Genetic Risk Categories Research Articles

Genetic Risk, Health-Associated Lifestyle, and Risk of Early-onset Total Cancer and Breast Cancer.

Early-onset cancer (diagnosed under age 50) generally manifests as an aggressive disease phenotype. The association between healthy lifestyle and early-onset cancer and whether it varies by common genetic variants remains unclear. We analyzed a prospective cohort of 66,308 participants who were under age 50 and free of cancer at baseline in the UK Biobank. Using Cox regression, we estimated Hazard ratios (HRs) and 95% confidence intervals (CIs) for early-onset total and breast cancer based on sex-specific composite total cancer polygenic risk scores (PRSs), a breast cancer-specific PRS, and sex-specific health-associated lifestyle scores (HLSs). In multivariable-adjusted analyses with 2-year latency, higher genetic risk (highest vs lowest tertile of PRS) was associated with significantly increased risks of early-onset total cancer in females (HR, 95% CI: 1.83, 1.49-2.26) and males (2.03, 1.51-2.73) as well as early-onset breast cancer in females (3.06, 2.20-4.26). An unfavorable lifestyle (highest vs lowest category of HLS) was associated with higher risk of total cancer and breast cancer in females across genetic risk categories; the association with total cancer and breast cancer was stronger in the highest genetic risk category than the lowest: HRs (95% CIs) were 1.55 (1.12, 2.14) and 1.69 (1.11, 2.57) in the highest genetic risk category and 1.03 (0.64, 1.67) and 0.81 (0.36, 1.85) in the lowest. Genetic and lifestyle factors were independently associated with early-onset total and breast cancer risk. Individuals with a high genetic risk may benefit more from adopting a healthy lifestyle in preventing early-onset cancer.

Healthy lifestyle practice correlates with decreased obesity prevalence in individuals with high polygenic risk: TMM CommCohort study.

Obesity and overweight, fundamental components of the metabolic syndrome, predispose individuals to lifestyle-related diseases. The extent to which adopting healthy lifestyles can reduce obesity risk, even in those with a high genetic risk, remains uncertain. Our aim was to assess the extent to which lifestyle modifications can improve outcomes in individuals with a high polygenic score (PGS) for obesity. We quantified the genetic risk of obesity using PGSs. Four datasets from the Tohoku Medical Megabank Community-Based Cohort (TMM CommCohort) were employed in the study. One dataset (n = 9958) was used to select the best model for calculating PGS. The remaining datasets (total n = 69,341) were used in a meta-analysis to validate the model and to evaluate associated risks. The odds ratio (OR) for obesity risk in the intermediate (11th-90th percentiles in the dataset) and high PGS categories (91st-100th) was 2.27 [95% confidence intervals: 2.12-2.44] and 4.83 [4.45-5.25], respectively, compared to that in the low PGS category (1st-10th). Trend analysis showed that an increase in leisure-time physical activity was significantly associated with reduced obesity risk across all genetic risk categories, representing an OR of 0.9 [0.87-0.94] even among individuals in the high PGS category. Similarly, sodium intake displayed a positive association with obesity across all genetic risk categories, yielding an OR of 1.24 [1.17-1.31] in the high PGS category. The risk of obesity was linked to the adoption of healthy lifestyles, even in individuals with high PGS. Our results may provide perspectives for integrating PGSs into preventive medicine.

Adherence to a planetary health diet, genetic susceptibility, and incident cardiovascular disease: a prospective cohort study from the UK Biobank

BackgroundThe influence of adherence to a planetary health diet (PHD) proposed by the EAT-Lancet Commission on cardiovascular disease (CVD) is inconclusive. Besides, whether genetic susceptibility to CVD can modify the association of PHD with CVD remains unknown. ObjectiveWe aimed to investigate the association between adherence to PHD and CVD, and to evaluate the interaction between PHD and genetic predisposition to CVD. MethodsThis study included 114,165 participants who completed at least two 24-h dietary recalls and were initially free of CVD from the UK Biobank. PHD score was calculated to assess adherence to PHD. Genetic risk was evaluated using the polygenic risk score. Incidence of total CVD, ischemic heart disease (IHD), atrial fibrillation (AF), heart failure (HF), and stroke were identified via electronic health records. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). ResultsDuring a median follow-up of 9.9 y, 10,071 (8.8%) incident CVD cases were documented. Compared with participants with the lowest adherence to PHD, HRs (95% CIs) for total CVD, IHD, AF, HF, and stroke among those with the highest adherence were 0.79 (0.74, 0.84), 0.73 (0.67, 0.79), 0.90 (0.82, 0.99), 0.69 (0.59, 0.82), and 0.88 (0.75, 1.04), respectively. No significant interaction between the genetic risk of CVD and PHD was observed. Participants with high genetic risk and low PHD score, as compared with those with low genetic risk and high PHD score, had a 48% (95% CI: 40%, 56%) higher risk of CVD. The population-attributable risk (95% CI) of CVD for poor adherence to PHD ranged from 8.79% (5.36%, 12.51%) to 14.00% (9.00%, 18.88%). ConclusionsThese findings suggest that higher adherence to PHD was associated with lower risk of total CVD, IHD, AF, and HF in populations across all genetic risk categories.

