Enhancing Selection of Alcohol Consumption Associated Genes by Random Forest.

Machine learning methods have been used in identifying omics markers for a variety of phenotypes. We aimed to examine whether a supervised machine learning algorithm can improve identification of alcohol-associated transcriptomic markers. In this study, we analyzed array-based, whole-blood derived expression data for 17,873 gene transcripts in 5,508 Framingham Heart Study participants. By using the Boruta algorithm, a supervised Random Forest (RF)-based feature selection method, we selected 25 alcohol-associated transcripts. In a testing set (30% of entire study participants), AUCs (area under the receiver operating characteristics curve) of these 25 transcripts were 0.73, 0.69, and 0.66 for nondrinkers vs. moderate drinkers, nondrinkers vs. heavy drinkers, and moderate drinkers vs. heavy drinkers, respectively. The AUCs of the selected transcripts by the Boruta method were comparable to those identified using conventional linear regression models, e.g., AUCs of 1,985 transcripts identified by conventional linear regression models (false discovery rate < 0.05) were 0.72, 0.68, and 0.68, respectively. With Bonferroni correction for the 25 Boruta method selected transcripts and three CVD risk factors (i.e., at P < 6.7e-4), we observed 13 transcripts were associated with obesity, 3 transcripts with type 2 diabetes, and 1 transcript with hypertension. For example, we observed that alcohol consumption was inversely associated with the expression of DOCK4, IL4R, and SORT1, and DOCK4 and SORT1 were positively associated with obesity and IL4R was inversely associated with hypertension. In conclusion, using a supervised machine learning method, the RF-based Boruta algorithm, we identified novel alcohol-associated gene transcripts.

Association analysis between an epigenetic alcohol risk score and blood pressure.

Background: Epigenome-wide association studies have revealed multiple DNA methylation sites (CpGs) associated with alcohol consumption, an important lifestyle risk factor for cardiovascular diseases. Results: We generated an alcohol consumption epigenetic risk score (ERS) based on previously reported 144 alcohol-associated CpGs and examined the association of the ERS with systolic blood pressure (SBP), diastolic blood pressure (DBP), and hypertension (HTN) in 3,898 Framingham Heart Study (FHS) participants. We found an association of alcohol intake with the ERS in the meta-analysis with 0.09 units higher ERS per drink consumed per day ( p < 0.0001). Cross-sectional analyses in FHS revealed that a one-unit increment of the ERS was associated with 1.93 mm Hg higher SBP ( p = 4.64E-07), 0.68 mm Hg higher DBP ( p = 0.006), and an odds ratio of 1.78 for HTN ( p < 2E-16). Meta-analysis of the cross-sectional association of the ERS with BP traits in eight independent external cohorts (n = 11,544) showed similar relationships with blood pressure levels, i.e., a one-unit increase in ERS was associated with 0.74 ( p = 0.002) and 0.50 ( p = 0.0006) mm Hg higher SBP and DBP, but could not confirm the association with hypertension. Longitudinal analyses in FHS (n = 3,260) and five independent external cohorts (n = 4,021) showed that the baseline ERS was not associated with a change in blood pressure over time or with incident HTN. Conclusions: Our findings provide proof-of-concept that utilizing an ERS is a useful approach to capture the recent health consequences of lifestyle behaviors such as alcohol consumption.

Genome-Wide Interaction Analysis With DASH Diet Score Identified Novel Loci for Systolic Blood Pressure.

