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Background: Coronary artery calcium (CAC) is a marker of subclinical atherosclerosis and is a complex heritable trait with both genetic and environmental risk factors, including sex and smoking. Methods: We performed genome-wide association (GWA) analyses for CAC among all participants and stratified by sex in the COPDGene study (n = 6144 participants of European ancestry and n = 2589 participants of African ancestry) with replication in the Diabetes Heart Study (DHS). We adjusted for age, sex, current smoking status, BMI, diabetes, self-reported high blood pressure, self-reported high cholesterol, and genetic ancestry (as summarized by principal components computed within each racial group). For the significant signals from the GWA analyses, we examined the single nucleotide polymorphism (SNP) by sex interactions, stratified by smoking status (current vs. former), and tested for a SNP by smoking status interaction on CAC. Results: We identified genome-wide significant associations for CAC in the chromosome 9p21 region [CDKN2B-AS1] among all COPDGene participants (p = 7.1 × 10-14) and among males (p = 1.0 × 10-9), but the signal was not genome-wide significant among females (p = 6.4 × 10-6). For the sex stratified GWA analyses among females, the chromosome 6p24 region [PHACTR1] had a genome-wide significant association (p = 4.4 × 10-8) with CAC, but this signal was not genome-wide significant among all COPDGene participants (p = 1.7 × 10-7) or males (p = 0.03). There was a significant interaction for the SNP rs9349379 in PHACTR1 with sex (p = 0.02), but the interaction was not significant for the SNP rs10757272 in CDKN2B-AS1 with sex (p = 0.21). In addition, PHACTR1 had a stronger association with CAC among current smokers (p = 6.2 × 10-7) than former smokers (p = 7.5 × 10-3) and the SNP by smoking status interaction was marginally significant (p = 0.03). CDKN2B-AS1 had a strong association with CAC among both former (p = 7.7 × 10-8) and current smokers (p = 1.7 × 10-7) and the SNP by smoking status interaction was not significant (p = 0.40). Conclusions: Among current and former smokers of European ancestry in the COPDGene study, we identified a genome-wide significant association in the chromosome 6p24 region [PHACTR1] with CAC among females, but not among males. This region had a significant SNP by sex and SNP by smoking interaction on CAC.

Regular exercise promotes whole-body health and prevents disease, but the underlying molecular mechanisms are incompletely understood1-3. Here, the Molecular Transducers of Physical Activity Consortium4 profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome and immunome in whole blood, plasma and 18 solid tissues in male and female Rattus norvegicus over eight weeks of endurance exercise training. The resulting data compendium encompasses 9,466 assays across 19 tissues, 25 molecular platforms and 4 training time points. Thousands of shared and tissue-specific molecular alterations were identified, with sex differences found in multiple tissues. Temporal multi-omic and multi-tissue analyses revealed expansive biological insights into the adaptive responses to endurance training, including widespread regulation of immune, metabolic, stress response and mitochondrial pathways. Many changes were relevant to human health, including non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health and tissue injury and recovery. The data and analyses presented in this study will serve as valuable resources for understanding and exploring the multi-tissue molecular effects of endurance training and are provided in a public repository ( https://motrpac-data.org/ ).

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer.

RATIONALE & OBJECTIVE: In the Lifestyle Interventions and Independence for Elders (LIFE) trial, a structured exercise intervention slowed kidney function decline in sedentary older adults. Biomarkers of kidney health could distinguish potential mechanisms for this beneficial effect. STUDY DESIGN: Randomized controlled trial. SETTING & POPULATION: A total of 1,381 sedentary adults aged 70-89 years enrolled in the LIFE trial. INTERVENTION: Structured, 2-year, moderate-intensity exercise intervention versus health education. OUTCOMES: Physical activity was measured by step count. Primary outcomes were changes in 14 serum and urine biomarkers of kidney health collected at baseline, year 1, and year 2. We determined the effect of randomization on changes in kidney measures and then evaluated observational associations of achieved activity on each measure. RESULTS: Participants assigned to exercise walked on average 291 more steps per day than participants assigned to health education. The intervention was not significantly associated with changes in biomarkers of kidney health. In observational analyses, persons in the highest versus lowest quartile of activity (≥3,470 vs

