Inherited Genetic Risk of Liver Fibrosis in Lean Versus Nonlean Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).

We hypothesized that subjects with genetic variants that increase sweet taste preference would consume more sucrose‐containing foods and have altered energy and glucose metabolisms, which would have interactions with lifestyles. Korean genome and epidemiology study (KoGES) was conducted to determine genetic variants and lifestyles including nutrient intakes by the Korean Center for Disease and Control during 2004–2013. Subjects were 8,842 adults aged 40–69 years in Ansan/Ansung cohorts in Korea. The associations between genetic risk scores(GRS) selected for influencing higher sweet preference and energy and glucose metabolism were examined using logistic regression after adjusting for covariates. GRS included 8 SNPs, TAS1R2_rs61761364, SLC2A5_rs11121306, SLC2A7_ rs769902, SLC2A5_rs765618, TRPM5_rs1965606, TRPV1_rs224495, TRPV1_ rs8065080, and TRPV1_rs8078502. Sweet taste preference was higher by 1.30‐folds in high GRS than in low GRS (p < .0001). Consistent with sweet taste preference, carriers with high GRS had a higher intake of sucrose‐containing foods by 1.25 (1.08–1.46)‐fold than those with low GRS after adjusting age, gender, BMI, and energy intake. However, glucose intolerance risk was rather lower by 0.861 (0.76–0.98)‐fold in high GRS than low GRS (p < .05). GRS tended to interact with mental stress to affect sucrose intake (p = .048). Only in low mental stress levels, sucrose‐containing food intake was higher in high GRS than low GRS. There was an interaction of GRS with physical activity to influence glucose intolerance. Serum glucose concentrations were lower by 0.808‐folds in high GRS than low GRS only in a high physical activity state. In conclusion, adults with genetically high sweet taste preference had a positive association with high sucrose‐containing food intakes and improved glucose tolerance. The genetic impact on sweetness preference was associated with offset by high mental stress and lack of physical activity.

MP69-12 ADDED VALUE OF GENETIC RISK SCORE TO THE PROSTATE CANCER PREVENTION TRIAL (PCPT) RISK CALCULATOR: FINDINGS FROM THE PCPT STUDY

Associations between maternal genetic risk for obesity and fetal weight were examined at the end of the first (13 weeks 6 days), second (27 weeks 6 days), and third (40 weeks 0 days) trimesters of pregnancy among four race/ethnic groups in the US. For 603 white, 591 black, 535 Hispanic, and 216 Asian women, maternal genetic risk score (GRS) was calculated as the sum of 189 BMI-increasing alleles and was categorized into high or low GRS. Associations between GRS (continuous and categorical) and estimated fetal weight were tested overall and stratified by prepregnancy BMI, gestational weight gain (GWG), and fetal sex. High GRS compared with low GRS was associated with increased fetal weight at the end of the second (β: 22.7 g; 95% CI: 2.4-43.1; P = 0.03) and third trimesters (β: 88.3 g; 95% CI: 9.0-167.6; P = 0.03) among Hispanic women. The effect of GRS was stronger among Hispanic women with normal prepregnancy weight, adequate first trimester GWG, or inadequate second trimester GWG (P < 0.05). Among Asian women, high GRS was associated with increased weight among male fetuses but decreased weight among female fetuses (P < 0.05). Maternal obesity genetic risk was associated with fetal weight with potential effect modifications by maternal prepregnancy BMI, GWG, and fetal sex.

High inherited risk predicts age-associated increases in fibrosis in patients with MASLD.