BACKGROUND: The Dietary Approaches to Stop Hypertension (DASH) diet score lowers blood pressure (BP). We examined interactions between genotype and the DASH diet score in relation to systolic BP. METHODS: We analyzed up to 9 420 585 single nucleotide polymorphisms in up to 127 282 individuals of 6 population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (n=35 660) and UK Biobank (n=91 622) and performed European population-specific and cross-population meta-analyses. RESULTS: We identified 3 loci in European-specific analyses and an additional 4 loci in cross-population analyses at Pinteraction<5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency, 0.03) and the DASH diet score (Pinteraction=4e-8; P for heterogeneity, 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (Pinteraction=9.4e-7) and 0.20±0.06 mm Hg (Pinteraction=0.001) in Cohorts for Heart and Aging Research in Genomic Epidemiology and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with cis-expression quantitative trait loci (eQTL) variants (P=4e-273) and cis-DNA methylation quantitative trait loci variants (P=1e-300). Although the closest gene for rs117878928 is MTHFS, the highest narrow sense heritability accounted by single nucleotide polymorphisms potentially interacting with the DASH diet score in this locus was for gene ST20 at 15q25.1. CONCLUSIONS: We demonstrated gene-DASH diet score interaction effects on systolic BP in several loci. Studies with larger diverse populations are needed to validate our findings.

Circulating metabolites may illustrate relationship of alcohol consumption with cardiovascular disease.

BACKGROUND: Metabolite signatures of long-term alcohol consumption are lacking. To better understand the molecular basis linking alcohol drinking and cardiovascular disease (CVD), we investigated circulating metabolites associated with long-term alcohol consumption and examined whether these metabolites were associated with incident CVD. METHODS: Cumulative average alcohol consumption (g/day) was derived from the total consumption of beer, wine, and liquor on average of 19 years in 2428 Framingham Heart Study Offspring participants (mean age 56 years, 52% women). We used linear mixed models to investigate the associations of alcohol consumption with 211 log-transformed plasma metabolites, adjusting for age, sex, batch, smoking, diet, physical activity, BMI, and familial relationship. Cox models were used to test the association of alcohol-related metabolite scores with fatal and nonfatal incident CVD (myocardial infarction, coronary heart disease, stroke, and heart failure). RESULTS: We identified 60 metabolites associated with cumulative average alcohol consumption (p < 0.05/211 ≈ 0.00024). For example, 1 g/day increase of alcohol consumption was associated with higher levels of cholesteryl esters (e.g., CE 16:1, beta = 0.023 ± 0.002, p = 6.3e - 45) and phosphatidylcholine (e.g., PC 32:1, beta = 0.021 ± 0.002, p = 3.1e - 38). Survival analysis identified that 10 alcohol-associated metabolites were also associated with a differential CVD risk after adjusting for age, sex, and batch. Further, we built two alcohol consumption weighted metabolite scores using these 10 metabolites and showed that, with adjustment age, sex, batch, and common CVD risk factors, the two scores had comparable but opposite associations with incident CVD, hazard ratio 1.11 (95% CI = [1.02, 1.21], p = 0.02) vs 0.88 (95% CI = [0.78, 0.98], p = 0.02). CONCLUSIONS: We identified 60 long-term alcohol consumption-associated metabolites. The association analysis with incident CVD suggests a complex metabolic basis between alcohol consumption and CVD.

Olfactory impairment and the risk of major adverse cardiovascular outcomes in older adults.

Background: Olfactory impairment is common in older adults and may be associated with adverse cardiovascular health; however, empirical evidence is sparse. Objective: To examine olfaction and the risk of coronary heart disease (CHD), stroke, and congestive heart failure (CHF). Methods: This study included 2,537 older adults (aged 75.6±2.8 years) from the Health ABC Study with olfaction assessed by the 12-item Brief Smell Identification Test in 1999-2000, defined as poor (score ≤8), moderate (9-10), or good (11-12). The outcomes were incident CHD, stroke, and CHF. Results: During up to 12-year follow-up, 353 incident CHD, 258 stroke, and 477 CHF events were identified. Olfaction was associated with incident CHF, but not with CHD or stroke. After adjusting for demographics, the cause-specific hazard ratio (HR) of CHF was 1.35 (95% confidence interval (CI): 1.08, 1.70) for moderate and 1.39 (95%CI: 1.09, 1.76) for poor olfaction. With additional adjustment for lifestyle, chronic diseases, and biomarkers of CHF, the HR was modestly attenuated to 1.32 (95%CI: 1.05, 1.66) for moderate and 1.28 (95%CI: 1.01, 1.64) for poor olfaction. These associations were robust in pre-planned subgroup analyses by age, sex, race, and prevalent CHD/stroke. However, the associations appeared to be evident among participants who reported very-good-to-excellent health (HR=1.47 (95%CI: 1.02, 2.13) for moderate and 1.76, (95%CI: 1.20, 2.57) for poor olfaction). In contrast, null association with CHF was found among those with fair-to-poor self-reported health. Conclusions: In community-dwelling older adults, a single olfaction test was associated with a long-term risk for incident CHF, particularly among those reporting very-good-to-excellent health.

