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Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 Pjoint< 5 × 10−8), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (Pint< 5 × 10−8). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (Pint= 2 × 10−6). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1and RGL3/ELAVL3previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (Pint< 10−3). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep–wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

Dairy consumption is related to chronic disease risk; however, the measurement of dairy consumption has largely relied upon self-report. Untargeted metabolomics allows for the identification of objective markers of dietary intake.

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.

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Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury1–4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries5. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.

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< 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.

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Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown1. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer2–4and coronary heart disease5—this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)6. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2germline locus enabled the identification of a causal variant that disrupts a TET2distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

Biomarkers that provide reliable evidence of future diabetic kidney disease (DKD) are needed to improve disease management. In a cross-sectional study, we previously identified 13 urine metabolites that had levels reduced in DKD compared with healthy controls. We evaluated associations of these 13 metabolites with future DKD progression.

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene–smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.

Genetic mechanisms involved in the susceptibility to salt sensitivity have not been completely clarified. This study aimed to comprehensively examine the association between genetic variants in the cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG/PRKG) genes and blood pressure (BP) responses to dietary sodium intervention in a Chinese population. A 7-day low-sodium intervention followed by a 7-day high-sodium intervention was conducted among 1906 Han participants from rural areas of northern China. Nine BP measurements were obtained at baseline and each intervention using a random-zero sphygmomanometer. Linear mixed-effect models were used to assess the additive association of 213 tag single-nucleotide polymorphisms (SNPs) in two PRKG genes (PRKG1and PRKG2) with salt sensitivity phenotypes. Gene-based analyses were conducted using the truncated product method. The Bonferroni method was used to adjust for multiple testing. Mean systolic BP response to low-sodium intervention significantly decreased with the number of minor T allele of marker rs10997916 in PRKG1(P= 2.4 × 10−5). Mean systolic BP responses (95% confidence interval) among those with genotypes CC, CT, and TT were −5.6 (−6.0, −5.3), −3.7 (−4.7, −2.8), and −1.3 (−4.6, 2.0) mmHg, respectively, during the low-sodium intervention. Gene-based analyses demonstrated that PRKG1was significantly associated with systolic BP response to low-sodium intervention (P= 1.2 × 10−3), whereas PRKG2was nominally significantly associated with diastolic BP responses to high-sodium intervention (P= 2.6 × 10−2). The current study suggested a significant association of genetic variants in the PRKG genes with variation of BP response to dietary sodium intake in Han Chinese population. These novel findings merit further replication in future.

IMPORTANCE: Clinical trials have documented that lowering blood pressure reduces cardiovascular disease and premature deaths. However, the optimal target for reduction of systolic blood pressure (SBP) is uncertain. OBJECTIVE: To assess the association of mean achieved SBP levels with the risk of cardiovascular disease and all-cause mortality in adults with hypertension treated with antihypertensive therapy. DATA SOURCES: MEDLINE and EMBASE were searched from inception to December 15, 2015, supplemented by manual searches of the bibliographies of retrieved articles. STUDY SELECTION: Studies included were clinical trials with random allocation to an antihypertensive medication, control, or treatment target. Studies had to have reported a difference in mean achieved SBP of 5 mm Hg or more between comparison groups. DATA EXTRACTION AND SYNTHESIS: Data were extracted from each study independently and in duplicate by at least 2 investigators according to a standardized protocol. Network meta-analysis was used to obtain pooled randomized results comparing the association of each 5–mm Hg SBP category with clinical outcomes after adjusting for baseline risk. MAIN OUTCOMES AND MEASURES: Cardiovascular disease and all-cause mortality. RESULTS: Forty-two trials, including 144 220 patients, met the eligibility criteria. In general, there were linear associations between mean achieved SBP and risk of cardiovascular disease and mortality, with the lowest risk at 120 to 124 mm Hg. Randomized groups with a mean achieved SBP of 120 to 124 mm Hg had a hazard ratio (HR) for major cardiovascular disease of 0.71 (95% CI, 0.60-0.83) compared with randomized groups with a mean achieved SBP of 130 to 134 mm Hg, an HR of 0.58 (95% CI, 0.48-0.72) compared with those with a mean achieved SBP of 140 to 144 mm Hg, an HR of 0.46 (95% CI, 0.34-0.63) compared with those with a mean achieved SBP of 150 to 154 mm Hg, and an HR of 0.36 (95% CI, 0.26-0.51) compared with those with a mean achieved SBP of 160 mm Hg or more. Likewise, randomized groups with a mean achieved SBP of 120 to 124 mm Hg had an HR for all-cause mortality of 0.73 (95% CI, 0.58-0.93) compared with randomized groups with a mean achieved SBP of 130 to 134 mm Hg, an HR of 0.59 (95% CI, 0.45-0.77) compared with those with a mean achieved SBP of 140 to 144 mm Hg, an HR of 0.51 (95% CI, 0.36-0.71) compared with those with a mean achieved SBP of 150 to 154 mm Hg, and an HR of 0.47 (95% CI, 0.32-0.67) compared with those with a mean achieved SBP of 160 mm Hg or more. CONCLUSIONS AND RELEVANCE: This study suggests that reducing SBP to levels below currently recommended targets significantly reduces the risk of cardiovascular disease and all-cause mortality. These findings support more intensive control of SBP among adults with hypertension.

