Higher Genetic Risk Score Research Articles

Polygenic risk score for obesity and the quality, quantity, and timing of workplace food purchases: A secondary analysis from the ChooseWell 365 randomized trial.

The influence of genetic risk for obesity on food choice behaviors is unknown and may be in the causal pathway between genetic risk and weight gain. The aim of this study was to examine associations between genetic risk for obesity and food choice behaviors using objectively assessed workplace food purchases. This study is a secondary analysis of baseline data collected prior to the start of the "ChooseWell 365" health-promotion intervention randomized control trial. Participants were employees of a large hospital in Boston, MA, who enrolled in the study between September 2016 and February 2018. Cafeteria sales data, collected retrospectively for 3 months prior to enrollment, were used to track the quantity (number of items per 3 months) and timing (median time of day) of purchases, and participant surveys provided self-reported behaviors, including skipping meals and preparing meals at home. A previously validated Healthy Purchasing Score was calculated using the cafeteria traffic-light labeling system (i.e., green = healthy, yellow = less healthy, red = unhealthy) to estimate the healthfulness (quality) of employees' purchases (range, 0%-100% healthy). DNA was extracted and genotyped from blood samples. A body mass index (BMI) genome-wide polygenic score (BMIGPS) was generated by summing BMI-increasing risk alleles across the genome. Additionally, 3 polygenic risk scores (PRSs) were generated with 97 BMI variants previously identified at the genome-wide significance level (P < 5 × 10-8): (1) BMI97 (97 loci), (2) BMICNS (54 loci near genes related to central nervous system [CNS]), and (3) BMInon-CNS (43 loci not related to CNS). Multivariable linear and logistic regression tested associations of genetic risk score quartiles with workplace purchases, adjusted for age, sex, seasonality, and population structure. Associations were considered significant at P < 0.05. In 397 participants, mean age was 44.9 years, and 80.9% were female. Higher genetic risk scores were associated with higher BMI. The highest quartile of BMIGPS was associated with lower Healthy Purchasing Score (-4.8 percentage points [95% CI -8.6 to -1.0]; P = 0.02), higher quantity of food purchases (14.4 more items [95% CI -0.1 to 29.0]; P = 0.03), later time of breakfast purchases (15.0 minutes later [95% CI 1.5-28.5]; P = 0.03), and lower likelihood of preparing dinner at home (Q4 odds ratio [OR] = 0.3 [95% CI 0.1-0.9]; P = 0.03) relative to the lowest BMIGPS quartile. Compared with the lowest quartile, the highest BMICNS quartile was associated with fewer items purchased (P = 0.04), and the highest BMInon-CNS quartile was associated with purchasing breakfast at a later time (P = 0.01), skipping breakfast (P = 0.03), and not preparing breakfast (P = 0.04) or lunch (P = 0.01) at home. A limitation of this study is our data come from a relatively small sample of healthy working adults of European ancestry who volunteered to enroll in a health-promotion study, which may limit generalizability. In this study, genetic risk for obesity was associated with the quality, quantity, and timing of objectively measured workplace food purchases. These findings suggest that genetic risk for obesity may influence eating behaviors that contribute to weight and could be targeted in personalized workplace wellness programs in the future. Clinicaltrials.gov NCT02660086.

Evaluation of Primary Angle-Closure Glaucoma Susceptibility Loci for Estimating Angle Closure Disease Severity