Abstract 3035: Associations Of Genetic And Lifestyle Risk Factors With Incident Peripheral Artery Disease: A Prospective Cohort Study

Background: The joint associations between genetic and lifestyle factors, and peripheral artery disease (PAD) remain unclear, yet understanding the connections is crucial for precise PAD prevention. Methods: Genetic susceptibility to PAD was estimated by a polygenic risk score of 50 genetic variants selected by P < 5х10 -8 and r 2 <0.01 from a GWAS including 31,307 cases. Tertiles categorized genetic risk into low, intermediate, and high. A healthy lifestyle score was constructed based on 4 lifestyle factors (never smoking, non-excessive alcohol consumption, high cardiometabolic healthy diet adherence, and regular physical activity) and categorized into favorable (3-4 healthy factors), intermediate (2 healthy factors), and unfavorable (0-1 healthy factors) groups. Cox regression estimated hazard ratios (HR) and 95% confidence interval (CI) with adjustment for age (time scale), sex, BMI, education, baseline cardiovascular risk factors, 20 principal components. Results: Over 11.9 years, 4299 incident PAD cases were diagnosed in 379,228 UK Biobank participants free of baseline PAD. Genetic risk and unhealthy lifestyle categories were monotonically associated with PAD. Compared with low genetic risk, the HR was 1.69 (95% CI 1.56-1.89) for high genetic risk. Compared with favorable lifestyle, the HR for unfavorable lifestyle was 2.70 (95% CI 2.50-2.94). There was no multiplicative interaction between genetic and lifestyle factors ( P = 0.461). The association between unfavorable lifestyle and higher PAD risk was consistent in genetic risk groups. Joint categorization analysis detected an HR for high genetic risk and favorable lifestyle was (1.85, 95% CI 1.54-2.22) reducing by > 50%, compared with high genetic risk and unfavorable lifestyle (HR 4.76, 95% CI 4.00-5.56). Conclusions: Genetic and lifestyle factors independently associated with incident PAD. Adhering to a favorable lifestyle substantially reduced PAD risk, even in individuals at high genetic risk.

Analysis of Post-Transplant Clinical Outcomes and Prognostic Factors in FLT3-ITD Mutated Acute Myeloid Leukemia Patients Under ELN 2022 Risk Stratification

Background In 2022 European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML), one of the most important changes made to the genetic risk classification of AML is that the FLT3-ITD allelic ratio (AR) is no longer considered in the risk classification; consequently, AML with FLT3-ITD (without adverse-risk genetic lesions) are now categorized in the intermediate-risk group, irrespective of the allelic ratio or concurrent presence of NPM1 mutation. Aims To investigate the survival outcomes of FLT3-ITD mutated AML patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), based on prognostic stratification defined by the 2017 and 2022 ELN guidelines, and to analyze the risk factors affecting transplant prognosis. Methods A total of 163 FLT3-ITD mutated AML patients underwent allo-HSCT were enrolled in this study. Bone marrow aspirates were obtained, cytogenetic and molecular characteristics were collected at the time of diagnosis. Genetic risk category was classified according to the 2017 and 2022 edition of the European LeukemiaNet (ELN) recommendations. HLA-haploidentical donor transplants were performed if no HLA matched sibling or unrelated donor was available. Patients received myeloablative conditioning with a modified Bu/Cy/Flu/Ara-c (busulfan/cyclophosphamide/fludarabine/cytarabine) or MCBC (melphalan/cladribine/busulfan/cyclophosphamide) preparative regimen. The therapeutic process and clinical outcomes were retrospectively analyzed. Results We assessed 163 adults with FLT3-mutated AML (median age 37 years) allografted between 2017 and 2022 in our clinical center. The median follow-up of alive patients was 24.9 months. The 2-year relapse-free survival (RFS) and overall survival (OS) were 67.2% and 71.9%, respectively. The 2-year incidences of relapse and non-relapse mortality were 27.9% and 12.5%, respectively. There was no significant difference in survival outcomes between the intermediate and high-risk groups after transplantation, both defined by the 2017 and 2022 ELN guidelines. High FLT3-ITD allelic ratio (≥0.5) at initial diagnosis was associated with elevated WBC counts ( P<0.001), but did not affect the response ratefollowing induction chemotherapy ( P=0.059) . Patients with high allelic ratio were more likely to benefit from maintenance therapy after transplantation ( P=0.048 for OS). In univariate analysis, presence of NPM1 mutation and the allelic ratio of FLT3-ITD did not affect any of the transplant outcomes. In multivariate analysis, MRD-negative at transplantation, occurrence of chronic GVHD and posttransplant maintenance therapy improved OS and RFS. Conclusion Allo-HSCT can overcome the poor prognosis in patients with FLT3-ITD mutated AML. Neither the presence of NPM1 mutation nor the FLT3-ITD allelic ratio affected survival. Prevention of disease relapse after transplantation remains a challenge. The main prognostic factors affecting transplant outcomes included pre-transplant MRD status and the application of maintenance therapy. Thus, introduction of FLT3 inhibitors as post-transplant maintenance therapy and the development of highly sensitive MRD assays will further reduce disease recurrence and improve survival.