The objective of this study was to evaluate long-term cardiovascular mortality according to the genetic risk score in a Southern European population with CAD. A cohort of 1464 CAD patients with angiographic proven CAD were followed up prospectively for up to 58.3 (interquartile range: 25.8-88.1) months. Genotyping of 32 single-nucleotide polymorphisms previously associated with CAD was performed using oligonucleotides probes marked with fluorescence for each allele. GRS was constructed according to the additive model assuming codominance and categorised using the median (=26). Cox Regression analysis was performed to determine independent multivariate predictors of cardiovascular mortality. Kaplan-Meier survival curves compared high vs low GRS using log-rank test. C-index was done for our population, as a measure of discrimination in survival analysis model. During a mean follow-up of 58.3months, 156 patients (10.7%) died, 107 (7.3%) of CV causes. High GRS (≥26) was associated with reduced cardiovascular survival. Survival analysis with Cox regression model adjusted for 8 variables showed that high GRS, dyslipidemia, diabetes and 3-vessel disease were independent risk factors for cardiovascular mortality (HR=1.53, P=.037; HR=3.64, P=.012; HR=1.75, P=.004; HR=2.97, P<.0001, respectively). At the end of follow-up, the estimated survival probability was 70.8% for high GRS and 80.8% for low GRS (Log-rank test 5.6; P=.018). C-Index of 0.71 was found when GRS was added to a multivariate survival model of diabetes, dyslipidemia, smoking, hypertension and 3 vessel disease, stable angina and dual antiplatelet therapy. Besides the classical risk factors management, this work highlights the relevance of the genetic profile in survival from CAD. It is expected that new therapies will be dirsected to gene targets with proven value in cardiovascular survival.

Cardiometabolic traits are complex interrelated traits that result from a combination of genetic and lifestyle factors. This study aimed to assess the interaction between genetic variants and dietary macronutrient intake on cardiometabolic traits [body mass index, waist circumference, total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, triacylglycerol, systolic blood pressure, diastolic blood pressure, fasting serum glucose, fasting serum insulin, and glycated haemoglobin]. This cross-sectional study consisted of 468 urban young adults aged 20±1 years, and it was conducted as part of the Study of Obesity, Nutrition, Genes and Social factors (SONGS) project, a sub-study of the Young Lives study. Thirty-nine single nucleotide polymorphisms (SNPs) known to be associated with cardiometabolic traits at a genome-wide significance level (P<5×10-8) were used to construct a genetic risk score (GRS). There were no significant associations between the GRS and any of the cardiometabolic traits. However, a significant interaction was observed between the GRS and carbohydrate intake on HDL-C concentration (Pinteraction=0.0007). In the first tertile of carbohydrate intake (≤327g/day), participants with a high GRS (>37 risk alleles) had a higher concentration of HDL-C than those with a low GRS (≤37 risk alleles) [Beta=0.06mmol/L, 95% confidence interval (CI), 0.01-0.10; P=0.018]. In the third tertile of carbohydrate intake (>452g/day), participants with a high GRS had a lower concentration of HDL-C than those with a low GRS (Beta=-0.04mmol/L, 95% CI -0.01 to-0.09; P=0.027). A significant interaction was also observed between the GRS and glycaemic load (GL) on the concentration of HDL-C (Pinteraction=0.002). For participants with a high GRS, there were lower concentrations of HDL-C across tertiles of GL (Ptrend=0.017). There was no significant interaction between the GRS and glycaemic index on the concentration of HDL-C, and none of the other GRS∗macronutrient interactions were significant. Our results suggest that young adults who consume a higher carbohydrate diet and have a higher GRS have a lower HDL-C concentration, which in turn is linked to cardiovascular diseases, and indicate that personalised nutrition strategies targeting a reduction in carbohydrate intake might be beneficial for these individuals.

> It is not in the stars to hold our destiny but in ourselves > > —William Shakespeare The widespread availability and lower costs of genotyping and sequencing have resulted in the performance of a large number of genotype–phenotype association studies in cardiovascular medicine. The stringent requirements for correction for multiple testing and replication have particularly favored genotype–phenotype studies examining the association between genetic variation and quantitative traits that allows for greater statistical power. Multiple genome-wide association studies and a subsequent meta-analysis have identified >180 common and rare genetic variants associated with lipid traits.1,2 However, the effect size of these individual genetic variants is small, explaining only a small fraction of phenotypic variation prompting investigators to use genetic risk scores (GRS) that represent an aggregate of genetic risk to demonstrate clinical utility. Single-nucleotide polymorphisms (SNPs) and GRS have been used to predict cardiovascular disease such as coronary artery disease (CAD) and hypertension, surrogate markers of disease such as coronary calcium, cardiovascular outcomes such as myocardial infarction, and intermediate traits such as blood pressure and lipids.3 Article, see p 495 The Global Lipids Genetics Consortium has performed the largest genetic association study of lipid levels in 188 577 individuals from a total of 60 studies.1,2 There were 157 genetic loci that were identified, 95 were described previously and 62 were novel. The lipid level variance explained by the novel loci in this study ranged from 1.6% for high-density lipoprotein cholesterol (HDL-C) levels to 2.6% for total cholesterol levels. The total lipid variance explained by the previously described loci was 10% to 12%. The population studied was predominantly of European ancestry, and subjects on lipid-lowering therapy were excluded. The association of these genetic loci with lipid levels and a change in lipid levels with intervention in a prediabetic population …