To investigate whether recently identified genetic loci for primary angle-closure glaucoma (PACG) are associated with disease severity. Case-control study. Eight hundred four PACG patients and 943 control participants of Chinese ethnicity from Singapore. The 8 PACG-associated single nucleotide polymorphisms (SNPs; rs11024102 at PLEKHA7, rs3753841 at COL11A1, rs1015213 located between PCMTD1 and ST18 on chromosome 8q, rs3816415 at EPDR1, rs1258267 at CHAT, rs736893 at GLIS3, rs7494379 at FERMT2, and rs3739821 mapping in between DPM2 and FAM102A) identified from genome-wide association studies were tested for association with disease severity using logistic regression adjusted for age and gender. A P value of 0.006 was set as significant after Bonferroni correction for testing of 8 loci. We also calculated the weighted genetic risk score (GRS) weighted by the estimated individual SNP effect size on PACG calculated as logarithm of the odds ratio (OR). Disease severity was based on the visual field mean deviation (MD) and classified as early to moderate (MD, >-12 dB) and severe (MD, <-20 dB). Association of PACG loci with severe disease. Of the 804 PACG patients, genotyping data were available for 768 individuals and included 436 with mild-to-moderate PACG and 206 with severe PACG. The PACG patients were significantly older (mean age, 64.3 ± 9.1 years vs. 56.4 ± 8.9 years; P < 0.001) and there were proportionately more women compared with control participants (58.4% vs. 49.0%; P < 0.001). Of the 8 loci investigated, we observed significant evidence of association with severe PACG at 1 SNP, namely rs3816415 in EPDR1 (OR, 2.03; 95% confidence interval [CI], 1.49-2.78; P= 1× 10-5). A higher-weighted GRS was associated significantly with severe PACG, with an OR of 3.11 (95% CI, 1.95-4.96) comparing the lowest quartile with the highest quartile. Our results show that EPDR1 is associated significantly with severe PACG, suggesting that it may predispose patients to more aggressive disease development. Individuals with PACG with a higher GRS were associated with a higher risk of severe PACG.

Genetic Associations of Chronotype in the Finnish General Population.

Individuals with a later chronotype (evening types) tend to have unhealthier behaviors and increased morbidity and mortality as compared with those with an earlier chronotype (morning types). However, the role of genetics in explaining evening types’ adverse health and health behavior is unclear. Our aim was to study genetic associations of chronotype among 8433 Finns from the cross-sectional National FINRISK 2007 and 2012 studies. First, we studied associations between chronotype and 20 key clock genes with a candidate-gene approach and then performed a full genome-wide association study (GWAS) of chronotype. We also developed a genetic risk score (GRS) for chronotype based on 313 single nucleotide polymorphisms (SNPs) that have previously been associated with chronotype. Chronotype was assessed with a shortened version of Horne and Östberg’s Morningness-Eveningness Questionnaire (sMEQ), and for comparison, we also used the single self-evaluation question on chronotype from the questionnaire. Linear and logistic regression was used for statistical analysis assuming additive effects. The clock gene analysis revealed 1 independent association signal within NR1D2 (lead SNP rs4131403) that was associated with chronotype (p < 0.05; as based on both chronotype assessment methods). The GWAS analysis did not yield any genome-wide significant associations (p > 5 × 10−8). However, higher GRS was associated with evening chronotype (p < 0.001; as based on both chronotype assessment methods). In conclusion, our findings indicated novel genetic associations between chronotype and the NR1D2 clock gene, which has previously been associated with carbohydrate and lipid metabolism. Furthermore, the GRS was able to capture the genetic aspect of chronotype in our study population. These findings expand our knowledge of the genetic basis of chronotype.

Sex-Specific Associations between Gut Prevotellaceae and Host Genetics on Adiposity.