Comparing the Efficacy and Safety of Venetoclax Combined with Decitabine Versus Conventional Chemotherapy As Induction Therapy for Young Adults with Newly Diagnosed Acute Myeloid Leukemia - Interim Analysis of a Multicenter, Randomized, Phase 2b Trial

Introduction: Venetoclax in combination with hypomethylating agents (HMAs) is a first-line induction regimen recommended by NCCN guidelines for older or unfit AML patients. In a phase 2 study (NCT04752527) from our group, venetoclax plus decitabine (VEN-DAC) resulted in a 93% of response rate in young adult patients with newly diagnosed (ND) ELN adverse-risk AML. Currently, there is a lack of data on the VEN-DAC regimen in ND young adults with favorable or intermediate risk AML who are fit for intensive chemotherapy. There are also no studies directly comparing the VEN-DAC regimen with intensive chemotherapy in patients with ND AML. Here, we report the results of an interim analysis of a multicenter, randomized, phase 2b trial (NCT05177731) , which explored the efficacy and safety of VEN-DAC versus intensive chemotherapy (idarubicin and cytarabine) in ND AML patients. Methods: Adult patients with newly diagnosed AML aged between 18 and 59 years were enrolled. The diagnosis was made according to the WHO 2016 criteria. Risk stratification was performed according to the 2017 ELN recommendations. Eligible patients were randomized in a 1:1 ratio to the VEN-DAC group (decitabine 20mg/m 2 on days 1-5 and venetoclax at an escalated dose of 100mg, 200mg and 400mg by day 28) or the IA-12 group (idarubicin 12mg/m 2 on days 1-3 and cytarabine 100mg/m 2 on days 1-7). Patients who did not respond to the treatment were allowed to receive another cycle of the original induction regimen. Intermediate-dose cytarabine (2g/m 2, q12h, days 1-3) were applied as consolidation therapy. The primary endpoint was the composite complete remission (CRc, including complete remission, CR and complete remission with incomplete hematologic recovery, CRi). The secondary endpoints included measurable residual disease (MRD) negative remission (defined as <1×10 -3 by flow cytometry), event-free survival (EFS) , overall survival (OS) and adverse events. Results: Since March, 2022, a total of 163 patients with AML were screened and 116 patients were randomized. Sixty patients received the VEN-DAC regimen and 55 patients received the IA-12 regimen. There were no differences in baseline characteristics between the two groups of patients (Table 1). Bythe cut-off date of July 11, 2023, a total of 102 patients have been evaluated, 55 in the VEN-DAC group and 47 in the IA-12 group. The overall CRc rate in the VEN-DAC group was 85.5%, which was comparable to that of the IA-12 group (78.7%, P=0.37). The MRD-negative CR rate in the VEN-DAC group was 67.3%, which was much higher than that in the IA-12 group (53.2%) ( P=0.147). According to univariate analysis, efficacy of the VEN-DAC regimen did not differ from that of the IA-12 regimen with respect to sex, age, initial bone marrow blast count, genetic risk category, and major molecular markers (Figure 1A). Notably, the CRc rate and MRD-negative CR rate were significantly higher in the VEN-DAC group than in the IA-12 group for intermediate-risk and adverse-risk patients, especially those with adverse risk ( P=0.031 for CRc, P=0.029 for MRD-negative CR) (Figure 1A). At median follow-ups of 7.8 months (range, 0.9-16.6), the EFS and OS were not reached in both groups. The median time for platelets to recovery to 20×10 9/L or above in the VEN-DAC group was 12 days after induction in the VEN-DAC group, which was shorter than that in the IA-12 group (21 days) ( P<0.01). In addition, patients in the VEN-DAC group required fewer platelet (5 U vs 7 U, P<0.01) and red blood cell infusions (3 U vs 5 U, P=0.023) during induction as compared with that in the IA-12 group. In addition, the incidence of grade 3 or higher febrile neutropenia (41.8% vs. 83.0%), infection (27.3% vs. 72.3%) and sepsis (5.5% vs. 31.9%) were all significantly lower in the VEN-DAC group than in the IA-12 group ( P<0.01) (Figure 1B). Conclusion: In newly diagnosed young AML patients, venetoclax in combination with decitabine as an induction regimen had comparable efficacy and a higher safety profile compared to IA-12 regimen. In particular, patients with adverse-risk AML showed higher and deeper remission rate in the venetoclax plus decitabine group as compared with the IA-12 group.