Background:Despite known associations of epigenetic age acceleration (EAA), or increased DNA methylation (DNAm)-based age relative to chronological age, with Alzheimer’s disease, few studies have investigated the relation of EAA with midlife cognitive function. We examined cross-sectional associations of EAA with cognition among the 1,252 middle-aged participants of the Bogalusa Heart Study 2013-2016 study visit.Methods:Whole-blood DNA methylation data was generated using the Illumina HumanMethylation450 BeadChip. Four EAA measures, including extrinsic EAA (EEAA), intrinsic EAA (IEAA), PhenoAA and GrimAA, were derived from the methylation data. Cognitive function was assessed by a standard battery of eight neurocognitive tests covering five cognition domains, and a global cognition score was calculated. Associations of EAA measures with cognitive function were assessed by 3 multivariable models sequentially adding (i) demographics (age, sex, race, education) and vocabulary; (ii) lifestyle behaviors (smoking, alcohol drinking, and depression), and (iii) clinical measures (blood pressure, lipids, body mass index, glycated hemoglobin, medication, and white blood cell count.Results:After Bonferroni correction (α=1.39E-3), PhenoAA and GrimAA were significantly associated with decreased processing speed (lower Digit coding test score) and decreased working memory (higher trail making test A score). GrimAA was also associated with lower global cognition score (Table). EEAA was associated with decreased processing speed (lower Digit coding test). After adjusting for lifestyle and clinical measures, such associations were slightly attenuated but remained at least nominally significant. IEAA was not associated with any cognitive test results.Conclusions:EAA measured by PhenoAA, GrimAA, and EEAA were significantly associated with decreased processing speed, working memory, and/or global cognition. The associations were independent of known cognitive decline risk factors.

Introduction:Uncontrolled high dose aspirin use impairs kidney function. Short-term low dose aspirin treatment has also been associated with kidney function in older patients. We aimed to evaluate the association of regular aspirin use with kidney function in middle-aged adults and to identify factors modifying the association.Methods:We performed cross-sectional analyses among 1,261 participants of the 2016 Bogalusa Heart Study (BHS) visit. Regular aspirin use was self-reported and confirmed by serum biomarker, salicyluric glucuronide. Aspirin users were categorized at the median of salicyluric glucuronidelevels into low and high dose users. A total of 887 known metabolites were profiled from the serum. Estimated glomerular filtration rate (eGFR) was calculated using the CKD-Epi equation. We tested associations of aspirin use with eGFR and examined interactions of aspirin with serum metabolites on eGFR. Age, sex, race, education, smoking, drinking, physical activity, BMI, blood pressure, and fasting glucose were adjusted in all analyses.Results:The mean age of BHS participants was 48.2, and 133 (10.5%) were self-reported aspirin users. Serum salicyluric glucuronidelevel was significantly correlated with self-reported aspirin usage (P=2.00х10-21). After adjusting for all covariables, mean eGFR for never, low dose, and high dose aspirin users were 92.9, 90.2, and 89.9 mL/min/1.73m2, respectively (P for trend=0.004). After Bonferroni correction, 28 metabolites modified the associations of aspirin use with eGFR (P<5.52х10-5), of which, 26 increased the aspirin's nephrotoxicity effect, while behenoylsphingomyelinand tricosanoylsphingomyelinsignificantly attenuated the eGFR lowering effect of aspirin (Table).Conclusion:Aspirin use is associated with decreased eGFR among middle-aged adults, and this association was modified by dietary, gut microbiome, and biomarkers of kidney disease, cardiovascular disease, and cancer. The findings may help develop better use strategies for regular users.