The gut microbiome has been recognized as a tool for understanding adiposity accumulation and for providing personalized nutrition advice for the management of obesity and accompanying metabolic complications. The genetic background is also involved in human energy homeostasis. In order to increase the value of nutrigenetic dietary advice, the interplay between genetics and microbiota must be investigated. The purpose of the present study was to evaluate interactive associations between gut microbiota composition and 95 obesity-related single nucleotide polymorphisms (SNPs) searched in the literature. Oral mucosa and fecal samples from 360 normal weight, overweight and obese subjects were collected. Next generation genotyping of these 95 SNPs and fecal 16S rRNA sequencing were performed. A genetic risk score (GRS) was constructed with 10 SNPs statistically or marginally associated with body mass index (BMI). Several microbiome statistical analyses at family taxonomic level were applied (LEfSe, Canonical Correspondence Analysis, MetagenomeSeq and Random Forest), and Prevotellaceae family was found in all of them as one of the most important bacterial families associated with BMI and GRS. Thus, in this family it was further analyzed the interactive association between BMI and GRS with linear regression models. Interestingly, women with higher abundance of Prevotellaceae and higher GRS were more obese, compared to women with higher GRS and lower abundance of Prevotellaceae. These findings suggest relevant interrelationships between Prevotellaceae and the genetic background that may determine interindividual BMI differences in women, which opens the way to new precision nutrition-based treatments for obesity.

Single-nucleotide polymorphisms based genetic risk score in the prediction of pancreatic cancer risk.

BACKGROUNDDisease-related single nucleotide polymorphisms (SNPs) based genetic risk score (GRS) has been proven to provide independent inherited risk other than family history in multiple cancer types.AIMTo evaluate the potential of GRS in the prediction of pancreatic cancer risk.METHODSIn this case-control study (254 cases and 1200 controls), we aimed to evaluate the association between GRS and pancreatic ductal adenocarcinoma (PDAC) risk in the Chinese population. The GRS was calculated based on the genotype information of 18 PDAC-related SNPs for each study subject (personal genotyping information of the SNPs) and was weighted by external odd ratios (ORs).RESULTSGRS was significantly different in cases and controls (1.96 ± 3.84 in PDACs vs 1.09 ± 0.94 in controls, P < 0.0001). Logistic regression revealed GRS to be associated with PDAC risk [OR = 1.23, 95% confidence interval (CI): 1.13-1.34, P < 0.0001]. GRS remained significantly associated with PDAC (OR = 1.36, 95%CI: 1.06-1.74, P = 0.015) after adjusting for age and sex. Further analysis revealed an association of increased risk for PDAC with higher GRS. Compared with low GRS (< 1.0), subjects with high GRS (2.0) were 99% more likely to have PDAC (OR: 1.99, 95%CI: 1.30-3.04, P = 0.002). Participants with intermediate GRS (1.0-1.9) were 39% more likely to have PDAC (OR: 1.39, 95%CI: 1.03-1.84, P = 0.031). A positive trend was observed (P trend = 0.0006).CONCLUSIONGRS based on PDAC-associated SNPs could provide independent information on PDAC risk and may be used to predict a high risk PDAC population.

Mental stress and physical activity interact with the genetic risk scores of the genetic variants related to sweetness preference in high sucrose-containing food and glucose tolerance.

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.

Genotype- and Phenotype-Based Subgroups in Geographic Atrophy Secondary to Age-Related Macular Degeneration: The EYE-RISK Consortium

Geographic atrophy (GA) secondary to age-related macular degeneration is considered a single entity. This study aimed to determine whether GA subgroups exist that can be defined by their genotype and phenotype. Retrospective analysis of cross-sectional data. Individuals (196 eyes of 196 patients) 50 years of age or older with GA from the EYE-RISK database. Participants were graded for the presence of each of the following fundus features on color fundus photography: large soft drusen, reticular pseudodrusen (RPD), refractile drusen, hyperpigmentation, location of atrophy (foveal vs. extrafoveal), and multifocal lesions. Genotypes of 33 single nucleotide polymorphisms previously assigned to the complement, lipid metabolism, or extracellular matrix (ECM) pathways and ARMS2 also were included, and genetic risk scores (GRSs) for each of those 3 pathways were calculated. Hierarchical cluster analysis was used to determine subgroups of participants defined by these features. The discriminative ability of genotype, phenotype, or both for each subgroup was determined with 10-fold cross-validated areas under the receiver operating characteristic curve (cvAUCs), and the agreement between predicted and actual subgroup membership was assessed with calibration plots. Identification and characterization of GA subgroups based on their phenotype and genotype. Cluster analyses identified 3 subgroups of GA. Subgroup 1 was characterized by high complement GRS, frequently associated with large soft drusen and foveal atrophy; subgroup 2 generally showed low GRS, foveal atrophy, and few drusen (any type); and subgroup 3 showed a high ARMS2 and ECM GRS, RPD, and extrafoveal atrophy. A high discriminative ability existed between subgroups for the genotype (cvAUC, ≥0.94), and a modest discriminative ability existed for the phenotype (cvAUC, <0.65), with good calibration. We identified 3 GA subgroups that differed mostly by their genotype. Atrophy location and drusen type were the most relevant phenotypic features.