Genome-Wide Interaction Analysis with DASH Diet Score Identified Novel Loci for Systolic Blood Pressure.

Objective: We examined interactions between genotype and a Dietary Approaches to Stop Hypertension (DASH) diet score in relation to systolic blood pressure (SBP). Methods: We analyzed up to 9,420,585 biallelic imputed single nucleotide polymorphisms (SNPs) in up to 127,282 individuals of six population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (CHARGE; n=35,660) and UK Biobank (n=91,622) and performed European population-specific and cross-population meta-analyses. Results: We identified three loci in European-specific analyses and an additional four loci in cross-population analyses at P for interaction < 5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency = 0.03) and the DASH diet score (P for interaction = 4e-8; P for heterogeneity = 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (P for interaction = 9.4e-7) and 0.20±0.06 mm Hg (P for interaction = 0.001) in CHARGE and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with cis-expression quantitative trait loci (eQTL) variants (P = 4e-273) and cis-DNA methylation quantitative trait loci (mQTL) variants (P = 1e-300). While the closest gene for rs117878928 is MTHFS, the highest narrow sense heritability accounted by SNPs potentially interacting with the DASH diet score in this locus was for gene ST20 at 15q25.1. Conclusion: We demonstrated gene-DASH diet score interaction effects on SBP in several loci. Studies with larger diverse populations are needed to validate our findings.

Enhanced measurement of tiny rotational angles using conjugate orbital angular momentum modes.

We report the enhanced experimental measurement of tiny rotational angles using two conjugate OAM modes upon rotation of a Dove prism. The two conjugate OAM modes interfere in a petal-like pattern and the orientation of the pattern depends on the phase difference between the two modes. We propose an accurate method of digital image processing to measure the tiny rotational angles of the Dove prism. In the presence of an imperfect pattern and light path, the measurement precision was enhanced by a factor of l. This scheme has potential applications in high-precision sensing and monitoring of tiny rotation angles.

Alcohol consumption and epigenetic age acceleration across human adulthood.

The alcohol-associated biological aging remains to be studied across adulthood. We conducted linear regression analyses to investigate the associations between alcohol consumption and two DNA methylation-based biological age acceleration metrics in 3823 Framingham Heart Study participants (24-92 years and 53.8% women) adjusting for covariates. We also investigated whether the two epigenetic aging metrics mediated the association of alcohol consumption with hypertension. We found that higher long-term average alcohol consumption was significantly associated with biological age acceleration assessed by GrimAge acceleration (GAA) and PhenoAge acceleration (PAA) in middle-aged (45-64 years, n = 1866) and older (65-92 years, n = 1267) participants while not in young participants (24-44 years, n = 690). For example, one additional standard drink of alcohol (~14 grams of ethanol per day) was associated with a 0.71 ± 0.15-year (p = 2.1e-6) and 0.60 ± 0.18-year (p = 7.5e-4) increase in PAA in middle-aged and older participants, respectively, but the association was not significant in young participants (p = 0.23). One additional standard serving of liquor (~14 grams of ethanol) was associated with a greater increase in GAA (0.82-year, p = 4.8e-4) and PAA (1.45-year, p = 7.4e-5) than beer (GAA: 0.45-year, p = 5.2e-4; PAA: 0.48-year, p = 0.02) and wine (GAA: 0.51-year, p = 0.02; PAA: 0.91-year, p = 0.008) in middle-aged participant group. We observed that up to 28% of the association between alcohol consumption and hypertension was mediated by GAA or PAA in the pooled sample. Our findings suggest that alcohol consumption is associated with greater biological aging quantified by epigenetic aging metrics, which may mediate the association of alcohol consumption with quantitative traits, such as hypertension.

