Genetic Risk Score Enhances Coronary Artery Disease Risk Prediction in Individuals With Type 1 Diabetes

OBJECTIVE Individuals with type 1 diabetes are at a high lifetime risk of coronary artery disease (CAD) calling for early interventions. This study explores the use of a genetic risk score (GRS) for CAD risk prediction, compares it to established clinical markers and investigates its performance according to the age and pharmacological treatment. <p>RESEARCH DESIGN AND METHODS This study in 3,295 individuals with type 1 diabetes from the Finnish Diabetic Nephropathy Study (467 incident CAD, 14.8 years follow-up) employed three risk scores: a GRS, a validated clinical score and their combined score. Hazard ratios (HR) were calculated with Cox regression and model performances compared with Harrel’s C-index. </p> <p>RESULTS A HR of 6.7 for CAD was observed between the highest and the lowest 5^th percentile of the GRS (<i>P</i>=1.8×10^-6). The performance of GRS (C-index [C] 0.562) was similar to HbA_1c (C=0.563, <i>p</i>-value for difference 0.96), HDL (C=0.571, <i>P</i>=0.6) and total cholesterol (C=0.594, <i>P</i>=0.1). The GRS was not correlated with the clinical score (<i>r</i>=-0.013, <i>P</i>=0.5). The combined score outperformed the clinical score (C=0.813 vs C=0.820, <i>P</i>=0.003). The GRS performed better in individuals below the median age (38.6 years) compared to those above (C=0.637 vs C=0.546). </p> <p>CONCLUSIONS A GRS identified individuals at high risk of CAD and worked better in younger individuals. GRS was also an independent risk factor for CAD with a predictive power comparable to that of HbA_1c, HDL and total cholesterol and, when incorporated into a clinical model, modestly improved the predictions. The GRS promises early risk stratification in clinical practice by enhancing the prediction of CAD. </p>

Genetic Risk Score Enhances Coronary Artery Disease Risk Prediction in Individuals With Type 1 Diabetes

OBJECTIVE Individuals with type 1 diabetes are at a high lifetime risk of coronary artery disease (CAD) calling for early interventions. This study explores the use of a genetic risk score (GRS) for CAD risk prediction, compares it to established clinical markers and investigates its performance according to the age and pharmacological treatment. <p>RESEARCH DESIGN AND METHODS This study in 3,295 individuals with type 1 diabetes from the Finnish Diabetic Nephropathy Study (467 incident CAD, 14.8 years follow-up) employed three risk scores: a GRS, a validated clinical score and their combined score. Hazard ratios (HR) were calculated with Cox regression and model performances compared with Harrel’s C-index. </p> <p>RESULTS A HR of 6.7 for CAD was observed between the highest and the lowest 5^th percentile of the GRS (<i>P</i>=1.8×10^-6). The performance of GRS (C-index [C] 0.562) was similar to HbA_1c (C=0.563, <i>p</i>-value for difference 0.96), HDL (C=0.571, <i>P</i>=0.6) and total cholesterol (C=0.594, <i>P</i>=0.1). The GRS was not correlated with the clinical score (<i>r</i>=-0.013, <i>P</i>=0.5). The combined score outperformed the clinical score (C=0.813 vs C=0.820, <i>P</i>=0.003). The GRS performed better in individuals below the median age (38.6 years) compared to those above (C=0.637 vs C=0.546). </p> <p>CONCLUSIONS A GRS identified individuals at high risk of CAD and worked better in younger individuals. GRS was also an independent risk factor for CAD with a predictive power comparable to that of HbA_1c, HDL and total cholesterol and, when incorporated into a clinical model, modestly improved the predictions. The GRS promises early risk stratification in clinical practice by enhancing the prediction of CAD. </p>

Genetic Risk Score Enhances Coronary Artery Disease Risk Prediction in Individuals With Type 1 Diabetes