Estimation of Absolute Risk of Colorectal Cancer Based on Healthy Lifestyle, Genetic Risk, and Colonoscopy Status in a Population-Based Study

Estimates of absolute risk of colorectal cancer (CRC) are needed to facilitate communication and better inform the public about the potentials and limits of cancer prevention. Using data from a large population-based case-control study in Germany (Darmkrebs: Chancen der Verhütung durch Screening [DACHS] study, which began in 2003) and population registry data, we calculated 30-year absolute risk estimates for development of CRC based on a healthy lifestyle score (derived from 5 modifiable lifestyle factors: smoking, alcohol consumption, diet, physical activity, and body fatness), a polygenic risk score (based on 90 single-nucleotide polymorphisms), and colonoscopy history. We analyzed data from 4220 patients with CRC and 3338 individuals without CRC. Adherence to a healthy lifestyle and colonoscopy in the preceding 10 years were associated with a reduced relative risk of CRC in men and women. We observed a higher CRC risk in participants with high or intermediate genetic risk scores. For 50-year-old men and women without a colonoscopy, the absolute risk of CRC varied according to the polygenic risk score and the healthy lifestyle score (men, 3.5%-13.4%; women, 2.5%-10.6%). For 50-year-old men and women with a colonoscopy, the absolute risk of developing CRC was much lower but still varied according to the polygenic risk score and the healthy lifestyle score (men, 1.2%-4.8%; women, 0.9%-4.2%). Among all risk factor profiles, the 30-year absolute risk estimates consistently decreased with adherence to a healthy lifestyle. In a population-based study, we found that a colonoscopy can drastically reduce the absolute risk of CRC and that the genetically predetermined risk of CRC can be further reduced by adherence to a healthy lifestyle. Our results show the magnitude of CRC prevention possible through colonoscopy and lifestyle at a predefined genetic risk. This observational study has been registered in the German Clinical Trials Register (DRKS00011793), which is a primary registry in the World Health Organization Registry Network.

Abstract 03: LDL-C Genetic Risk Score Predicts Hyperlipidemia and Modifies Lipid Trajectory Over the Life Course: The Bogalusa Heart Study

Introduction: Variability in lipid levels is decreased in childhood compared to adulthood. However, few studies have assessed whether genetic information may help to predict hyperlipidemia beyond measured lipid values at this critical developmental stage. Hypothesis: We hypothesized that a low-density lipoprotein cholesterol (LDL-C) genetic risk score (GRS) would predict hyperlipidemia and LDL-C over the life course, even after adjustment for childhood measures. Methods: The analysis included 651 Bogalusa Heart Study participants (63% women, 31% African American, baseline age=9.8 + 3.1 years, median follow-up=40 years) with genome-wide association study (GWAS) data and at least one childhood and one adulthood measure of LDL-C. A weighted LDL-C GRS was constructed using loci from previous GWAS meta-analyses. Hyperlipidemia was defined as an LDL-C &gt; 130 mg/dL or statin use. Cox proportional hazards regression models examined the associations between GRS and hyperlipidemia. Linear and mixed linear regression models were employed to examine the associations of GRS with adulthood LDL-C and life-course LDL-C trajectory, respectively. All models adjusted for age, sex, and childhood LDL-C. Results: Among participants of European ancestry, increasing GRS tertile conferred strong, dose-response increases in the hazards of hyperlipidemia ( Figure ). Similarly, the highest GRS tertile was associated with a 20 mg/dl increased LDL-C level in middle-aged adults compared to the lowest tertile (P&lt;0.0001). Each tertile increase in GRS was also associated with 5.5 mg/dL larger 10-year increase in LDL-C (interaction-P=0.04). No associations were observed among participants of African ancestry. Conclusions: A LDL-C GRS was associated with adulthood LDL-C phenotypes independently of childhood LDL-C values in participants of European but not African ancestry. These findings highlight a need for increased genomics research in diverse populations and suggest a predictive utility of genetic information in childhood.