Expression quantitative trait methylation analysis elucidates gene regulatory effects of DNA methylation: the Framingham Heart Study.

Expression quantitative trait methylation (eQTM) analysis identifies DNA CpG sites at which methylation is associated with gene expression. The present study describes an eQTM resource of CpG-transcript pairs derived from whole blood DNA methylation and RNA sequencing gene expression data in 2115 Framingham Heart Study participants. We identified 70,047 significant cis CpG-transcript pairs at p < 1E-7 where the top most significant eGenes (i.e., gene transcripts associated with a CpG) were enriched in biological pathways related to cell signaling, and for 1208 clinical traits (enrichment false discovery rate [FDR] ≤ 0.05). We also identified 246,667 significant trans CpG-transcript pairs at p < 1E-14 where the top most significant eGenes were enriched in biological pathways related to activation of the immune response, and for 1191 clinical traits (enrichment FDR ≤ 0.05). Independent and external replication of the top 1000 significant cis and trans CpG-transcript pairs was completed in the Women's Health Initiative and Jackson Heart Study cohorts. Using significant cis CpG-transcript pairs, we identified significant mediation of the association between CpG sites and cardiometabolic traits through gene expression and identified shared genetic regulation between CpGs and transcripts associated with cardiometabolic traits. In conclusion, we developed a robust and powerful resource of whole blood eQTM CpG-transcript pairs that can help inform future functional studies that seek to understand the molecular basis of disease.

Circulating Metabolites May Illustrate Relationship of Alcohol Consumption with Cardiovascular Disease.

Background: Metabolite signatures of long-term alcohol consumption are lacking. To better understand the molecular basis linking alcohol drinking and cardiovascular disease (CVD), we investigated circulating metabolites associated with long-term alcohol consumption and examined whether these metabolites were associated with incident CVD. Methods: Cumulative average alcohol consumption (g/day) was derived from the total consumption of beer, wine and liquor on average of 19 years in 2,428 Framingham Heart Study Offspring participants (mean age 56 years, 52% women). We used linear mixed models to investigate the associations of alcohol consumption with 211 log-transformed plasma metabolites, adjusting for age, sex, batch, smoking, diet, physical activity, BMI, and familial relationship. Cox models were used to test the association of alcohol-related metabolite scores with fatal and nonfatal incident CVD (myocardial infarction, coronary heart disease, stroke, and heart failure). Results: We identified 60 metabolites associated with cumulative average alcohol consumption (p<0.05/211≈0.00024). For example, one g/day increase of alcohol consumption was associated with higher levels of cholesteryl esters (e.g., CE 16:1, beta=0.023±0.002, p=6.3e-45) and phosphatidylcholine (e.g., PC 32:1, beta=0.021±0.002, p=3.1e-38). Survival analysis identified that 10 alcohol-associated metabolites were also associated with a differential CVD risk after adjusting for age, sex, and batch. Further, we built two alcohol consumption weighted metabolite scores using these 10 metabolites and showed that, with adjustment age, sex, batch, and common CVD risk factors, the two scores had comparable but opposite associations with incident CVD, hazard ratio 1.11(95% CI=[1.02, 1.21],p=0.02) vs 0.88 (95% CI=[0.78, 0.98], p=0.02). Summary: We identified 60 long-term alcohol consumption-associated metabolites. The association analysis with incident CVD suggests a complex metabolic basis between alcohol consumption and CVD.

Smoking, blood DNA methylation sites and lung cancer risk.