Disclosure: N. Nguyen: None. H. Fan: None. Y. Chen: None. Context: The evidence regarding effects of different lifestyle pratices, such as sun bathing, exercising, rope jumping, sleep duration, and milk intake, on growth velocity remain controversial and the influence of genetically determined characteristics on this association is less studied. Objective: To assess the impacts of different lifestyle pratices on annualized growth velocity and evaluate the role of several combined height-related alleles, mirrorred by the genetic risk score, on the association between lifestyle practices and growth among adolescents. Design: Prospective cohort study (mean follow-up duration: 2 years) Setting: Primary Care Participants: The Taiwan Puberty Longitudinal Study cohort, including male and female adolescent aged 6-17 (N = 1036) who were examined at both baseline and follow-up clinic visits. Main Outcome Measures: The effects of regular lifestyle practices (sun soaking, exercise habit, jumping rope, milk intake and sleep duration) on changes in height measurements. Participants will be stratified by either low or high genetic risk score. Results: Among lifestyle practices, sleep duration was significantly associated with growth velocity. Sleeping hours ranging between 7-8 hours per night were linked with a greatest growth. This relation was mainly driven by differences in males and was more obvious during Tanner’s stage II-III. The positive association between sleep duration and growth velocity was driven by significance in participants with low genetic risk score but not in those with high genetic risk score. Meanwhile, milk intake of greater than or equal to one cup per day had a modest effect on height velocity in male during Tanner’s stage I. Conclusions: Sleep duration was associated with growth velocity, in which 7-8 hours per night was optimal. The benefit of adequate sleep was greater in individuals having low genetic risk score. Milk intake may have modest effect on growth velocity. Presentation: Thursday, June 15, 2023

Introduction and Objective: Identifying risk of diabetes complications at diabetes onset is vital to a precision medicine approach to managing diabetes. A genetic risk score (GRS) could do this decades before positive biochemical tests. Therefore, we developed a novel GRS for predicting diabetic kidney disease (DKD), assessed its performance and analyzed clinical differences between genetic risk groups. Methods: The GRS was developed with data from &amp;gt;2000 subjects. Its performance was tested on 429 adults with type 1 or type 2 diabetes attending a tertiary hospital. Cases were those with eGFR &amp;lt;30 mL/min. Controls had diabetes for &amp;gt;10 years and eGFR &amp;gt;60 mL/min. Clinical differences between GRS groups were tested with sample t-test, Fisher’s exact or Chi2 test, as appropriate. Results: People with a high GRS had an OR of 9.40 for developing DKD (95% CI 5.78-17.57, p&amp;lt;0.0001). Those with low GRS and DKD were more likely to have a history of smoking, dyslipidaemia, hypertension, and other diabetes complications. Those with high GRS and DKD were also more likely to have other diabetes complications including cardiovascular disease. This group developed DKD more rapidly than those with low GRS and DKD. There were no statistically significant differences in HbA1c, BMI and duration of diabetes between those with and without DKD, in either risk group. A lower HbA1c throughout follow up did not affect progression to DKD. Conclusion: The GRS performed well in identifying risk of DKD. It also identified those with high risk of other diabetes complications. Disclosure A. Ali: None. K. Kishore: None. S. Golub: None. G. Morahan: Stock/Shareholder; Advanced Genetic Diagnostics. E.I. Ekinci: Research Support; Amgen Inc, Novo Nordisk, Lilly Diabetes, AstraZeneca, Endogenex, Versanis. Advisory Panel; Lilly Diabetes, Novo Nordisk. Funding Diabetes Australia Research Grant (Y22G-ALIA)