Differential Effect of Genetic Burden on Disease Phenotypes in Crohn's Disease and Ulcerative Colitis in a Canadian Cohort.

Background and AimsCrohn’s disease (CD) and ulcerative colitis (UC) demonstrate considerable phenotypic heterogeneity and course. Accurate predictors of disease behaviour are lacking. The contribution of genetics and specific polymorphisms is widely appreciated; however, their cumulative effect(s) upon disease behaviour remains poorly understood. Here, we investigate the relationship between genetic burden and disease phenotype in a Canadian inflammatory bowel disease (IBD) Cohort.MethodsWe retrospectively examined a cohort of CD and UC patients recruited from a single tertiary referral center genotyped using a Goldengate Illumina platform. A genetic risk score (GRS) incorporating strength of association (log odds ratio) and allele dose for 151 IBD-risk loci was calculated and evaluated for phenotypic associations.ResultsAmong CD patients, higher GRS was associated with earlier onset of disease (regression coefficient −2.19, 95% confidence interval [CI] −3.77 to −0.61, P = 0.007), ileal disease (odds ratio [OR] 1.45), stricturing/penetrating disease (OR 1.72), perianal disease (OR 1.57) and bowel resection (OR 1.66). Higher GRS was associated with use of anti-tumor necrosis factor (TNF) (P < 0.05) but not immunomodulators. Interestingly, we could not demonstrate an association between higher GRS and family history of IBD (OR 1.27, P = 0.07). Onset of disease remained statistically significant for never smokers (P = 0.03) but not ever smokers (P = 0.13). For UC, having a higher GRS did not predict the age of diagnosis nor was it predictive of UC disease extent (P = 0.18), the need for surgery (P = 0.74), nor medication use (immunomodulators P = 0.53, anti-TNF P = 0.49). We could not demonstrate an association between increased GRS and having a family history of IBD in the UC group.ConclusionsIncreasing genetic burden is associated with early age of diagnosis in CD and may be useful in predicting disease behaviour in CD but not UC.

Do Serum Urate-associated Genetic Variants Influence Gout Risk in People Taking Diuretics? Analysis of the UK Biobank.

The aim of this study was to determine whether serum urate (SU)-associated genetic variants differ in their influence on gout risk in people taking a diuretic compared to those not taking a diuretic. This research was conducted using the UK Biobank Resource (n = 359,876). Ten SU-associated single-nucleotide polymorphisms (SNP) were tested for their association with gout according to diuretic use. Gene-diuretic interactions for gout association were tested using a genetic risk score (GRS) and individual SNP by logistic regression adjusting for relevant confounders. After adjustment, use of a loop diuretic was positively associated with prevalent gout (OR 2.34, 95% CI 2.08-2.63), but thiazide diuretics were inversely associated with prevalent gout (OR 0.60, 95% CI 0.55-0.66). Compared with a lower GRS (< mean), a higher GRS (≥ mean) was positively associated with gout in those not taking diuretics (OR 2.63, 2.49-2.79), in those taking loop diuretics (OR 2.04, 95% CI 1.65-2.53), in those taking thiazide diuretics (OR 2.70, 2.26-3.23), and in those taking thiazide-like diuretics (OR 2.11, 95% CI 1.37-3.25). No nonadditive gene-diuretic interactions were observed. In people taking diuretics, SU-associated genetic variants contribute strongly to gout risk, with a similar effect to that observed in those not taking a diuretic. These findings suggest that the contribution of genetic variants is not restricted to people with "primary" gout, and that genetic variants can play an important role in gout susceptibility in the presence of other risk factors.