Use of Geriatric Assessment and Genetic Profiling to Personalize Selection of Intensive Versus Low Intensity Chemotherapy in Older Adults with Acute Myeloid Leukemia (AML): Final Results of a Phase II Trial

Introduction: Geriatric assessment can predict the risk of toxicities of chemotherapy in older adults. Genetic risk categories are associated with survival following intensive chemotherapy in AML. Integrating geriatric assessment for patient profiling and genetic profiling of leukemic cells represents an innovative precision medicine approach to personalize therapy selection in older adults with AML. We report final results of a pragmatic phase II trial using such strategy, aiming to reduce early mortality (NCT03226418). Methods: Patients ≥60 years with a new diagnosis of AML underwent geriatric assessment prior to initiation of treatment. Geriatric assessment of physical function, cognitive function and comorbidity burden were used to determine fitness for intensive chemotherapy (Table 1). Additional assessment included Karnofsky Performance Scale (KPS), Patient Health Questionnaire-9 (PHQ-9), and Mini Nutritional Assessment-Short Form (MNA). Genetic profiling for therapy selection relied on karyotyping and followed the 2017 European LeukemiaNet criteria. While available mutation test results were incorporated to risk stratify, the study did not require waiting for the results prior to therapy initiation, given an anticipated turnaround time of 1-2 weeks for mutation test results. Therapy selection followed the algorithm in Figure 1. Patients with good or intermediate-risk AML received intensive chemotherapy such as 7+3 +/- gemtuzumab or midostaurin if determined to be fit. Patients with high-risk AML received low-intensity chemotherapy such as a hypomethylating agent with or without venetoclax or novel drugs (based on timing of FDA approval of these drugs), or CPX 351 if they were fit and met the FDA-approved indications. Patients with organ dysfunction (e.g. creatinine ≥2 mg/dl) and those requiring chemotherapy for other malignancy were eligible for low-intensity chemotherapy. Chemotherapy could be administered in community oncology settings. Patients were followed for quality of life assessments, as well as functional and oncologic outcomes. Results: Between July 2017-October 2022, 75 patients were consented; 2 patients were considered screen failure. Baseline characteristics of 73 eligible patients included a median age of 69 years (range 60-87 years), 49% female, 92% white, and a median KPS of 80 (range 60-100). As presented in Table 1, most had ≥3 comorbidities (55%), impaired physical function measured by Short Physical Performance Battery (70% had a score of 9 or less) and impaired cognition measured by Montreal Cognitive Assessment (64% had a score of 25 or less). Genetic risk categories included adverse (62%), intermediate (22%), and good-risk AML (16%). Patients had one or more of the following mutations: TET2 (26%), NPM1 (22%), RUNX1 (19%), ASXL1 (19%), TP53 (19%), DNMT3A (16%), IDH2 (15%), IDH1 (11%), FLT3 ITD (10%), FLT3 TKD (10%), biallelic CEBPA (4%), EZH2 (2%). Seven patients (10%) received intensive chemotherapy; CPX 351 (n=4) or 7+3 based regimen (n=3). Other patients received low-intensity chemotherapy: azacitidine or decitabine and venetoclax (n=43, 59%), decitabine or azacitidine alone (n=18, 24%) prior to approval of venetoclax, and other (n=5, 7%). The median time from diagnosis to therapy initiation was 6 days and from enrollment to therapy initiation was 1 day (range 0-13). Mortality at 30 days from diagnosis was 6.8% (95% confidence interval, CI 3.0-15.1%) and at 90 days was 21.9% (95% CI 14.0-32.7%). Mortality compared favorably to an unmatched historical cohort of patients ≥60 years treated at our center between 2011-2016, where 30-day mortality was 30% (95% CI 22-40%) and 90-day was 41% (95% CI 32-52%) (Future Oncol. 2019;15:1989-95). Conclusions: Our model to personalize AML therapy selection represents an innovative approach to precision medicine that incorporates both geriatric assessment for patient profiling and genetic profiling of leukemia cells. Geriatric assessment demonstrated high frequency of impairment in objective physical and cognitive function. Patients were able to start therapy within a median of 1 day following enrollment. Pragmatic aspects of the trial included broad eligibility criteria and co-management of patients with community oncologists. The results from our final analysis appear promising with lower rates of early mortality compared to unmatched historical controls.

The brain structure, immunometabolic and genetic mechanisms underlying the association between lifestyle and depression

Lifestyle factors have been acknowledged to be modifiable targets that can be used to counter the increasing prevalence of depression. This study aims to investigate combining an extensive range of lifestyle factors, including alcohol consumption, diet, physical activity, sleep, smoking, sedentary behavior and social connection, that contribute to depression, and examine the underlying neurobiological mechanisms. Over nine years of follow-up, a multivariate Cox model was utilized on 287,282 participants from UK Biobank to demonstrate the protective roles of seven lifestyle factors and combined lifestyle score on depression. Combining genetic risk and lifestyle category in 197,344 participants, we found that a healthy lifestyle decreased the risk of depression across a population with varied genetic risk. Mendelian randomization confirmed the causal relationship between lifestyle and depression. A broad range of brain regions and peripheral biomarkers were related to lifestyle, including the pallidum, the precentral cortex, triglycerides and C-reactive protein. Structural equation modeling on 18,244 participants revealed underlying neurobiological mechanisms involving lifestyle, brain structure, immunometabolic function, genetics and depression. Together, our findings suggest that adherence to a healthy lifestyle could aid in the prevention of depression.

Education counteracts the genetic risk of Alzheimer's disease without an interaction effect.