Altered DNA methylation (DNAm) might be a biological intermediary in the pathway from smoking to lung cancer. In this study, we investigated the contribution of differential blood DNAm to explain the association between smoking and lung cancer incidence. Blood DNAm was measured in 2321 Strong Heart Study (SHS) participants. Incident lung cancer was assessed as time to event diagnoses. We conducted mediation analysis, including validation with DNAm and paired gene expression data from the Framingham Heart Study (FHS). In the SHS, current versus never smoking and pack-years single-mediator models showed, respectively, 29 and 21 differentially methylated positions (DMPs) for lung cancer with statistically significant mediated effects (14 of 20 available, and five of 14 available, positions, replicated, respectively, in FHS). In FHS, replicated DMPs showed gene expression downregulation largely in trans, and were related to biological pathways in cancer. The multimediator model identified that DMPs annotated to the genes AHRR and IER3 jointly explained a substantial proportion of lung cancer. Thus, the association of smoking with lung cancer was partly explained by differences in baseline blood DNAm at few relevant sites. Experimental studies are needed to confirm the biological role of identified eQTMs and to evaluate potential implications for early detection and control of lung cancer.

Dietary and supplemental intake of vitamins C and E is associated with altered DNA methylation in an epigenome-wide association study meta-analysis.

BACKGROUND: Dietary intake of antioxidants such as vitamins C and E protect against oxidative stress, and may also be associated with altered DNA methylation patterns. METHODS: We meta-analysed epigenome-wide association study (EWAS) results from 11,866 participants across eight population-based cohorts to evaluate the association between self-reported dietary and supplemental intake of vitamins C and E with DNA methylation. EWAS were adjusted for age, sex, BMI, caloric intake, blood cell type proportion, smoking status, alcohol consumption, and technical covariates. Significant results of the meta-analysis were subsequently evaluated in gene set enrichment analysis (GSEA) and expression quantitative trait methylation (eQTM) analysis. RESULTS: In meta-analysis, methylation at 4,656 CpG sites was significantly associated with vitamin C intake at FDR ≤ 0.05. The most significant CpG sites associated with vitamin C (at FDR ≤ 0.01) were enriched for pathways associated with systems development and cell signalling in GSEA, and were associated with downstream expression of genes enriched in the immune response in eQTM analysis. Furthermore, methylation at 160 CpG sites was significantly associated with vitamin E intake at FDR ≤ 0.05, but GSEA and eQTM analysis of the top most significant CpG sites associated with vitamin E did not identify significant enrichment of any biological pathways investigated. CONCLUSIONS: We identified significant associations of many CpG sites with vitamin C and E intake, and our results suggest that vitamin C intake may be associated with systems development and the immune response.

Integrative Mendelian randomization reveals the soluble receptor for advanced glycation end products as protective in relation to rheumatoid arthritis.

Rheumatoid arthritis (RA) is a risk factor for atherosclerotic cardiovascular diseases (CVD). Given the critical roles of the immune system and inflammatory signals in the pathogenesis of CVD, we hypothesized that interrogation of CVD-related proteins using integrative genomics might provide new insights into the pathophysiology of RA. We utilized two-sample Mendelian randomization (MR) for causal inference between circulating protein levels and RA by incorporating genetic variants, followed by colocalization to characterize the causal associations. Genetic variants from three sources were obtained: those associated with 71 CVD-related proteins measured in nearly 7000 Framingham Heart Study participants, a published genome-wide association study (GWAS) of RA (19 234 cases, 61 565 controls), and GWAS of rheumatoid factor (RF) levels from the UK Biobank (n = 30 565). We identified the soluble receptor for advanced glycation end products (sRAGE), a critical inflammatory pathway protein, as putatively causal and protective for both RA (odds ratio per 1-standard deviation increment in inverse-rank normalized sRAGE level = 0.364; 95% confidence interval 0.342-0.385; P = 6.40 × 10-241) and RF levels (ß [change in RF level per sRAGE increment] = - 1.318; SE = 0.434; P = 0.002). Using an integrative genomic approach, we highlight the AGER/RAGE axis as a putatively causal and promising therapeutic target for RA.

A Healthy Diet is Associated with a Lower Risk of Hepatic Fibrosis.