OBJECTIVE Individuals with type 1 diabetes are at a high lifetime risk of coronary artery disease (CAD), calling for early interventions. This study explores the use of a genetic risk score (GRS) for CAD risk prediction, compares it to established clinical markers, and investigates its performance according to the age and pharmacological treatment. RESEARCH DESIGN AND METHODS This study in 3,295 individuals with type 1 diabetes from the Finnish Diabetic Nephropathy Study (467 incident CAD, 14.8 years follow-up) used three risk scores: a GRS, a validated clinical score, and their combined score. Hazard ratios (HR) were calculated with Cox regression, and model performances were compared with the Harrell C-index (C-index). RESULTS A HR of 6.7 for CAD was observed between the highest and the lowest 5th percentile of the GRS (P = 1.8 × 10−6). The performance of GRS (C-index = 0.562) was similar to HbA1c (C-index = 0.563, P = 0.96 for difference), HDL (C-index = 0.571, P = 0.6), and total cholesterol (C-index = 0.594, P = 0.1). The GRS was not correlated with the clinical score (r = −0.013, P = 0.5). The combined score outperformed the clinical score (C-index = 0.813 vs. C-index = 0.820, P = 0.003). The GRS performed better in individuals below the median age (38.6 years) compared with those above (C-index = 0.637 vs. C-index = 0.546). CONCLUSIONS A GRS identified individuals at high risk of CAD and worked better in younger individuals. GRS was also an independent risk factor for CAD, with a predictive power comparable to that of HbA1c and HDL and total cholesterol, and when incorporated into a clinical model, modestly improved the predictions. The GRS promises early risk stratification in clinical practice by enhancing the prediction of CAD.

The Association between Fasting Glucose and Sugar Sweetened Beverages Intake Is Greater in Latin Americans with a High Polygenic Risk Score for Type 2 Diabetes Mellitus

Chile has the highest per capita intake of sugar-sweetened beverages (SSB) world-wide. However, it is unknown whether the effects from this highly industrialized food will mimic those reported in industrialized countries or whether they will be modified by local lifestyle or population genetics. Our goal was to evaluate the association between SSB intake and fasting glucose in the Chilean population. We calculated a weighted genetic risk score (GRSw) based on 16 T2D risk SNPs in 2828 non-diabetic participants of the MAUCO cohort. SSB intake was categorized in four levels using a food frequency questionnaire. Log-fasting glucose was regressed on SSB and GRSw tertiles while accounting for socio-demography, lifestyle, obesity, and Amerindian ancestry. Fasting glucose increased systematically per unit of GRSw (β = 0.02 ± 0.006, p = 0.00002) and by SSB intake (β[cat4] = 0.04 ± 0.009, p = 0.0001), showing a significant interaction, where the strongest effect was observed in the highest GRSw-tertile and in the highest SSB consumption category (β = 0.05 ± 0.02, p = 0.02). SNP-wise, SSB interacted with additive effects of rs7903146 (TCF7L2) (β = 0.05 ± 0.01, p = 0.002) and with the G/G genotype of rs10830963 (MTNRB1B) (β = 0.19 ± 0.05, p = 0.001). Conclusions: The association between SSB intake and fasting glucose in the Chilean population without diabetes is modified by T2D genetic susceptibility.

The moderation of the genetic risk for alcohol and drug use disorders in a Swedish national sample by the genetic aptitude for educational attainment