A nutrigenetics approach to study the impact of genetic and lifestyle factors on cardiometabolic traits in various ethnic groups: findings from the GeNuIne Collaboration.

Several studies on gene-diet interactions (nutrigenetics) have been performed in western populations; however, there are only a few studies to date in lower middle-income countries (LMIC). A large-scale collaborative project called gene-nutrient interactions (GeNuIne) Collaboration, the main objective of which is to investigate the effect of GeNuIne on cardiometabolic traits using population-based studies from various ethnic groups, has been initiated at the University of Reading, UK. While South Asians with higher genetic risk score (GRS) showed a higher risk of obesity in response to a high-carbohydrate diet, South East and Western Asian populations with higher GRS showed an increased risk of central obesity in response to a high-protein diet. The paper also provides a summary of other gene-diet interaction analyses that were performed in LMIC as part of this collaborative project and gives an overview of how these nutrigenetic findings can be translated to personalised and public health approaches for the prevention of cardiometabolic diseases such as obesity, type 2 diabetes and CVD.

Performance of FRAX in Predicting Fractures in US Postmenopausal Women with Varied Race and Genetic Profiles.

Background: Whether the Fracture Risk Assessment Tool (FRAX) performed differently in estimating the 10-year fracture probability in women of different genetic profiling and race remained unclear. Methods: The genomic data in the Women’s Health Initiative (WHI) study was analyzed (n = 23,981). The genetic risk score (GRS) was calculated from 14 fracture-associated single nucleotide polymorphisms (SNPs) for each participant. FRAX without bone mineral density (BMD) was used to estimate fracture probability. Results: FRAX significantly overestimated the risk of major osteoporotic fracture (MOF) in the WHI study. The most significant overestimation was observed in women with low GRS (predicted/observed ratio (POR): 1.61, 95% CI: 1.45–1.79) specifically Asian women (POR: 3.5, 95% CI 2.48–4.81) and in African American women (POR: 2.59, 95% CI: 2.33–2.87). Compared to the low GRS group, the 10-year probability of MOF adjusted for the FRAX score was 21% and 30% higher in the median GRS group and high GRS group, respectively. Asian, African American, and Hispanic women respectively had a 78%, 76%, and 56% lower hazard than Caucasian women after the FRAX score was adjusted. The results were similar for hip fractures. Conclusions: Our study suggested the FRAX performance varies significantly by both genetic profile and race in postmenopausal women.

Effect of 15 BMI-Associated Polymorphisms, Reported for Europeans, across Ethnicities and Degrees of Amerindian Ancestry in Mexican Children.

