Lee ◽

Young-Mi Lee ◽

Kyu Hun Choi ◽

Hyun Chul Lee ◽

Byung-Wan Lee ◽

...

Keyword(s):

Cox Regression ◽

Diabetic Patients ◽

Ckd Progression ◽

Type 2 Diabetic Patients ◽

Baseline Serum ◽

Cox Regression Analysis ◽

Disease Epidemiology ◽

Increased Risk ◽

Type 2 Diabetic

Aim.To compare two creatinine-based estimated glomerular filtration rate (eGFR) equations, the chronic kidney disease epidemiology collaboration (CKD-EPI) and the modification of diet in renal disease (MDRD), for predicting the risk of CKD progression in type 2 diabetic patients with nephropathy.Methods.A total of 707 type 2 diabetic patients with 24 hr urinary albumin excretion of more than 30 mg/day were retrospectively recruited and traced until doubling of baseline serum creatinine (SCr) levels was noted.Results.During the follow-up period (median, 2.4 years), the CKD-EPI equation reclassified 10.9% of all MDRD-estimated subjects: 9.1% to an earlier stage of CKD and 1.8% to a later stage of CKD. Overall, the prevalence of CKD (eGFR < 60 mL/min/1.73 m2) was lowered from 54% to 51.6% by applying the CKD-EPI equation. On Cox-regression analysis, both equations exhibited significant associations with an increased risk for doubling of SCr. However, only the CKD-EPI equation maintained a significant hazard ratio for doubling of SCr in earlier-stage CKD (eGFR ≥ 45 mL/min/1.73 m2), when compared to stage 1 CKD (eGFR ≥ 90 mL/min/1.73 m2).Conclusion.In regard to CKD progression, these results suggest that the CKD-EPI equation might more accurately stratify earlier-stage CKD among type 2 diabetic patients with nephropathy than the MDRD study equation.

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