Living alone, particularly for individuals with poor physical health, can increase the likelihood of mortality. This study aimed to explore the individual and joint associations of living alone and physical health with overall mortality among breast cancer survivors in the Women's Healthy Eating and Living (WHEL). We collected baseline, 12-month and 48-month data among 2869 women enrolled in the WHEL cohort. Living alone was assessed as a binary variable (Yes, No), while scores of physical health were measured using the RAND Short Form-36 survey (SF-36), which include four domains (physical function, role limitation, bodily pain, and general health perceptions) and an overall summary score of physical health. Cox proportional hazard models were used to evaluate associations. No significant association between living alone and mortality was observed. However, several physical health measures showed significant associations with mortality (p-values < 0.05). For physical function, the multivariable model showed a hazard ratio (HR) of 2.1 (95% CI = 1.02-4.23). Furthermore, the study examined the joint impact of living alone and physical health measures on overall mortality. Among women with better physical function, those living alone had a 3.6-fold higher risk of death (95% CI = 1.01-12.89) compared to those not living alone. Similar trends were observed for pain. However, regarding role limitation, the pattern differed. Breast cancer survivors living alone with worse role limitations had the highest mortality compared to those not living alone but with better role limitations (HR = 2.6, 95% CI = 1.11-5.95). Similar trends were observed for general health perceptions. Our findings highlight that living alone amplifies the risk of mortality among breast cancer survivors within specific health groups.

Breast cancer survivors often have a reduced digestive capacity to digest whole grains due to cancer treatment. The purpose of this study was to investigate the independent and joint associations of whole grain and refined grain consumption with total mortality among breast cancer survivors. We studied a cohort of 3081 female breast cancer survivors who provided demographic, dietary, and lifestyle data at baseline, year 1 and year 4. Mortality was assessed via semi-annual telephone interviews and confirmed by the National Death Index (NDI) and death certificates. We assessed the associations of whole grain and refined grain with incident of mortalities using Cox proportional hazards models. Increased whole grain consumption was marginally associated with an increased risk of total mortality (p = 0.07) but was not significantly associated with breast cancer-specific mortality (p = 0.55). An increased intake of refined grains was associated with an increased risk of both total (HR = 1.74; 95% CI,1.17 to 2.59) and breast cancer-specific mortality (HR = 1.16; 95% CI, 1.08 to 1.26). Furthermore, we examined the joint associations of whole grain and refined grain with total mortality. Among those with a high consumption of refined grain, those with high consumption of whole grain had a higher risk of total mortality (HR = 1.52, 95% CI, 1.07 to 2.14) than those with a low consumption of whole grain. Increased consumption of whole grains may exacerbate the adverse associations of refined grain with mortality among breast cancer survivors. Our findings indicate the need to revisit current dietary guidelines for breast cancer survivors regarding whole grain intake.

Insomnia is prevalent in up to 40% of breast cancer survivors. Few studies have examined pessimism and dietary factors as risk factors for insomnia among breast cancer survivors. We leveraged a cohort of 2944 breast cancer survivors who enrolled in the Women’s Healthy Eating and Living study; these survivors provided dietary, insomnia, mental health, demographic, and lifestyle information at baseline and at 1- and 4-year follow-up assessments. Insomnia symptoms were assessed using the Women’s Health Initiative (WHI)-Insomnia Rating Scale, and pessimism was assessed using the Life Orientation Test Revised (LOT-R). Total calorie intake and acid-producing diets were assessed using 24 h dietary recalls. Multivariable-adjusted generalized estimating equation (GEE) models were used to test the independent and joint effects of psychological and dietary factors on insomnia. In the multivariable model, women in the third tertile of pessimism had greater odds (OR = 1.57 95% CI [1.37−1.79]) of insomnia when compared to women in the lowest tertile. Total calorie intake and acid-producing diets were each independently and significantly associated with insomnia symptoms. Further, pessimism and calorie intake/acid-producing diets were jointly associated with insomnia. For instance, women with pessimism scores in tertile 3 and total calorie intakes < median reported 2 times the odds (OR = 2.09; 95% CI [1.51−3.47]) of insomnia compared to women with pessimism score in tertile 1 and calorie intakes < median. Our results highlight the need for patient care regarding mental health, and recommendations of healthy dietary intakes for breast cancer survivors.