Background Does the genetic aptitude for educational attainment (GAEA) moderate the genetic risk for alcohol use disorder (AUD) and drug use disorder (DUD)? Methods In the native Swedish population, born 1960–1980 and followed through 2017 (n = 1 862 435), the family genetic risk score (FGRS) for AUD and DUD and GAEA were calculated from, respectively, the educational attainment and risk for AUD and DUD, of 1st through 5th degree relatives from Swedish national registers. Analyses utilized Aalen's linear hazards models. Results Risk for AUD was robustly predicted by the main effects of FGRSAUD [b = 6.32 (95% CI 6.21–6.43), z = 64.9, p < 0.001) and GAEA [b = −2.90 (2.83–2.97), z = 44.1, p < 0.001] and their interaction [b = −1.93 (1.83–2.03), z = 32.9, p < 0.001]. Results were similar for the prediction of DUD by the main effects of FGRSDUD [b = 4.65 (CI 4.56–4.74), z = 59.4, p < 0.001] and GAEA [−2.08 (2.03–2.13), z = 46.4, p < 0.001] and their interaction [b = −1.58 (1.50–1.66)), z = 30.2, p < 0.001]. The magnitude of the interactions between GAEA and FGRSAUD and FGRSDUD in the prediction of, respectively, AUD and DUD was attenuated only slightly by the addition of educational attainment to the model. Conclusions and relevance The genetic propensity to high educational attainment robustly moderates the genetic risk for both AUD and DUD such that the impact of the genetic liability to AUD and DUD on the risk of illness is substantially attenuated in those with high v. low GAEA. This effect is not appreciably mediated by the actual level of educational attainment. These naturalistic findings could form the basis of prevention efforts in high-risk youth.

Olfactory Function, Genetic Predisposition, and Cognitive Performance in Chinese adults

Objective: The objective of this study is to examine the association of olfactory function and genetic predisposition of Alzheimer’s disease (AD) with cognitive performance in adults. Methods: A total of 2049 Chinese adults from Rugao Longevity and Ageing Study (RuLAS, n=1460, mean age 78 years) and Central China Cohort (CCC, n=589, mean age 48 years) were included in this study. A standard interview-based survey, clinical information, and blood samples were collected in both cohorts. Olfactory function in terms of olfactory identification was measured by the brief version of the Chinese Smell Identification Test consisted of 18 full points. Cognitive performance was measured by the Chinese version of the Mini-mental State Examination. A genetic risk score (GRS) was calculated from 5 single nucleotide polymorphisms, which were robustly related to Alzheimer’s disease in Caucasians and cognitive performance in our Chinese population. Results: In the pooled analyses, participants at the lowest quartile of olfactory function had significantly higher odds of cognitive impairment (adjusted odds ratio [95% CI] =1.45 [1.00 to 2.09], Ptrend =0.005), and such association was stronger among participants with a stronger genetic predisposition of Alzheimer’s disease (β coefficient±SE, -0.06±0.03 in participants with a lower GRS vs. -0.19±0.05 in those with a higher GRS, respectively, Pinteraction=0.01). Similar associations were observed in RuLAS (P-trend=0.06) and in CCC (P-trend<0.001). Conclusion: In this study, a decreased olfactory function was associated with worse cognitive performance in adults, especially among participants with a higher genetic risk of Alzheimer’s disease. Further studies are warranted to evaluate the causal relationship between olfaction and cognitive performance.

Distribution and Associated Factors of Hepatic Iron—A Population-Based Imaging Study

Hepatic iron overload can cause severe organ damage; therefore, an early diagnosis and the identification of potential risk factors is crucial. We aimed to investigate the sex-specific distribution of hepatic iron content (HIC) in a population-based cohort and identify relevant associated factors from a panel of markers. We analyzed N = 353 participants from a cross-sectional sample (KORA FF4) who underwent whole-body magnetic resonance imaging. HIC was assessed by single-voxel spectroscopy with a high-speed T2-corrected multi-echo technique. A large panel of markers, including anthropometric, genetic, and laboratory values, as well as behavioral risk factors were assessed. Relevant factors associated with HIC were identified by variable selection based on LASSO regression with bootstrap resampling. HIC in the study sample (mean age at examination: 56.0 years, 58.4% men) was significantly lower in women (mean ± SD: 39.2 ± 4.1 s−1) than in men (41.8 ± 4.7 s−1, p < 0.001). Relevant factors associated with HIC were HbA1c as well as prediabetes for men and visceral adipose tissue as well as age for women. Hepatic fat, alcohol consumption, and genetic risk score for iron levels were associated with HIC in both sexes. In conclusion, there are sex-specific associations of HIC with markers of body composition, glucose metabolism, and alcohol consumption.

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.