The Polymorphism rs2293855 MTMR9 Gene and Genetic Score Are Associated With Higher Atherogenic Risk in Brazilian Schoolchildren

Purpose: Evaluate the associations of FTO (rs9939609), MC4R (rs17782313), MTMR9 (rs2293855), and the genetic score with atherogenic risk in Brazilian children. Methods: This is a cross-sectional study conducted with 544 children aged 4 to 9 years old. We obtained sociodemographic and lifestyle data by questionnaires, and biological sample (DNA) through oral swab. The single nucleotide polymorphisms (SNP) FTO (rs9939609), MC4R (rs17782313), and MTMR9 (rs2293855) were identified by the system taqman SNP genotyping and evaluated the obesity-related genetic risk score. Blood samples were collected for the lipid profile analysis (serum total cholesterol, HDLc, LDL-c, triglycerides). The atherogenic indexes (Castelli I and II indexes, atherogenic coefficient - AC, lipoprotein combination index - LCI and plasma atherogenic index - AIP) were calculated. We compared the distributions of outcomes (lipid profile and atherogenic indexes) by genotype categories using multivariable linear regression. Results: Children with AG/AA genotypes in the polymorphism MTMR9 (rs2293855), had lower HDL-c level and higher TC/HDL-c, LDL-c/HDL-c ratios, and AC. Those with one or more polymorphisms (FTO rs9939609, MC4R rs17782313, and MTMR9 rs2293855) in the genetic risk score had lower HDL-c and higher TC/HDL-c, AC, LCI, and AIP. Conclusion: The risk allele (AG/AA) of the MTMR9 (rs2293855) and the higher obesity-related genetic risk score were positively associated with higher atherogenic risk in Brazilian children.

Body mass index but not genetic risk is longitudinally associated with altered structural brain parameters

Evidence from previous studies suggests that elevated body mass index (BMI) and genetic risk for obesity is associated with reduced brain volume, particularly in areas of reward-related cognition, e.g. the medial prefrontal cortex (AC-MPFC), the orbitofrontal cortex (OFC), the striatum and the thalamus. However, only few studies examined the interplay between these factors in a joint approach. Moreover, previous findings are based on cross-sectional data. We investigated the longitudinal relationship between increased BMI, brain structural magnetic resonance imaging (MRI) parameters and genetic risk scores in a cohort of n = 502 community-dwelling participants from the Study of Health in Pomerania (SHIP) with a mean follow-up-time of 4.9 years. We found that (1) increased BMI values at baseline were associated with decreased brain parameters at follow-up. These effects were particularly pronounced for the OFC and AC-MPFC. (2) The genetic predisposition for BMI had no effect on brain parameters at baseline or follow-up. (3) The interaction between the genetic score for BMI and brain parameters had no effect on BMI at baseline. Finding a significant impact of overweight, but not genetic predisposition for obesity on altered brain structure suggests that metabolic mechanisms may underlie the relationship between obesity and altered brain structure.

A multi-variant recall-by-genotype study of the metabolomic signature of body mass index

Objective: We estimated the effect of body mass index (BMI) on circulating metabolites in young adults using a recall-by-genotype (RbG) study design. Methods: An RbG study was implemented in the Avon Longitudinal Study of Parents and Children. Samples from 756 participants were selected for untargeted metabolomics analysis based on low/high genetic liability for higher BMI defined by a genetic score (GS). Regression analyses were performed to investigate the association between BMI GS groups and relative abundance of 973 metabolites. Results: After correction for multiple testing, 29 metabolites were associated with BMI GS group. Bilirubin was amongst the most strongly associated metabolites with reduced levels measured in individuals with the highest BMI GS (beta=-0.32, 95% confidence interval (CI): -0.46, -0.18, Benjamini-Hochberg (BH) adjusted p=0.005). We observed associations between BMI GS group and levels of several potentially diet-related metabolites including hippurate which had lower mean abundance in individuals in the high BMI GS group (beta=-0.29, 95% CI: -0.44, -0.15, BH adjusted p=0.008). Conclusions: Together with existing literature our results suggest a genetic predisposition to higher BMI captures differences in metabolism leading to adiposity gain. In the absence of prospective data, separating these effects from the downstream consequences of weight gain is challenging.