The purpose of this study was to examine the independent and joint associations of acid-producing diets and depressive symptoms with physical health among breast cancer survivors. We studied a cohort of 2944 early stage breast cancer survivors who provided dietary, physical health, demographic, and lifestyle information at baseline, year 1, and year 4. We assessed the intakes of acid-producing diets via two commonly used dietary acid load scores: potential renal acid load (PRAL) and net endogenous acid production (NEAP). Physical health was measured using the Rand 36-Item Short Form Health Survey (SF-36), consisting of physical functioning, role limitation due to physical function, bodily pain, general health, and overall physical health subscales. Increased dietary acid load and depression were each independently and significantly associated with reduced physical health subscales and overall physical health. Further, dietary acid load and depression were jointly associated with worse physical health. For instance, depressed women with dietary acid load higher than median reported 2.75 times the risk (odds ratio = 2.75; 95% confidence interval: 2.18-3.47) of reduced physical function and 3.10 times the risk of poor physical health (odds ratio = 3.10; 95% confidence interval: 2.53-3.80) compared to non-depressed women with dietary acid load lower than median. Our results highlight the need of controlling acid-producing diets and the access of mental care for breast cancer survivors.

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P

Abstract: Cancer survivors are at accelerated risk of aging and more susceptible to unhealthy diets and lifestyles than people without cancers. However, current dietary guidelines for cancer survivors not quite different from that for general healthy population. Further, these guidelines are not specific for cancer survivors who are past smokers. Acid-producing diet can accelerate aging and stimulate cancer development if acid-base balance is not regulated properly. Cancer survivors and past smokers have reduced capacities to adjust acid-base balance. Thus, we conducted prospective cohort analyses among 2950 early-stage breast cancer survivors who enrolled in the Women’s Healthy Eating and Living study and provided dietary information through 24-hour recalls at baseline and during follow-up. We assessed dietary acid load using two common dietary acid load scores, potential renal acid load (PRAL) score, and net endogenous acid production (NEAP) score. We assessed past smoking intensity by pack-years of smoking. After an average of 7.3 years of follow-up, there were 295 total death, and 249 breast cancer-specific death. Increased PRAL and NEAP scores were positively associated with total mortality and breast cancer-specific mortality (p for trend

The incidence of depression is two-to-three times higher in cancer survivors than the general population. Acid-producing diets may play important roles in the development of depression. Cancer survivors are more susceptible to acid-producing diets, yet few prospective studies have investigated the association of acid-producing diets with depression among breast cancer survivors. We leveraged a large cohort of 2975 early stage breast cancer survivors, which collected detailed dietary data via 24-h recalls. Potential renal acid load (PRAL) and net endogenous acid production (NEAP), two commonly used dietary acid load scores, were used to estimate acid-producing diets. Intakes of PRAL and NEAP were assessed at baseline and years one and four. Increased PRAL and NEAP were each independently associated with increased depression in the longitudinal analyses, after adjusting for covariates. The magnitude of the associations was stronger for PRAL than NEAP. Women with the highest quartile intakes of PRAL had 1.34 (95% CI 1.11-1.62) times the risk of depression compared to women with the lowest quartile. Furthermore, we also observed a joint impact of PRAL and younger age on depression, as well as a joint impact of PRAL and physical activity on depression. Decreasing the consumption of acid-producing diets may be a novel and practical strategy for reducing depressive symptoms among breast cancer survivors, especially those who are younger and have a sedentary lifestyle.

Current dietary guidelines do not consider cancer survivors' and past smokers' low capacity to regulate their acid-base balance. People with a low capacity to regulate their acid-base balance are more susceptible to acid-producing diets. We studied a cohort of 2950 early stage breast cancer survivors who provided dietary information at baseline and during follow-up. We assessed the intakes of acid-producing diets via two commonly used dietary acid load scores: potential renal acid load (PRAL) and net endogenous acid production (NEAP). We assessed past smoking intensity by pack-years of smoking. After an average of 7.3 years of follow-up, there were 295 total deaths, 249 breast cancer-specific deaths, and 490 cases of recurrent breast cancer. Increased intakes of dietary acid load and pack-years of smoking were each independently and jointly associated with increased total mortality and breast cancer-specific mortality; tests for trends and overall associations were statistically significant for NEAP and marginally significant for PRAL. Compared to women in the lowest tertile of NEAP and pack-year of smoking = 0, women in the highest tertile of NEAP and pack-years of smoking >15 had the greatest increased risk of total mortality (HR = 3.23, 95%CI 1.99-5.26). Further, dietary acid scores were associated with increased breast cancer recurrence among women with pack-years of smoking >0 but not in those with pack-years of smoking = 0 (p values for interactions