In Mexico, the genetic mechanisms underlying childhood obesity are poorly known. We evaluated the effect of loci, known to be associated with childhood body mass index (BMI) in Europeans, in Mexican children from different ethnic groups. We performed linear and logistic analyses of BMI and obesity, respectively, in Mestizos and Amerindians (Seris, Yaquis and Nahuatl speakers) from Northern (n = 369) and Central Mexico (n = 8545). We used linear models to understand the effect of degree of Amerindian ancestry (AMA) and genetic risk score (GRS) on BMI z-score. Northern Mexican Mestizos showed the highest overweight-obesity prevalence (47.4%), followed by Seri (36.2%) and Central Mexican (31.5%) children. Eleven loci (SEC16B/rs543874, OLFM4/rs12429545/rs9568856, FTO/rs9939609, MC4R/rs6567160, GNPDA2/rs13130484, FAIM2/rs7132908, FAM120AOS/rs944990, LMX1B/rs3829849, ADAM23/rs13387838, HOXB5/rs9299) were associated with BMI and seven (SEC16B/rs543874, OLFM4/rs12429545/rs9568856, FTO/rs9939609, MC4R/rs6567160, GNPDA2 rs13130484, LMX1B/rs3829849) were associated with obesity in Central Mexican children. One SNP was associated with obesity in Northern Mexicans and Yaquis (SEC16B/rs543874). We found higher BMI z-score at higher GRS (β = 0.11, p = 0.2 × 10−16) and at lower AMA (β = −0.05, p = 6.8 × 10−7). The GRS interacts with AMA to increase BMI (β = 0.03, p = 6.08 × 10−3). High genetic BMI susceptibility increase the risk of higher BMI, including in Amerindian children.

Single-Nucleotide Polymorphism–Based Genetic Risk Score and Patient Age at Prostate Cancer Diagnosis

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.

High genetic risk score is associated with early disease onset, damage accrual and decreased survival in systemic lupus erythematosus

ObjectivesTo investigate associations between a high genetic disease risk and disease severity in patients with systemic lupus erythematosus (SLE).MethodsPatients with SLE (n=1001, discovery cohort and n=5524, replication cohort) and healthy...

Multiple plasma metals, genetic risk and serum C-reactive protein: A metal-metal and gene-metal interaction study

BackgroundC-reactive protein (CRP) is a well-recognized biomarker of inflammation, which can be used as a predictor of cardiovascular disease. Evidence have suggested exposure to multiple metals/metalloids may affect immune system and give rise to cardiovascular disease. However, it is lack of study to comprehensively evaluate the association of multiple metals and CRP, the interactions between metals, and the gene-metal interaction in relation to CRP levels. AimsTo explore the associations of multiple plasma metals with serum CRP, and to test the interactions between metals, and gene-metal interactions on the levels of serum CRP. MethodsWe included 2882 participants from the Dongfeng-Tongji cohort, China, and measured 23 plasma metals and serum CRP concentrations. The genetic risk score (GRS) was calculated based on 7 established CRP-associated variants. For metals which were associated with the levels of CRP, we further tested the interactions between metals on CRP, and analyzed the gene-metal interactions on CRP. ResultsThe median level for CRP in the total population was 1.17 mg/L. After multivariable adjustment, plasma copper was positively associated with serum CRP (FDR < 0.001), whereas selenium was negatively associated with serum CRP (FDR = 0.01). Moreover, selenium and zinc attenuated the positive association between high plasma copper and CRP (P for interaction < 0.001). Participants with a higher GRS had a higher CRP level, with the increase in ln-transformed CRP per increment of 5 risk alleles were 0.64 for weighted GRS, and 0.54 for unweighted GRS (both P < 0.001). Furthermore, the genetic association with CRP was modified by copper concentration (P for interaction < 0.001). ConclusionsOur results suggest that serum CRP is positively associated with plasma concentration of copper, and inversely associated with selenium. Plasma zinc, selenium and CRP genetic predisposition would modify the associations between plasma copper and serum CRP.

Differential Cumulative Risk of Genetic Polymorphisms in Familial and Nonfamilial Esophageal Squamous Cell Carcinoma.