BackgroundThe second-and third-generation drug-eluting stents (DESs) in-stent restenosis (ISR) genetic risk score (GRS) model has been previously validated. However, the model has not been validated in geriatric patients. Therefore, we conducted this study to test the feasibility of the DES-ISR GRS model in geriatric patients with coronary artery disease (CAD) in Taiwan.MethodsWe conducted a retrospective, single-center cohort study and included geriatric patients (age ≥ 65 years) with CAD and second-or third-generation DES(s) deployment. Patients undergoing maintenance dialysis were excluded. ISR was defined as ≥ 50% luminal narrowing on the follow-up coronary arteriography. The DES-ISR GRS model included five selected exonic single-nucleotide polymorphisms (SNPs): CAMLG, GALNT2, C11orf84, THOC5, and SAMD11. The GRS was defined as the sum of the five selected SNPs for the risk allele.ResultsWe enrolled 298 geriatric patients from January 2010 and December 2019 in this study. After propensity score matching, there were 192 geriatric patients with CAD in the final analysis, of which 32 patients had ISR. Patients were divided into two groups based on their GRS values: low (0–2) and high (≥ 3) GRS. A high GRS was significantly associated with DES-ISR in geriatric patients.ConclusionThose geriatric patients with a high GRS had significantly higher second-or third-generation DES ISR rates. The five SNP-derived DES-ISR GRS model could provide genetic information for interventional cardiologists to treat geriatric patients with CAD.Trial registrationThe primary study protocol was registered with clinicaltrials.org. with registration number: NCT03877614; on March 15, 2019. (http://clinicaltrials.gov/ct2/show/NCT03877614)

Prostate cancer (PCa) is a highly heritable disease with large disparities in incidence rates across racial and ethnic populations. The inadequate representation of diverse populations in current genome-wide association studies (GWAS) limits the translational potential of findings to the world's populations and could result in biased risk prediction, further exacerbating health disparities. To improve our understanding of genetic risk of PCa, we conducted the largest multiethnic PCa GWAS meta-analysis to date with 107,247 cases and 127,006 controls from the Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome (PRACTICAL) consortium, including 85,554 cases and 91,972 controls of European ancestry, 10,368 cases and 10,986 controls of African ancestry, 8,611 cases and 18,809 controls of Asian ancestry, and 2,714 cases and 5,239 controls of Hispanic ethnicity. We identified 269 genetic risk variants independently associated with PCa risk, 86 of which were novel. Of the 183 previously reported prostate cancer risk variants, we identified stronger markers of risk for 62 variants using fine-mapping. To understand the aggregate effect of the 269 variants, we constructed a genetic risk score (GRS) using the multiethnic weights of the risk variants. Compared to men in the average 40-60% GRS category, the estimated OR for men in the top GRS decile (90-100%) was 5.06 [95% CI 4.84-5.29] for men of European ancestry, 3.74 [95% CI 3.36-4.17] for men of African ancestry, 4.47 [95% CI 3.52-5.68] for men of Asian ancestry, and 4.15 [95% CI 3.33-5.17] for Hispanic men. Men of African ancestry were estimated to have a 2.18-times higher mean GRS [95% CI 2.14-2.22], and men of Asian ancestry 0.73-times lower [95% CI 0.71-0.76], than men of European ancestry. Age significantly modified the GRS association with PCa risk, such that in men of European ancestry, the top decile GRS category was associated with an OR of 6.71 [95 % CI 5.99-7.52] for men ages 55 years or younger and 4.39 [95% CI 4.19-4.60] for men older than 55 years. Similarly, in men of African ancestry, the top GRS decile category was associated with an OR of 4.70 [95 % CI 3.65-6.07] for men ages 55 years or younger and 3.37 [95% CI 2.99-3.80] for men older than 55 years. We found that 51% of aggressive cases of European ancestry and 45% of aggressive cases of African ancestry were within the top 20% of the GRS. The lifetime absolute risk of PCa for men in the top decile of the GRS reached 38% for both African Americans [95% CI 36-41%] and Whites [95% CI 37-39%], 31% [95% CI 27-36%] for Hispanics and 26% [95% CI 22-30%] for Asians. For comparison, we constructed a genome-wide GRS, including the 269 variants and variants associated with PCa with P&amp;lt;1.0 × 10−5. ORs calculated with genome-wide GRS were similar and had nearly identical discriminative ability as the 269 GRS in independent samples of 6,852 cases and 193,117 controls of European ancestry and 1,586 cases and 1,047 controls of African ancestry. This suggests that a genome-wide GRS may not have improved ability to predict PCa risk compared to the 269 GRS. To understand the biological mechanisms impacted by genetic risk of PCa, we conducted integrative analyses of the GRS and serum metabolomics in 611 African ancestry men from the Multiethnic Cohort. We found that a higher GRS was associated with lower sphingolipid levels (beta=-0.08, P=3.1 × 10−4), lower androgenic steroids (beta=-0.06, P=0.003), and higher sarcosine levels (beta=0.11, P=0.002). Further, using a latent clustering approach, we found that these metabolites in conjunction with the GRS contributed to the clustering of men with low-risk, intermediate-risk, and high-risk of PCa. These findings support the role of germline variation contributing to racial and ethnic disparities in PCa risk, with the GRS offering an approach for personalized risk prediction across populations and informing the biological mechanisms underlying PCa risk. Citation Format: Burcu F. Darst, Lilit Moss, Edward J. Saunders, Nicholas Mancuso, Xin Sheng, Alisha Chou, Tokhir Dadaev, Sonja I. Berndt, Stephen K. Van Den Eeden, Stephen J. Chanock, Michael B. Cook, Tracy M. Layne, Demetrius Albanes, Hidewaki Nakagawa, John S. Witte, Practical Consortium, Rosalind A. Eeles, Zsofia Kote-Jarai, David V. Conti, Christopher A. Haiman. Multiethnic prostate cancer GWAS meta-analysis identifies novel variants, improves genetic risk prediction across populations, and informs biological mechanisms of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr NG03.