BackgroundMetabolic acidosis promotes cancer metastasis. No prospective studies have examined the association between dietary acid load and breast cancer recurrence among breast cancer survivors, who are susceptible to metabolic acidosis. Hyperglycemia promotes cancer progression and acid formation; however, researchers have not examined whether hyperglycemia can modify the association between dietary acid load and breast cancer recurrence.MethodsWe studied 3081 early-stage breast cancer survivors enrolled in the Women's Healthy Eating and Living study who provided dietary information through 24-h recalls at baseline and during follow-up and had measurements of hemoglobin A1c (HbA1c) at baseline. We assessed dietary acid load using two common dietary acid load scores, potential renal acid load (PRAL) score and net endogenous acid production (NEAP) score.ResultsAfter an average of 7.3 years of follow-up, dietary acid load was positively associated with recurrence when baseline HbA1c levels were ≥ 5.6% (median level) and ≥5.7% (pre-diabetic cut-point). In the stratum with HbA1c ≥ 5.6%, comparing the highest to the lowest quartile of dietary acid load, the multivariable-adjusted hazard ratio was 2.15 (95% confidence interval [CI] 1.34-3.48) for PRAL and was 2.31 (95% CI 1.42-3.74) for NEAP. No associations were observed in the stratum with HbA1c levels were

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.

BackgroundCoronary artery calcified plaque (CAC) is strongly predictive of cardiovascular disease (CVD) events and mortality, both in general populations and individuals with type 2 diabetes at high risk for CVD. CAC is typically reported as an Agatston score, which is weighted for increased plaque density. However, the role of CAC density in CVD risk prediction, independently and with CAC volume, remains unclear.MethodsWe examined the role of CAC density in individuals with type 2 diabetes from the family-based Diabetes Heart Study and the African American-Diabetes Heart Study. CAC density was calculated as mass divided by volume, and associations with incident all-cause and CVD mortality [median follow-up 10.2 years European Americans (n = 902, n = 286 deceased), 5.2 years African Americans (n = 552, n = 93 deceased)] were examined using Cox proportional hazards models, independently and in models adjusted for CAC volume.ResultsIn European Americans, CAC density, like Agatston score and volume, was consistently associated with increased risk of all-cause and CVD mortality (p ≤ 0.002) in models adjusted for age, sex, statin use, total cholesterol, HDL, systolic blood pressure, high blood pressure medication use, and current smoking. However, these associations were no longer significant when models were additionally adjusted for CAC volume. CAC density was not significantly associated with mortality, either alone or adjusted for CAC volume, in African Americans.ConclusionsCAC density is not associated with mortality independent from CAC volume in European Americans and African Americans with type 2 diabetes.

We demonstrate highly sensitive, efficient, ambient-stable organic photodetectors (OPDs) in an inverted platform. The bilayer structure of poly{[N,N′′-bis(2-octyldodecyl)-naphthalene-1,4,5,8-bis(dicarboximide)-2,6-diyl]-alt-5,5′-(2,2′bithiophene)}/poly[9,9-bis(6′-(N,N-diethylamino)propyl)-fluorene-alt-9,9-bis-(3-ethyl(oxetane-3-ethyloxy)-hexyl)-fluorene] (N2200/PFN-OX) with hydrophobic surface characteristics is implemented as an electron-transport layer (ETL) for the fabrication of ITO/N2200/PFN-OX/P3HT:PCBM/MoO3/Ag bulk heterojunction type OPDs. Devices with a 15-nm-thick N2200/PFN-OX layer are able to produce an ultra-low dark current density of 1.58 × 10−11 A cm−2 at 0 V, a faster response time of 4.9 μs, a wide linear dynamic range (LDR) value of >138 dB, and an impressive detectivity of 1.20 × 1014 cm Hz1/2 W−1. Additionally, after 63 days, the OPDs retain 85% and 70% of their initial responsivity and detectivity, respectively, in contrast to those with hydrophilic ZnO as the ETL having 70% and 30% residuals, respectively. The superior performance of the proposed OPDs can be attributed to the hydrophobic surface characteristics of the polymer bilayer, which enables the formation of an excellent interface with the photoactive layer to facilitate charge transport and minimize the influence of water molecules. Our approach is very useful and can be generalized to other highly efficient photoactive blends and even other organic optoelectronic devices for developing high-performance, ambient-stable devices. [ABSTRACT FROM AUTHOR]