Prenatal alcohol consumption and child IQ and cognition: a Mendelian randomization study

Background: Previous studies using Mendelian randomization have found that fetal alcohol exposure may be associated with lower IQ and test scores in childhood. Objectives: We aim to replicate and extend these findings in Generation R Study, a birth cohort based in Rotterdam, the Netherlands. Methods: We used data from Generation R which recruited pregnant women between 2002 and 2006. Alcohol use was assessed via questionnaire during each trimester. IQ was measured in the children between ages 5 and 8 using the Snijders-Oomen Non-Verbal Intelligence Test. Scores from a national standardized test administered around age 12 were used as a measure of cognition. We estimated the associations between ten genetic variants in the mothers previously found to be related to alcohol consumption and metabolism and each of the outcomes. In the children, we also estimated the association between the same genetic variants as well as two polygenic scores for alcohol consumption and the outcomes. Results: Maternal genetic variants were not found to be related to either outcome but wide confidence intervals did not preclude important effects. A few genetic variants in the children were suggestive of a decrease in IQ. Likewise, one genetic variant and the genetic score had estimates and confidence intervals consistent with increases in standardized test scores. Conclusions: Our results provide slight support for associations between genetic variants in children related to maternal prenatal alcohol consumption and IQ and cognition outcomes. These findings are in line with two previous studies on this topic.

A Clinical-Genetic Score for Predicting Weight Loss after Bariatric Surgery: The OBEGEN Study

Around 30% of the patients that undergo bariatric surgery (BS) do not reach an appropriate weight loss. The OBEGEN study aimed to assess the added value of genetic testing to clinical variables in predicting weight loss after BS. A multicenter, retrospective, longitudinal, and observational study including 416 patients who underwent BS was conducted (Clinical.Trials.gov- NCT02405949). 50 single nucleotide polymorphisms (SNPs) from 39 genes were examined. Receiver Operating Characteristic (ROC) curve analysis were used to calculate sensitivity and specificity. Satisfactory response to BS was defined as at nadir excess weight loss >50%. A good predictive model of response [area under ROC of 0.845 (95% CI 0.805–0.880), p < 0.001; sensitivity 90.1%, specificity 65.5%] was obtained by combining three clinical variables (age, type of surgery, presence diabetes) and nine SNPs located in ADIPOQ, MC4R, IL6, PPARG, INSIG2, CNR1, ELOVL6, PLIN1 and BDNF genes. This predictive model showed a significant higher area under ROC than the clinical score (p = 0.0186). The OBEGEN study shows the key role of combining clinical variables with genetic testing to increase the predictability of the weight loss response after BS. This finding will permit us to implement a personalized medicine which will be associated with a more cost-effective clinical practice.

HMG-Coenzyme A Reductase as a Drug Target for the Prevention of Ankylosing Spondylitis