BACKGROUND: Higher diet quality is associated with a lower risk of NAFLD. OBJECTIVES: We examined the relationship between diet quality and hepatic fibrosis. METHODS: We analyzed cross-sectional associations between 3 a priori diet quality scores-the Dietary Approaches to Stop Hypertension (DASH) score, the Alternative Healthy Eating Index (AHEI), and a modified Mediterranean-style Diet Score (MDS)-and hepatic fat [controlled attenuation parameter (CAP)] and fibrosis [liver stiffness measurement (LSM)] measured by vibration-controlled transient elastography (VCTE) in 2532 Framingham Heart Study (FHS) participants and 3295 participants of the National Health and Nutrition Examination Survey (NHANES). RESULTS: Higher diet quality scores were associated with lower LSM in both FHS and NHANES after adjustment for demographic and lifestyle factors. Additional adjustment for CAP or BMI attenuated the observed associations. Association strength was similar across all 3 diet quality scores. Fixed-effect meta-analysis demonstrated that, under CAP-adjusted models, the LSM decreases associated with 1-SD increase of the DASH, AHEI, and MDS scores were 2% (95% CI: 0.7%, 3.3%; P = 0.002), 2% (95% CI: 0.7%, 3.3%; P = 0.003), and 1.7% (95% CI: 0.7%, 2.6%; P = 0.001), respectively, whereas in the meta-analysis of BMI-adjusted models, LSM reductions associated with 1-SD increase of the DASH, AHEI, and MDS scores were 2.2% (95% CI: -0.1%, 2.2%; P = 0.07), 1.5% (95% CI: 0.3%, 2.7%; P = 0.02), and 0.9 (95% CI: -0.1%, 1.9%; P = 0.07), respectively. CONCLUSIONS: We demonstrated associations of higher diet quality with favorable hepatic fat and fibrosis measures. Our data suggest that a healthy diet may reduce the likelihood of obesity and hepatic steatosis as well as the progression of steatosis to fibrosis.

Bright semiconductor single-photon sources pumped by heterogeneously integrated micropillar lasers with electrical injections.

The emerging hybrid integrated quantum photonics combines the advantages of different functional components into a single chip to meet the stringent requirements for quantum information processing. Despite the tremendous progress in hybrid integrations of III-V quantum emitters with silicon-based photonic circuits and superconducting single-photon detectors, on-chip optical excitations of quantum emitters via miniaturized lasers towards single-photon sources (SPSs) with low power consumptions, small device footprints, and excellent coherence properties is highly desirable yet illusive. In this work, we present realizations of bright semiconductor SPSs heterogeneously integrated with on-chip electrically-injected microlasers. Different from previous one-by-one transfer printing technique implemented in hybrid quantum dot (QD) photonic devices, multiple deterministically coupled QD-circular Bragg Grating (CBG) SPSs were integrated with electrically-injected micropillar lasers at one time via a potentially scalable transfer printing process assisted by the wide-field photoluminescence (PL) imaging technique. Optically pumped by electrically-injected microlasers, pure single photons are generated with a high-brightness of a count rate of 3.8 M/s and an extraction efficiency of 25.44%. Such a high-brightness is due to the enhancement by the cavity mode of the CBG, which is confirmed by a Purcell factor of 2.5. Our work provides a powerful tool for advancing hybrid integrated quantum photonics in general and boosts the developments for realizing highly-compact, energy-efficient and coherent SPSs in particular.

Bitter- and Umami-Related Genes are Differentially Associated with Food Group Intakes: the Framingham Heart Study.