Sugar-sweetened beverage (SSB) and fruit juice (FJ) consumption may promote lipid abnormalities in childhood. We examined the association between SSB/FJ intake and lipid levels using electronic health record data for 2816 adolescents. Multivariable logistic regression models treated clinical cutpoints for abnormal lipid levels (triglycerides [TG], high-density lipoprotein (HDL), low-density lipoprotein [LDL], and total cholesterol) as dependent variables. In models not adjusted for adiposity, elevated SSB and FJ consumption was associated with increased odds of having abnormally high TG (SSB: odds ratio [OR] = 1.28 (95% confidence interval [CI] = [1.07-1.52], P =.007); FJ: 1.35 ([1.09-1.69], P =.007)) and abnormally low HDL (SSB: 1.47 ([1.17-1.86], P =.001); FJ: 1.35 ([1.02-1.78], P =.03)). Adjusting for adiposity, a likely mediator of the relationship, attenuated these associations. These findings support the need for identifying unhealthy beverage consumption habits during childhood health care visits as a modifiable behavior associated with cardiometabolic risk. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. Because many genes associate with DKD, multiomics approaches were used to narrow the list of functional genes, gene products, and related pathways providing insights into the pathophysiological mechanisms of DKD. The Kidney Precision Medicine Project human kidney single-cell RNA-sequencing (scRNA-seq) data set and Mendeley Data on human kidney cortex biopsy proteomics were used. The R package Seurat was used to analyze scRNA-seq data and data from a subset of proximal tubule cells. PathfindR was applied for pathway analysis in cell type–specific differentially expressed genes and the R limma package was used to analyze differential protein expression in kidney cortex. A total of 790 differentially expressed genes were identified in proximal tubule cells, including 530 upregulated and 260 downregulated transcripts. Compared with differentially expressed proteins, 24 genes or proteins were in common. An integrated analysis combining protein quantitative trait loci, genome-wide association study hits (namely, estimated glomerular filtration rate), and a plasma metabolomics analysis was performed using baseline metabolites predictive of DKD progression in our longitudinal Diabetes Heart Study samples. The aldo-keto reductase family 1 member A1 gene (AKR1A1) was revealed as a potential molecular hub for DKD cellular dysfunction in several cross-linked pathways featured by deficiency of this enzyme. Article Highlights: It is critical to identify credible biomarkers for progression of diabetic kidney disease (DKD) useful in clinical practice. We used multiomics approaches to uncover and cross-verify DKD biomarkers using publicly available genomics, single-cell transcriptomics, and proteomics data, as well as our unique immunofluorescence microscopy and metabolomics data. We found that the aldo-keto reductase family-1 member A1 (AKR1A1) transcript and protein/enzyme level was significantly lower in proximal tubule cells of patients with DKD than in those of control cells. DKD progression was supported by higher plasma metabolic end products catalyzed by AKR1A1. Our results suggest AKR1A1 and/or its metabolic end products may serve as biomarkers for DKD. [ABSTRACT FROM AUTHOR]

Background and Purpose- White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. Methods- In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies. Results- At 17q25, we confirmed the association of multiple common variants in TRIM65, FBF1, and ACOX1 ( P

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

BACKGROUND:Data are sparse regarding the value of physical activity (PA) surveillance among older adults-particularly among those with mobility limitations. The objective of this study was to examine longitudinal associations between objectively measured daily PA and the incidence of cardiovascular events among older adults in the LIFE (Lifestyle Interventions and Independence for Elders) study. METHODS AND RESULTS:Cardiovascular events were adjudicated based on medical records review, and cardiovascular risk factors were controlled for in the analysis. Home-based activity data were collected by hip-worn accelerometers at baseline and at 6, 12, and 24 months postrandomization to either a physical activity or health education intervention. LIFE study participants (n=1590; age 78.9±5.2 [SD] years; 67.2% women) at baseline had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500 steps taken per day based on activity data (hazard ratio, 0.89; 95% confidence interval, 0.84-0.96; P=0.001). At baseline, every 30 minutes spent performing activities ≥500 counts per minute (hazard ratio, 0.75; confidence interval, 0.65-0.89 [P=0.001]) were also associated with a lower incidence of cardiovascular events. Throughout follow-up (6, 12, and 24 months), both the number of steps per day (per 500 steps; hazard ratio, 0.90, confidence interval, 0.85-0.96 [P=0.001]) and duration of activity ≥500 counts per minute (per 30 minutes; hazard ratio, 0.76; confidence interval, 0.63-0.90 [P=0.002]) were significantly associated with lower cardiovascular event rates. CONCLUSIONS:Objective measurements of physical activity via accelerometry were associated with cardiovascular events among older adults with limited mobility (summary score >10 on the Short Physical Performance Battery) both using baseline and longitudinal data. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01072500.