Alzheimer's disease (AD) is a major cause of disability and mortality in older adults. This study aimed to investigate the association of AD with education and genetic factors. We conducted a prospective cohort study using data from the UK Biobank. Genetic risk was assessed using a polygenic risk score for AD. The educational level was categorized as either low, intermediate, or high. AD was defined using the International Classification of Diseases and Related Health Problems, 10th revision. Logistic regression models were used to investigate the independent and combined effects of genetic factors and educational levels on the risk of AD. We included 318,535 participants in this study (age: 56.53 ± 8.09 years; male: 44.81%). Compared with a low genetic risk, a high genetic risk was associated with a significantly greater risk of AD (OR = 7.09, 95% CI: 6.09-8.26). A high educational level was associated with a 30% lower risk of AD compared with a low educational level (OR = 0.70, 95% CI: 0.60-0.81). Combining genetic risk and education categories, individuals with a low genetic risk and high educational level had a more than 90% (OR = 0.09, 95% CI: 0.05-0.16) lower risk of AD compared to those with a high genetic risk and low educational level. There was no significant interaction between genetic risk and educational level regarding AD risk (p for interaction = 0.359). Education counteracts the genetic risk of AD, without an interaction effect. Increasing education to reduce the incidence of AD is of same importance across individuals with different genetic risk.

Long-term exposure to ambient air pollution, genetic susceptibility, and the incidence of bipolar disorder: A prospective cohort study

There is mounting recent evidence showing that air pollution exposure may be related to the risk of mental health, yet the association between long-term exposure to air pollution and the risk of incident bipolar disorder (BD) remains unclear. Thus we aim to identify associations between air pollution and the incidence of BD in a prospective population-based cohort. In total, 482,726 participants who were free of BD from the UK Biobank were included in this prospective study. We applied time-varying Cox proportional hazards models, accounting for relevant confounders, and used annual-year moving averages of air pollution as time-varying exposures. The genetic risk for BD was categorized into three categories (low, intermediate, and high) according to the tertiles of polygenic risk score. During a median of 10.79-year follow-up, 923 incident BD events were recorded. Long-term exposures to PM2.5, PM10, NO2, and NOx were associated with increased BD risk. Estimated HRs (95% CIs) for each interquartile range increase in PM2.5, PM10, NO2, and NOx concentrations were 1.31 (1.18–1.45), 1.19 (1.09–1.31), 1.19 (1.08–1.30), and 1.16 (1.07–1.26), respectively. Associations were still observed and even stronger at pollutant concentrations lower than WHO air quality guideline. In subgroup analysis stratified by genetic risk, we observed consistent associations between all pollutants and BD risk in intermediate and high genetic risk groups, but not in low genetic risk group. For example, the HRs (95% CIs) for PM2.5 were 1.00 (0.94–1.53), 1.30 (1.06–1.59), and 1.34 (1.16–1.54) in low, intermediate, and high genetic groups, respectively. In conclusion, long-term exposure to air pollution was significantly associated with an elevated risk of BD. Associations of air pollution with BD occurred only within intermediate and high genetic risk categories and were even stronger at the pollutants levels below WHO air quality guidelines. These findings could help inform policy makers regarding ambient air quality standards and BD management.

Association Between Glucosamine Use and the Risk of Incident Heart Failure: The UK Biobank Cohort Study and Mendelian Randomization Analysis

ObjectiveTo evaluate the association between regular glucosamine intake and heart failure (HF) and to explore whether the association is mediated by relevant cardiovascular disease. Patients and MethodsWe included 479,650 participants with data available for supplement use and without HF at baseline from the UK Biobank study. Using 12 single-nucleotide polymorphisms linked to HF, a weighted genetic risk score was calculated. We evaluated the association between glucosamine use and HF by Cox regression models after inverse probability of treatment weighting. A validation and mediation analysis were performed through two-sample Mendelian randomization. The study was from May 18, 2006, to February 16, 2018. ResultsDuring a median follow-up of 9.0 (IQR, 8.3-9.8) years, we documented 5501 incident cases of HF. In multivariable analysis, the HR of glucosamine users for HF was 0.87 (95% CI, 0.81 to 0.94). The inverse associations were stronger in males and participants with unfavorable lifestyle (P<.05 for interaction). Genetic risk categories did not modify this association (P>.05 for interaction). Multivariable Mendelian randomization showed that taking glucosamine was protective against HF (HR, 0.92; 95% CI, 0.87 to 0.96). The mediated proportion of coronary heart disease and stroke were 10.5% (95% CI, 7.6% to 13.4%) and 14.4% (95% CI, 10.8% to 18.0%), respectively. The two-mediator combination accounted for 22.7% (95% CI, 17.2% to 28.2%) of the effect of glucosamine use. ConclusionRegular glucosamine supplementation was associated with a lower risk of HF regardless of genetic risk status, and to a lesser extent, coronary heart disease and stroke mediated this effect. The results may inform novel pathway for prevention and intervention toward HF.