Statins are an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). Growing evidence indicates that statins may have an anti-inflammatory effect. Whether genetically proxied HMGCR inhibition can reduce the risk of ankylosing spondylitis is unknown. We constructed an HMGCR genetic score comprising nearly randomly inherited variants significantly associated with LDL cholesterol levels within ± 100 kb from HMGCR to proxy for inhibition of HMGCR. We also constructed PCSK9 and NPC1L1 scores as well as the LDL polygenetic score to proxy for the inhibition of these drug targets as well as serum LDL cholesterol levels, respectively. We then compared the associations of these genetic scores with the risk of ankylosing spondylitis. Of 33,998 participants in the primary cohort, 12,596 individuals had been diagnosed with ankylosing spondylitis. Genetically proxied inhibition of HMGCR scaled to per mmol/L decrease in LDL cholesterol levels by the HMGCR score was associated with a lower risk of ankylosing spondylitis (OR, 0.57; 95% CI, 0.38–0.85; P value = 5.7 × 10–3). No significant association with ankylosing spondylitis was observed for the PCSK9 score (OR, 0.89; 95% CI, 0.68–1.16) and the NPC1L1 score (OR, 1.50; 95% CI, 0.39–5.77). For the LDL score, genetically determined per mmol/L decrease in LDL cholesterol levels led to a reduced risk of ankylosing spondylitis (OR, 0.64; 95% CI, 0.43–0.94), with significant heterogeneity and pleiotropy in the estimate. Exploratory analyses showed that genetically proxied inhibition of HMGCR appeared to have a similar effect to long-term statin therapy in modifying the risk of coronary artery disease and type 2 diabetes, suggesting that the HMGCR score might be a reliable model to assess the effect of statin. Genetically proxied inhibition of HMGCR was associated with a decreased risk of ankylosing spondylitis. This mechanism-based estimate was in line with existing observations suggesting the clinical benefits of statin therapy for ankylosing spondylitis.

Genetic risk for obesity and the effectiveness of the ChooseWell 365 workplace intervention to prevent weight gain and improve dietary choices

ABSTRACT Background It is unknown whether behavioral interventions to improve diet are effective in people with a genetic predisposition to obesity. Objectives To examine associations between BMI genetic risk and changes in weight and workplace purchases by employees participating in a randomized controlled trial of an automated behavioral workplace intervention to promote healthy food choices. Methods Participants were hospital employees enrolled in a 12-mo intervention followed by a 12-mo follow-up. Hospital cafeterias utilized a traffic-light labeling system (e.g., green = healthy, red = unhealthy) that was used to calculate a validated Healthy Purchasing Score (HPS; higher = healthier). A weighted genome-wide BMI genetic score was generated by summing BMI-increasing alleles. Results The study included 397 adults of European ancestry (mean age, 44.9 y; 80.9% female). Participants in the highest genetic quartile (Q4) had a lower HPS and higher purchases of red-labeled items relative to participants in the lowest quartile (Q1) at baseline [Q4–Q1 Beta HPS, –4.66 (95% CI, –8.01 to –1.32); red-labeled items, 4.26% (95% CI, 1.45%–7.07%)] and at the 12-mo [HPS, –3.96 (95% CI, –7.5 to –0.41); red-labeled items, 3.20% (95% CI, 0.31%–6.09%)] and 24-mo [HPS, –3.70 (95% CI, –7.40 to 0.00); red-labeled items, 3.48% (95% CI, 0.54%–6.41%)] follow-up periods. In the intervention group, increases in HPS were similar in Q4 and Q1 at 12 mo (Q4–Q1 Beta, 1.04; 95% CI, –2.42 to 4.50). At the 24-mo follow-up, the change in BMI from baseline was similar between Q4 and Q1 (0.17 kg/m2; 95% CI, –0.55 to 0.89 kg/m2) in the intervention group, but higher in Q4 than Q1 (1.20 kg/m2; 95% CI, 0.26–2.13 kg/m2) in the control group. No interaction was evident between the treatment arm and genetic score for BMI or HPS. Conclusions Having a high BMI genetic risk was associated with greater increases in BMI and lower quality purchases over 2 y. The 12-mo behavioral intervention improved employees’ food choices, regardless of the genetic burden, and may have attenuated weight gain conferred by having the genetic risk.