Insertions and deletions (INDELs) represent a significant fraction of interindividual variation in the human genome yet their contribution to phenotypes is poorly understood. To confirm the quality of imputed INDELs and investigate their roles in mediating cardiometabolic phenotypes, genome-wide association and linkage analyses were performed for 15 phenotypes with 1,273,952 imputed INDELs in 1,024 Mexican-origin Americans. Imputation quality was validated using whole exome sequencing with an average kappa of 0.93 in common INDELs (minor allele frequencies [MAFs] ≥ 5%). Association analysis revealed one genome-wide significant association signal for the cholesterylester transfer protein gene (CETP) with high-density lipoprotein levels (rs36229491, P = 3.06 × 10-12 ); linkage analysis identified two peaks with logarithm of the odds (LOD) > 5 (rs60560566, LOD = 5.36 with insulin sensitivity (SI ) and rs5825825, LOD = 5.11 with adiponectin levels). Suggestive overlapping signals between linkage and association were observed: rs59849892 in the WSC domain containing 2 gene (WSCD2) was associated and nominally linked with SI (P = 1.17 × 10-7 , LOD = 1.99). This gene has been implicated in glucose metabolism in human islet cell expression studies. In addition, rs201606363 was linked and nominally associated with low-density lipoprotein (P = 4.73 × 10-4 , LOD = 3.67), apolipoprotein B (P = 1.39 × 10-3 , LOD = 4.64), and total cholesterol (P = 1.35 × 10-2 , LOD = 3.80) levels. rs201606363 is an intronic variant of the UBE2F-SCLY (where UBE2F is ubiquitin-conjugating enzyme E2F and SCLY is selenocysteine lyase) fusion gene that may regulate cholesterol through selenium metabolism. In conclusion, these results confirm the feasibility of imputing INDELs from array-based single nucleotide polymorphism (SNP) genotypes. Analysis of these variants using association and linkage replicated previously identified SNP signals and identified multiple novel INDEL signals. These results support the inclusion of INDELs into genetic studies to more fully interrogate the spectrum of genetic variation.

BackgroundWhile low vitamin K status has been associated with several chronic diseases that can lead to lower extremity disability, it is not known if low vitamin K status is associated with worse lower extremity function.MethodsVitamin K status was measured according to plasma phylloquinone (vitamin K1) and dephosphorylated-uncarboxylated MGP (dp-ucMGP) in 1,089 community-dwelling older adults (mean ± SD age =74±3 years; 67% female). Lower extremity function was assessed using the short physical performance battery (SPPB), gait speed, and isokinetic leg strength. Linear regression and mixed models were used to determine the cross-sectional and longitudinal associations between vitamin K status and functional outcome measures.ResultsCross-sectionally, higher plasma phylloquinone was associated with better SPPB scores and 20-m gait speed (p ≤ .05). After 4-5 years, those with ≥1.0nM plasma phylloquinone (the concentration achieved when recommended intakes are met) had better SPPB scores (p = .03) and 20-m gait speed (p < .05). Lower plasma dp-ucMGP (reflective of better vitamin K status) was associated with better SPPB scores and leg strength cross-sectionally (p ≤ .04), but not longitudinally. Neither measure of vitamin K status was associated with walking endurance or with the rate of decline in function.ConclusionOlder adults with higher vitamin K status had better physical performance scores at baseline, but data are less consistent longitudinally. Since lower extremity disability is a common consequence of multiple chronic diseases for which a role of vitamin K has been suggested, future studies are needed to determine if vitamin K supplementation could improve function in those with vitamin K insufficiency and clarify underlying mechanism(s).