Few studies have evaluated the association between a single-nucleotide polymorphism-based genetic risk score (GRS) and patient age at prostate cancer (PCa) diagnosis. To test the association between a GRS and patient age at PCa diagnosis and to compare the performance of a GRS with that of family history (FH) in PCa risk stratification. A cohort study of 3225 white men was conducted as a secondary analysis of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) chemoprevention trial, a 4-year, randomized, double-blind, placebo-controlled multicenter study conducted from March 2003 to April 2009 to evaluate the safety and efficacy of dutasteride in reducing PCa events. Participants were confirmed to be cancer free by prostate biopsy (6-12 cores) within 6 months prior to the study and underwent 10 core biopsies every 2 years per protocol. The dates for performing data analysis were from July 2016 to October 2019. A well-established, population-standardized GRS was calculated for each participant based on 110 known PCa risk-associated single-nucleotide polymorphisms, which is a relative risk compared with the general population. Men were classified into 3 GRS risk groups based on predetermined cutoff values: low (<0.50), average (0.50-1.49), and high (≥1.50). Prostate cancer diagnosis-free survival among men of different risk groups. Among 3225 men (median age, 63 years [interquartile range, 58-67 years]) in the study, 683 (21%) were classified as low risk, 1937 (60%) as average risk, and 605 (19%) as high risk based on GRS alone. In comparison, 2789 (86%) were classified as low or average risk and 436 (14%) as high risk based on FH alone. Men in higher GRS risk groups had a PCa diagnosis-free survival rate that was worse than that of those in the lower GRS risk group (χ2 = 53.3; P < .001 for trend) and in participants with a negative FH of PCa (χ2 = 45.5; P < .001 for trend). Combining GRS and FH further stratified overall genetic risk, indicating that 957 men (30%) were at high genetic risk (either high GRS or positive FH), 1667 men (52%) were at average genetic risk (average GRS and negative FH), and 601 men (19%) were at low genetic risk (low GRS and negative FH). The median PCa diagnosis-free survival was 74 years (95% CI, 73-75 years) for men at high genetic risk, 77 years (95% CI, 75 to >80 years) for men at average genetic risk, and more than 80 years (95% CI, >80 to >80 years) for men at low genetic risk. In contrast, the median PCa diagnosis-free survival was 73 years (95% CI, 71-76 years) for men with a positive FH and 77 years (95% CI, 76-79 years) for men with a negative FH. This study suggests that a GRS is significantly associated with patient age at PCa diagnosis. Combining FH and GRS may better stratify inherited risk than FH alone for developing personalized PCa screening strategies.