BACKGROUND: As suboptimal diet quality remains the leading modifiable contributor to chronic disease risk, it is important to better understand the individual-level drivers of food choices. Recently, a genetic component of food choices was proposed based on variants (SNPs) in genes related to taste perception (taste-related SNPs). OBJECTIVES: This study aimed to determine the cumulative contribution of taste-related SNPs for basic tastes (bitter, sweet, umami, salt, and sour), summarized as "polygenic taste scores," to food group intakes among adults. METHODS: Cross-sectional analyses were performed on 6230 Framingham Heart Study participants (mean age ± SD: 50 ± 14 y; 54% female). Polygenic taste scores were derived for tastes with ≥2 related SNPs identified in prior genome-wide association studies, and food group intakes (servings per week [sev/wk]) were tabulated from food frequency questionnaires. Associations were determined via linear mixed-effects models, using false discovery rates and bootstrap resampling to determine statistical significance. RESULTS: Thirty-three taste-related SNPs (9 bitter, 19 sweet, 2 umami, 2 sour, 1 salt) were identified and used to derive polygenic taste scores for bitter, sweet, umami, and sour. Per additional allele for higher bitter perception, whole grain intakes were lower by 0.17 (95% CI: -0.28, -0.06) sev/wk, and for higher umami perception, total and red/orange vegetable intakes were lower by 0.73 (95% CI: -1.12, -0.34) and 0.25 (95% CI: -0.40, -0.10) sev/wk, respectively. Subsequent analyses at the SNP level identified four novel SNP-diet associations-two bitter-related SNPs with whole grains (rs10960174 and rs6782149) and one umami-related SNP with total and red/orange vegetables (rs7691456)-which may have been driving the identified associations. CONCLUSIONS: Taste-related genes for bitter and umami were differentially associated with food choices that may impact diet quality. Hence, a benefit could be derived from leveraging knowledge of taste-related genes when developing personalized risk reduction dietary guidance.

Investigating Gene-Diet Interactions Impacting the Association Between Macronutrient Intake and Glycemic Traits.

Few studies have demonstrated reproducible gene-diet interactions (GDIs) impacting metabolic disease risk factors, likely due in part to measurement error in dietary intake estimation and insufficient capture of rare genetic variation. We aimed to identify GDIs across the genetic frequency spectrum impacting the macronutrient-glycemia relationship in genetically and culturally diverse cohorts. We analyzed 33,187 participants free of diabetes from 10 National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program cohorts with whole-genome sequencing, self-reported diet, and glycemic trait data. We fit cohort-specific, multivariable-adjusted linear mixed models for the effect of diet, modeled as an isocaloric substitution of carbohydrate for fat, and its interactions with common and rare variants genome-wide. In main effect meta-analyses, participants consuming more carbohydrate had modestly lower glycemic trait values (e.g., for glycated hemoglobin [HbA1c], -0.013% HbA1c/250 kcal substitution). In GDI meta-analyses, a common African ancestry-enriched variant (rs79762542) reached study-wide significance and replicated in the UK Biobank cohort, indicating a negative carbohydrate-HbA1c association among major allele homozygotes only. Simulations revealed that >150,000 samples may be necessary to identify similar macronutrient GDIs under realistic assumptions about effect size and measurement error. These results generate hypotheses for further exploration of modifiable metabolic disease risk in additional cohorts with African ancestry. ARTICLE HIGHLIGHTS: We aimed to identify genetic modifiers of the dietary macronutrient-glycemia relationship using whole-genome sequence data from 10 Trans-Omics for Precision Medicine program cohorts. Substitution models indicated a modest reduction in glycemia associated with an increase in dietary carbohydrate at the expense of fat. Genome-wide interaction analysis identified one African ancestry-enriched variant near the FRAS1 gene that may interact with macronutrient intake to influence hemoglobin A1c. Simulation-based power calculations accounting for measurement error suggested that substantially larger sample sizes may be necessary to discover further gene-macronutrient interactions.

Blood transcriptomic biomarkers of alcohol consumption and cardiovascular disease risk factors: the Framingham Heart Study.