Lifestyle, Genetic Susceptibility, and the Risk of Idiopathic Pulmonary Fibrosis: A Large Prospective Cohort Study

Lifestyle is thought to be an important contributor of age-related chronic disease, but the association between lifestyle and the risk of idiopathic pulmonary fibrosis (IPF) remains unknown. Also, the extent to which genetic susceptibility modifies the effects of lifestyle on IPF remains unclear. Whether there is joint effect or interaction of lifestyle and genetic susceptibility on the risk of developing IPF? Our study included 407615 participants from the UK Biobank. We constructed a lifestyle score and a polygenic risk score (PRS) for each participant, separately. Participants were then classified into 3 lifestyle categories and 3 genetic risk categories based on the corresponding score. Cox models were fitted to assess the association of lifestyle and genetic risk with the risk of incident IPF. With favorable lifestyle as the reference group, intermediate lifestyle (hazard ratio (HR): 1.384, 95% confidence interval (CI): 1.218-1.574) and unfavorable lifestyle (HR: 2.271, 95% CI: 1.852-2.785) were significantly associated with increased risk of IPF. For the combined effect of lifestyle and PRS, participants with unfavorable lifestyle and high genetic risk had the highest risk of IPF (HR: 7.796, 95% CI: 5.482-11.086) compared to those with favorable lifestyle and low genetic risk. Moreover, approximately 32.7% (11.3%, 54.1%) of IPF risk could be attributed to the interaction of an unfavorable lifestyle and high genetic risk. Exposure to unfavorable lifestyle significantly increased the risk of IPF, particularly in those with high genetic risk.

Genetic risk, muscle strength and risk of incident major depressive disorder: results from the UK Biobank.

Genetic factors and muscle strength both contribute to the risk of major depressive disorder (MDD), but whether high muscle strength can offset the risk of MDD with different genetic risk is unknown. This study aims to examine whether a higher muscle strength is associated with lower risk of MDD regardless of genetic risk among middle-aged and older adults. This cohort study obtained data from the UK Biobank, which includes 345,621 individuals aged 40-69years (mean (standard deviation): 56.7 (7.99) years) without baseline MDD. Polygenic risk score for MDD was categorised as low, intermediate or high. The mean of the right- and left-hand grip strength values was used in the analysis and was divided into three categories. 9,753 individuals developed MDD within 2,752,461 person-years of follow-up. The multivariable adjusted hazard ratios (HRs) (95% confidence intervals (CIs)) of MDD across increased grip strength categories were 1.00, 0.72 (0.68-0.75) and 0.56 (0.53-0.59) (P for trend <0.0001). The HRs (95% CIs) of incident MDD across the genetic risk categories were 1.00, 1.11 (1.05-1.17) and 1.20 (1.13-1.28) (P for trend <0.0001); 4.07% of individuals with a high genetic risk and low grip strength developed MDD, and 1.72% of individuals with a low genetic risk and high grip strength developed MDD, with an HR (95% CI) of 0.44 (0.39-0.50). Both muscle strength and genetic risk were significantly associated with incident MDD. A higher muscle strength was associated with a lower MDD risk among individuals with a high genetic risk. Improving muscle strength should be encouraged for all individuals, including individuals with high genetic risk for MDD.

Effect of genetic polymorphisms on outcomes following nivolumab for advanced renal cell carcinoma in the SNiP-RCC trial.

Anti-PD-1 antibodies are widely used for cancer treatment including advanced renal cell carcinoma (RCC). However, their therapeutic and adverse effects vary among patients. This study aimed to identify genetic markers that predict outcome after nivolumab anti-PD-1 antibody treatment for advanced RCC. This study was registered on the website of the University Hospital Medical Information Network (protocol ID, UMIN000037739). Patient enrollment was conducted at 23 institutions in Japan between August 19, 2019, and September 30, 2020. Patient follow-up ended on March 31, 2021. Patients were treated with nivolumab for advanced clear cell RCC. A genome-wide association study was performed in the development set, while genotyping of target regions in the validation set was undertaken. Single nucleotide polymorphisms (SNPs) in genes of interest CD274, PDCD1LG2 and PDCD1 were genotyped in the combined set. The primary endpoint was the association of SNPs with objective response following nivolumab treatment. As secondary endpoints, the associations of SNPs with radiographic progression-free survival (rPFS) and treatment-related grade ≥ 3 adverse events (AEs) were evaluated. A genome-wide association study followed by a validation study identified that SNPs in FARP1 (rs643896 and rs685736) were associated with objective response and rPFS but not AEs following nivolumab treatment. Furthermore, SNPs in PDCD1LG2 (rs822339 and rs1411262) were associated with objective response, rPFS, and AEs following nivolumab treatment. Genetic risk category determined according to the number of risk alleles in SNPs (rs643896 in FARP1 and rs4527932 in PDCD1LG2) excellently predicted objective response and rPFS in nivolumab treatment. This study revealed that SNPs in FARP1 and PDCD1LG2 were correlated with outcome in nivolumab treatment. The use of these SNPs may be beneficial in selecting appropriate treatment for individual patients and may contribute to personalized medicine.

The Contribution of Genetic Risk and Lifestyle Factors in the Development of Adult-Onset Inflammatory Bowel Disease: A Prospective Cohort Study.