Genome-wide association studies identified single nucleotide polymorphisms (SNPs) associated with body mass index (BMI) in middle-aged populations; however, it is unclear whether these SNPs are associated with body fatness in elderly people. We examined the association between genetic risk score (GRS) from BMI-associated SNPs and body fatness in elderly Japanese men. We also examined the contribution of GRS, dietary macronutrient intake, and physical activity to body fatness by different age groups. GRS was calculated from 10 BMI-associated SNPs in 84 middle-aged (30-64years) and 97 elderly (65-79years) Japanese men; subjects were divided into low, middle, and high GRS groups. Dietary macronutrient intake was assessed using a questionnaire, and physical activity was evaluated using both a questionnaire and an accelerometer. The middle-aged individuals with a high GRS had greater BMI; waist circumference; and total abdominal fat, visceral fat, and subcutaneous fat areas than the middle-aged individuals with low GRS, whereas the indicators were not different between the GRS groups in elderly individuals. Multiple linear regression analysis showed that GRS was the strongest predictor of BMI, total abdominal fat, and visceral fat in the middle-aged group, whereas fat, alcohol, and protein intakes or vigorous-intensity physical activity were more strongly associated with these indicators than was GRS in the elderly group. These results suggest that GRS from BMI-associated SNPs is not predictive of body fatness in elderly Japanese men. The stronger contribution of dietary macronutrient intake and physical activity to body fatness may attenuate the genetic predisposition in elderly men.

Genetic risk score correlates with immune profile and risk of HCC and cirrhosis development in Hispanics with MASLD

BackgroundInflammation is not only involved in the development and progression of cancer but also affects the response to therapy. The aim of this study was to investigate the association of single nucleotide polymorphisms (SNPs) in inflammation genes with the prognosis of advanced non-small cell lung cancer (NSCLC) patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs).MethodsForty-seven SNPs were genotyped in 318 advanced NSCLC patients receiving EGFR-TKIs. Of 318 patients, 182 (57.2%) patients died during follow-up period. We assessed the association of SNPs with the progression-free survival (PFS) and overall survival (OS) as well as calculated the weighted genetic risk score (GRS). We also explored the expression levels and prognostic values of inflammation genes in lung adenocarcinoma (LUAD) in Gene Expression Profiling Interactive Analysis (GEPIA) and using UCSC Xena, respectively. The relationship between the expression levels of IL15, IL17RA, AGER, MIF, and TNFRSF1A and EGFR mutation status was analyzed using UCSC Xena.ResultsIn single variant analyses, 3 SNPs (rs10519613, rs4819554, and rs4149570) were significantly associated with worse PFS. Five SNPs (rs10519613, rs4819554, rs2070600, rs755622, and rs4149570) were significantly with worse OS. In addition, high and intermediate GRSs (based on rs10519613, rs4819554, and rs4149570) were associated with worse PFS than those with low GRS. For OS, patients with high GRSs (based on rs10519613, rs4819554, rs2070600, rs755622, and rs4149570) had shorter survival time than those with low GRS. Furthermore, IL15, IL17RA, AGER, MIF, and TNFRSF1A were dysregulated in LUAD. There was difference in the expression level of TNFRSF1A between EGFR wildtype and EGFR-mutant LUAD. Both low AGER expression and high TNFRSF1A expression were significantly associated with worse PFS in LUAD. In addition, low IL17RA and AGER expression, high MIF and TNFRSF1A expression were significantly associated with worse OS in LUAD.ConclusionSNPs in inflammation genes could serve as prognostic biomarkers for NSCLC patients treated with EGFR-TKIs.