BACKGROUND: The relations of alcohol consumption and gene expression remain to be elucidated. MATERIALS AND METHODS: We examined cross-sectional associations between alcohol consumption and whole blood derived gene expression levels and between alcohol-associated genes and obesity, hypertension, and diabetes in 5531 Framingham Heart Study (FHS) participants. RESULTS: We identified 25 alcohol-associated genes. We further showed cross-sectional associations of 16 alcohol-associated genes with obesity, nine genes with hypertension, and eight genes with diabetes at P < 0.002. For example, we observed decreased expression of PROK2 (ß = -0.0018; 95%CI: -0.0021, -0.0007; P = 6.5e - 5) and PAX5 (ß = -0.0014; 95%CI: -0.0021, -0.0007; P = 6.5e - 5) per 1 g/day increase in alcohol consumption. Consistent with our previous observation on the inverse association of alcohol consumption with obesity and positive association of alcohol consumption with hypertension, we found that PROK2 was positively associated with obesity (OR = 1.42; 95%CI: 1.17, 1.72; P = 4.5e - 4) and PAX5 was negatively associated with hypertension (OR = 0.73; 95%CI: 0.59, 0.89; P = 1.6e - 3). We also observed that alcohol consumption was positively associated with expression of ABCA13 (ß = 0.0012; 95%CI: 0.0007, 0.0017; P = 1.3e - 6) and ABCA13 was positively associated with diabetes (OR = 2.57; 95%CI: 1.73, 3.84; P = 3.5e - 06); this finding, however, was inconsistent with our observation of an inverse association between alcohol consumption and diabetes. CONCLUSIONS: We showed strong cross-sectional associations between alcohol consumption and expression levels of 25 genes in FHS participants. Nonetheless, complex relationships exist between alcohol-associated genes and CVD risk factors.

Whole genome DNA and RNA sequencing of whole blood elucidates the genetic architecture of gene expression underlying a wide range of diseases.

To create a scientific resource of expression quantitative trail loci (eQTL), we conducted a genome-wide association study (GWAS) using genotypes obtained from whole genome sequencing (WGS) of DNA and gene expression levels from RNA sequencing (RNA-seq) of whole blood in 2622 participants in Framingham Heart Study. We identified 6,778,286 cis-eQTL variant-gene transcript (eGene) pairs at p < 5 × 10-8 (2,855,111 unique cis-eQTL variants and 15,982 unique eGenes) and 1,469,754 trans-eQTL variant-eGene pairs at p < 1e-12 (526,056 unique trans-eQTL variants and 7233 unique eGenes). In addition, 442,379 cis-eQTL variants were associated with expression of 1518 long non-protein coding RNAs (lncRNAs). Gene Ontology (GO) analyses revealed that the top GO terms for cis-eGenes are enriched for immune functions (FDR < 0.05). The cis-eQTL variants are enriched for SNPs reported to be associated with 815 traits in prior GWAS, including cardiovascular disease risk factors. As proof of concept, we used this eQTL resource in conjunction with genetic variants from public GWAS databases in causal inference testing (e.g., COVID-19 severity). After Bonferroni correction, Mendelian randomization analyses identified putative causal associations of 60 eGenes with systolic blood pressure, 13 genes with coronary artery disease, and seven genes with COVID-19 severity. This study created a comprehensive eQTL resource via BioData Catalyst that will be made available to the scientific community. This will advance understanding of the genetic architecture of gene expression underlying a wide range of diseases.

Efficient second harmonic generation by harnessing bound states in the continuum in semi-nonlinear etchless lithium niobate waveguides.

Integrated photonics provides unprecedented opportunities to pursue advanced nonlinear light sources with low-power consumptions and small footprints in a scalable manner, such as microcombs, chip-scale optical parametric oscillators and integrated quantum light sources. Among a variety of nonlinear optical processes, high-efficiency second harmonic generation (SHG) on-chip is particularly appealing and yet challenging. In this work, we present efficient SHG in highly engineerable semi-nonlinear waveguides consisting of electron-beam resist waveguides and thin-film silicon nitride (SiN)/lithium niobate (LN). By carefully designing octave-separating bound states in the continuum (BICs) for the nonlinear interacting waves in such a hybrid structure, we have simultaneously optimized the losses for both fundamental frequency (FF) and second harmonic (SH) waves and achieved modal phasing matching and maximized the nonlinear modal overlap between the FF and SH waves, which results in an experimental conversion efficiency up to 4.05% W-1cm-2. Our work provides a versatile and fabrication-friendly platform to explore on-chip nonlinear optical processes with high efficiency in the context of nanophotonics and quantum optics.