To explore the relationship between family history of esophageal cancer, SNPs, and the risk of esophageal squamous cell carcinoma (ESCC), we performed a population-based case-control study and developed a genetic family history-related risk (GFR) score and non-family history-related risk (GnFR) score to quantify the cumulative number of risk genotypes carried by each individual. We used data of 700 patients with nonfamilial ESCC, 341 patients with familial ESCC, 1,445 controls without a family history of esophageal cancer, and 319 controls with a family history. We genotyped 87 genetic variants associated with the risk for ESCC, and constructed GFR and GnFR scores for cases and controls. Our results show that ESCC risk increased with higher GFR score (P trend = 0.0096). Among the familial subgroup, we observed a nearly 7-fold [95% confidence interval (CI), 1.92-24.77] higher risk of ESCC in the highest GFR score group. The corresponding estimate was only 2-fold (95% CI, 1.41-3.93) higher risk of ESCC, in the stratum without a reported family history of esophageal cancer. Certain cell signaling pathways and immune-related pathways were enriched, specifically in familial ESCC. Results from a reconstructed cohort analysis demonstrated that cumulative risk to get esophageal cancer by age 75 years was 13.3%, 10.2%, 8.2%, and 5.1%, respectively, in four subgroups as defined by first-degree relatives of cases or controls with high or low genetic risk score. In particular, the cohort of relatives of ESCC cases with low genetic risk score exhibit a higher cumulative risk than the cohort of relatives of controls with high genetic risk score. It demonstrates that environmental factors play a major role in esophageal cancer. Further studies are warranted to dissect the mechanisms of shared environmental and genetic susceptibility affecting the risk of getting ESCC. Our study highlights that the need of preventive strategies to screen certain genetic polymorphisms, especially in individuals whose relatives had ESCC.

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

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

Predicting Benefit From Evolocumab Therapy in Patients With Atherosclerotic Disease Using a Genetic Risk Score: Results From the FOURIER Trial.

The ability of a genetic risk score to predict risk in established cardiovascular disease and identify individuals who derive greater benefit from PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition has not been established. We studied 14 298 patients with atherosclerotic cardiovascular disease from the FOURIER trial (Further Cardiovascular Outcomes Researh With PCSK9 Inhibition in Subjects With Elevated Risk). A 27-single-nucleotide polymorphism genetic risk score defined low (quintile 1), intermediate (quintiles 2-4), and high (quintile 5) genetic risk. Patients were also categorized by major atherosclerotic risk factors including diabetes mellitus, hypertension, low-density lipoprotein cholesterol ≥100 mg/dl, and smoking; multiple (≥2) risk factors was considered high clinical risk. Outcomes consisted of major coronary events (coronary heart death, myocardial infarction, or coronary revascularization) and major vascular events (major coronary events and ischemic stroke). Median follow-up was 2.3 years. After we adjusted for clinical factors, the genetic risk score was associated with risk for both major vascular events (Ptrend=0.005) and major coronary events (Ptrend<0.0001). Individuals with intermediate and high genetic risk scores had 1.23- and 1.65-fold increased hazard for major coronary events, respectively. Elevated genetic risk was additive to major atherosclerotic risk factors and identified patients more likely to benefit from evolocumab. There was no benefit for major vascular events in patients without multiple clinical risk factors or high genetic risk (hazard ratio [HR], 1.02; absolute risk reduction [ARR], -0.2%, P=0.86). In contrast, there was a 13% relative risk reduction (HR, 0.87 [0.75-0.998], P=0.047) and a 1.4% ARR in patients with multiple clinical risk factors but without high genetic risk and a 31% relative risk reduction (HR, 0.69 [0.55-0.86], P=0.0012), and 4.0% ARR in patients with high genetic risk, irrespective of clinical risk (Ptrend for HR=0.017, ARR Ptrend=0.004). Patients with high genetic risk who received evolocumab had event rates similar to patients with a low burden of both genetic and clinical risk. Patients without multiple clinical risk factors or high genetic risk had a low event rate and did not appear to derive benefit from evolocumab over 2.3 years. Conversely, patients with multiple clinical risk factors but without high genetic risk had intermediate risk and intermediate risk reduction. Patients with high genetic risk, regardless of clinical risk, had a high event rate and derived the greatest relative and absolute benefit from evolocumab, which mitigated this risk.