The joint associations across genetic risk, modifiable lifestyle factors, and inflammatory bowel disease (IBD) remains unclear. Genetic susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) was estimated by polygenic risk scores and further categorized into high, intermediate, and low genetic risk categories. Weighted healthy lifestyle scores were constructed based on 5 common lifestyle factors and categorized into favorable (4 or 5 healthy lifestyle factors), intermediate (3 healthy lifestyle factors), and unfavorable (0-2 healthy lifestyle factors) groups. Cox proportional hazards regression model was used to estimate the hazard ratios (HR) and 95% confidence interval (CI) for their associations. During the 12-year follow-up, 707 cases with CD and 1576 cases with UC were diagnosed in the UK Biobank cohort. Genetic risk and unhealthy lifestyle categories were monotonically associated with CD and UC risk with no multiplicative interaction between them. The HR of CD and UC were 2.24 (95% CI 1.75-2.86) and 2.15 (95% CI 1.82-2.53) for those with a high genetic risk, respectively. The HR of CD and UC for individuals with an unfavorable lifestyle were 1.94 (95% CI 1.61-2.33) and 1.98 (95% CI 1.73-2.27), respectively. The HR of individuals with a high genetic risk but a favorable lifestyle (2.33, 95% CI 1.58-3.44 for CD, and 2.05, 95% CI 1.58-2.66 for UC) were reduced nearly by half, compared with those with a high genetic risk but an unfavorable lifestyle (4.40, 95% CI 2.91-6.66 for CD and 4.44, 95% CI 3.34-5.91 for UC). Genetic and lifestyle factors were independently associated with susceptibility to incident CD and UC. Adherence to a favorable lifestyle was associated with a nearly 50% lower risk of CD and UC among participants at a high genetic risk.

Genetic Predisposition, Fruit Intake and Incident Stroke: A Prospective Chinese Cohort Study.

The aim of this study was to evaluate the association between fruit intake and stroke risk considering the genetic predisposition. We used data from 34,871 participants from the project of Prediction for Atherosclerotic Cardiovascular Disease Risk in China (China-PAR project) from 2007 to 2020. A polygenic risk score comprising 534 genetic variants associated with stroke and its related factors was constructed to categorize individuals into low, intermediate, and high genetic risk groups. The associations of genetic and fruit intake with incident stroke were assessed by the Cox proportional hazard regression. We documented 2586 incident strokes during a median follow-up of 11.2 years. Compared with fruit intake < 200 g/week, similar relative risk reductions in stroke with adherence to fruit intake > 100 g/day across the genetic risk categories were observed (28−32%), but the absolute risk reductions were relatively larger in the highest genetic risk group (p for trend = 0.03). In comparison to those with a fruit intake < 200 g/week, those with a fruit intake >100 g/day in the low, intermediate, and high genetic risk groups had an average of 1.45 (95% CI, 0.61−2.31), 2.12 (1.63−2.59), and 2.19 (1.13−3.22) additional stroke-free years at aged 35, respectively. Our findings suggest that individuals with a high genetic risk could gain more absolute risk reductions and stroke-free years than those with a low genetic risk from increasing fruit intake for the stroke primary prevention.

Abstract 12593: Type 2 Diabetes Mellitus Polygenic Score Predicts New Onset Diabetes in Patients With Established Atherosclerotic Cardiovascular Disease: A FOURIER Sub-Study

Introduction: Polygenic scores (PS) have been created to predict the risk of developing type 2 diabetes (T2D). We tested whether a contemporary T2D PS predicts new-onset T2D in individuals with established atherosclerotic cardiovascular disease (ACSVD) and across a range of HbA1c and BMI levels. Methods: We analyzed individuals without T2D at baseline with available genotyping data from the FOURIER trial. Genetic risk was characterized using a PS for T2D based on 554 previously identified genome-wide significant single nucleotide polymorphisms. PS was analyzed continuously and categorized as high (top 20%) vs. low (bottom 80%). New-onset T2D was pre-specified and adjudicated centrally according to the American Diabetes Association definitions. HRs were calculated and adjusted for baseline age, sex, BMI, HbA1c, SBP, DBP, HDL-C, and triglycerides. Results: The 9115 participants in this study had mean age of 63±9 yrs and 22.5% were women. Mean HbA1c and BMI were 5.6±0.4% and 28.7±5 kg/m 2 , respectively. A total of 641 new-onset diabetes cases occurred over a median of 2.3 years of follow up. T2D PS significantly predicted new-onset T2D (adjusted HR per 1-SD increase 1.13 95% CI 1.04-1.23, P=0.006). The rates of new-onset T2D in the high and low genetic risk categories were 10.8% vs. 6.6 %, respectively (adjusted HR 1.41 95% CI 1.18-1.69, P&lt;0.001, Panel A). The predictive strength of high genetic risk for T2D appeared strongest in those without key clinical risk factors, namely, those without pre-diabetes [HR 2.01 (1.03-3.89); Panel B] and those with normal weight [HR 2.77 (1.65-4.66); Panel C]. There was no treatment interaction with evolocumab for new-onset T2D. Conclusions: Within a relatively short follow up, we found that a contemporary T2D PS strongly predicted new-onset T2D in patients with established ASCVD. This genetic risk appeared more discriminatory in those lacking traditional clinical risk factors.