Evaluating a polygenic hazard score to predict risk of developing metastatic or fatal prostate cancer in the multi-ancestry Million Veteran Program cohort

Importance: Early detection of prostate cancer to reduce mortality remains controversial because there is often also overdiagnosis of low-risk disease and unnecessary treatment. Genetic scores may provide an objective measure of a man's risk of dying from prostate cancer and thus inform screening decisions, especially in men of African ancestry, who have a higher average risk of prostate cancer death but are often treated as a homogeneous group. Objective: Determine whether a polygenic hazard score based on 290 genetic variants (PHS290) is associated with risk of metastatic or fatal prostate cancer in a racially and ethnically diverse population. Design: Million Veteran Program (MVP) cohort study, 2011-2021. Setting: Nation-wide study of United States military veterans. Participants: Population-based volunteer sample of male participants. Exposure(s): Genotype data were used to calculate the genetic score, PHS290. Family history of prostate cancer and ancestry group (harmonized genetic ancestry and self-reported race/ethnicity: European, African, Hispanic, or Asian) were also studied. Main Outcome(s) and Measure(s): Study designed after MVP data collected. Primary outcome: age at death from prostate cancer. Key secondary outcome: age at diagnosis of prostate cancer metastases. Hypothesis: A germline genetic score (PHS290) is associated with risk of fatal (or metastatic) prostate cancer. Results: 513,997 MVP participants were included. Median age at last follow-up: 69 years. PHS290 was associated with age at death from prostate cancer in the full cohort and for each ancestry group (p<1e-16). Comparing men in the highest 20% of PHS290 to those in the lowest 20%, the hazard ratio for death from prostate cancer was 4.41 [95% CI: 3.9-5.02]. Corresponding hazard ratios for European, African, Hispanic, and Asian subsets were 4.26 [3.66-4.9], 2.4 [1.77-3.23], 4.72 [2.68-8.87], and 10.46 [2.01-101.0]. When accounting for family history and ancestry group, PHS290 remained a strong independent predictor of fatal prostate cancer. PHS290 was also associated with metastasis. PHS290 was higher, on average, among men with African ancestry. Conclusions and Relevance: PHS290 stratified US veterans of diverse ancestry for lifetime risk of metastatic or fatal prostate cancer. Predicting genetic risk of lethal prostate cancer with PHS290 might inform individualized decisions about prostate cancer screening.

1036Independent evaluation of melanoma polygenic risk scores in UK and Australian prospective cohorts

Background To improve melanoma early detection, tools to predict personal risk based on genetic information (polygenic risk scores, PRS) have been developed, but require external validation. Methods We analysed invasive melanoma incidence in UK Biobank (UKB; n = 395,647; 1,651 cases) and the Melbourne Collaborative Cohort Study (MCCS, Australia; n = 4,765; 303 cases). Three PRS were evaluated: 68 genetic variants (SNPs) at 54 loci from a 2020 meta-analysis (PRS68); 50 SNPs significant in the 2020 meta-analysis excluding UKB (PRS50); 45 SNPs at 21 loci known pre-2020 (PRS45). 10-year melanoma risks were calculated from population-level cancer registry data by age group and sex, with and without PRS adjustment. Results All PRS were strongly associated with melanoma incidence, including after adjustment for age, sex, ethnicity, and ease of tanning. Predicted absolute melanoma risks based on age and sex alone underestimated melanoma incidence in UKB (ratio expected/observed cases E/O=0.65, 95% confidence interval 0.62-0.68) and MCCS (E/O=0.65, 0.57-0.73). For UKB, this was reduced by PRS-adjustment, e.g. PRS50-adjusted risks E/O=0.91 (0.87-0.95). Discriminative ability for PRS68- and PRS50-adjusted absolute risks was higher than for risks based on age and sex alone (deltaAUC 0.07-0.1, p &lt; 0.0001), and higher than for PRS45-adjusted risks (deltaAUC 0.02-0.04, p &lt; 0.001). Conclusions A PRS derived from a larger, more diverse meta-analysis improves melanoma risk prediction compared to an earlier PRS. Re-calibration of absolute risks may be necessary for application to specific populations. Key messages A genetic score can improve prediction of melanoma risk and might help tailor melanoma prevention and early detection strategies to different risk levels.