Genetic risk, incident colorectal cancer, and the benefits of adhering to a healthy lifestyle: A prospective study using data from UK Biobank and FinnGen.

BackgroundGenetic factors increase the individual risk of colorectal cancer (CRC); however, the extent to which a healthy lifestyle can offset increased genetic risk is unknown. This study investigated whether a healthy lifestyle is associated with lower CRC risk, regardless of genetic risk.MethodsWe recruited 390,365 participants without cancer at baseline (2006–2010) from the UK Biobank. The primary outcome was CRC incidence. A healthy lifestyle score constructed using 16 factors of six dimensions (smoking, drinking, body mass index, diet, exercise, and sleep) was categorized into three risk categories: favorable, intermediate, and unfavorable. To calculate the polygenic risk scores (PRSs) of UK Biobank participants, we extracted 454,678 single nucleotide polymorphisms (SNPs) from the UK Biobank and FinnGen Biobank after quality control. Cox proportional hazards regression was performed to evaluate the associations and was expressed as hazard ratios (HRs) with 95% confidence intervals (CIs).ResultsDuring a median follow-up of 10.90 years, 4,090 new CRC cases were reported in the UK Biobank. The “best-fit” PRSs were constructed using 59 SNPs based on the UK Biobank cohort and FinnGen genome-wide association study summary data (R2 = 0.23%) and were divided into low (lowest quintile), intermediate (including second–fourth quintile), and high (highest quintile) genetic risk categories. The multivariate-adjusted Cox model revealed that participants with favorable lifestyles had HRs of 0.66 (95% CI = 0.60–0.72) for developing CRC vs. those with unfavorable lifestyles; low genetic risk was associated with a decreased risk of CRC (HR = 0.67, 95% CI =0.61–0.74) compared with those with high genetic risk. The HRs for low genetic risk participants with favorable lifestyles were 0.44 (95% CI =0.36–0.55) vs. participants with high genetic risk and unfavorable lifestyles. Among the participants with low, intermediate, or high genetic risk, the HRs of favorable vs. unfavorable lifestyles were 0.74, 0.64, and 0.72 (all p< 0.05).ConclusionsLow genetic risk and a favorable lifestyle were significantly associated with a decreased risk of CRC. A favorable lifestyle was associated with a lower CRC risk, regardless of genetic risk.

Association of Lifestyle With Incidence of Heart Failure According to Metabolic and Genetic Risk Status: A Population-Based Prospective Study.

Whether lifestyle factors are similarly associated with risk of heart failure (HF) for individuals with different metabolic or genetic risk status remains unclear. We included 464 483 participants from UK Biobank who were free of major cardiovascular disease or HF during baseline recruitment. Healthy lifestyle factors included avoidance of smoking, no obesity, regular physical activity, and healthy diet. Lifestyle was categorized as favorable (3 or 4 healthy lifestyle factors), intermediate (2 healthy lifestyle factors), and unfavorable (0 or 1 healthy lifestyle factor) lifestyles. Metabolic status was defined by the presence of hypertension, high total cholesterol, or diabetes at baseline. A weighted genetic risk score was created based on 12 single-nucleotide polymorphisms associated with HF. Compared with favorable lifestyle, the multivariable-adjusted hazard ratios of HF were 1.79 (95% CI, 1.68-1.90) and 2.90 (95% CI, 2.70-3.11) for intermediate lifestyle and unfavorable lifestyle, respectively (Ptrend <0.0001). This association was largely consistent regardless of the presence of any single metabolic risk factor or the number of metabolic risk factors (Pinteraction ≥0.21). The association was also similar across different genetic risk categories (Pinteraction=0.92). In a joint analysis, the hazard ratio of HF was 4.05 (95% CI, 3.43-4.77) comparing participants who had both higher genetic risk and an unfavorable lifestyle with those having lower genetic risk and a favorable lifestyle. Combined lifestyle was associated with incident HF regardless of metabolic or genetic risk status, supporting the recommendation of healthy lifestyles for HF prevention across the entire population.

Multiple Myeloma Immunophenotype Related to Chromosomal Abnormalities Used in Risk Assessment.

(1) Background: At diagnosis, multiplemyeloma risk estimation includes disease burden, end-organ damage, and biomarkers, with increasing emphasis on genetic abnormalities. Multicolor flow cytometry (MFC) is not always considered in risk estimation. We demonstrate associations found between genetic abnormalities and antigen expression of plasma cells measured by MFC. (2) Methods: Single nucleotide polymorphism microarray (SNP-A) karyotyping as well as MFC using standardized next-generation flow (NGF) panels and instrument settings were performed from bone marrow aspirates at the time of diagnosis. (3) Results: We uncovered specific immunophenotype features related to different genetic risk factors. Specifically, we found higher malignant/normal plasma cell ratio and lower expression of CD27, CD38, CD45, CD56, CD117 and CD138 in higher-risk genetic groups or risk categories.