Introduction:Mechanisms for metabolically healthy obesity (MHO) are not well studied.Methods:We performed cross-sectional analyses among 1,261 participants of the Bogalusa Heart Study 2013-2016 survey. A total of 887 known serum metabolites were profiled using an untargeted approach. Participants who met all the following five criteria were considered metabolically healthy, otherwise, unhealthy: 1) SBP <130 mm Hg and DBP <85 mm Hg; 2) fasting glucose <100 mg/dl; 3) triglycerides <150 mg/dl; 4) HDL ≥40 mg/dl in men and ≥50 mg/dl in women; and 5) not taking medications for hypertension, diabetes, or dyslipidemia. We tested associations of metabolites with metabolic health status, controlling for age, sex, race, education, smoking, drinking, and kidney function.Results:Among 648 obese participants (BMI≥30 kg/m2), 66 (10.2%) had MHO. After Bonferroni correction, 26 metabolites differed between MHO and metabolically unhealthy obesity (MUO) groups. Amino acids serine, glycine,and histidine, fatty acid N-linoleoylserine, 4 sphingolipids, and 3 plasmalogens were significantly higher among MHO individuals. These metabolites are functionally relevant to metabolic health (Table). Carbohydrates mannose, lactate,and pyruvate, urate, amino acids glutamate, 1-carboxyethylvaline, 1-carboxyethylleucine, 3-methyl-2-oxovalerate, and 3-methyl-2-oxobutyrate, PE(18:0/18:2(9Z,12Z)), and 5 diacylglycerols were significantly higher in the MUO group. These metabolites are mostly food additives or reduce gut microbiota diversity (Table). Furthermore, histidinewas associated with metabolic health only among overweight and obese participants. Odds ratios of being metabolically healthy per SD increase of histidineamong normal weight, overweight, and obese participants were 1.05 (95% CI: 0.83-1.32), 1.54 (95% CI: 1.10-2.14), and 2.12 (95% CI: 1.56-2.89), respectively (P for group difference=1.41E-4).Conclusion:We identified potential intervention targets to improve metabolic health in obesity.

Introduction:There is a lack of objective biomarkers of dietary intake. Untargeted studies can unbiasedly identify dairy biomarkers and inform the creation of robust dietary assessment tools that integrate questionnaire and biospecimen data.Methods:Dairy products from interviewer-administered questionnaires were categorized as either low-fat or high-fat dairy. Total dairy was a composite of low-fat and high-fat dairy items. Linear regression models were used to assess associations between dairy intake and 360 serum metabolites in the Atherosclerosis Risk in Communities (ARIC) Study (n=3907). Significant associations were then tested for replication in the Bogalusa Heart Study (BHS) (n=819).Results:In the ARIC study, 34 dairy-metabolite associations were identified (total dairy, n = 16; low-fat dairy, n = 10; high-fat dairy, n = 8). Total dairy shared 7 metabolic associations each with low-fat dairy and high-fat dairy. Low-fat dairy was associated with pantothenate, vitamin B5, and the catabolic product of vitamin B6, pyridoxate. High-fat dairy was associated with one amino acid, 3-hydroxy-2-ethylpropionate, and eight lipid metabolites, including myristate (14:0), 10-nonadecenoate (19:1n9), and myristoleate (14:1n5). Of the metabolites available for replication in BHS (total dairy, n = 15; low-fat dairy, n = 9; high-fat dairy, n = 8), 2 total dairy metabolites were replicated and 2 low-fat dairy metabolites were replicated (Table).Conclusions:We identified metabolomic markers of total, low-fat, and high-fat dairy. Pantothenate, myristate (14:0), and tiglyl carnitine replicated across two large, diverse study populations, suggesting that they are markers of dairy consumption.

Introduction:Current guidelines recommend ≥2 servings of fish/week for the prevention of atherosclerotic cardiovascular disease (ASCVD). However, a recent large meta-analysis suggested that the benefit may exist only for persons with a prior ASCVD event. Whether coronary artery calcium (CAC) can help to identify individuals who are likely to benefit from habitual fish consumption is unknown.Hypothesis:CAC will stratify persons who may and may not benefit from habitual fish consumption.Methods:There were 4977 participants in the Multi-Ethnic Study of Atherosclerosis who reported their frequency of fish intake and underwent CAC scanning at Visit 1. Adjusted Cox proportional hazards regression models stratified by the presence/absence of CAC assessed the association between fish intake and incident ASCVD over a median follow-up of 15.7 years.Results:The mean age was 61 years old, 53% were women, 26% were Black, and 49% of participants had prevalent CAC. A similar proportion of individuals reported consuming ≥2 servings of fish/week for those with CAC=0 and CAC >0 (35% versus 33%, p=0.12). The absolute ASCVD event rate for those with <2 or ≥2 servings of fish/week was 5.5 vs. 4.2 per 1,000 person-years for CAC=0 and 18.2 vs. 19.0 person-years for CAC >0 (Figure 1). Each additional serving of fish/week was associated with a 9% lower risk of ASCVD for participants with CAC=0 (HR=0.91, 95% CI: 0.83-0.99) whereas there was no significant association for persons with CAC >0 (HR=1.03, 95% CI: 0.99-1.07).Conclusions:A higher amount of fish consumption was associated with a lower risk of incident ASCVD for participants with CAC=0, but not those with CAC >0, although the absolute ASCVD event rate was low for persons with CAC=0 regardless of fish consumption frequency.

Mutations in genes encoding subunits of the epithelial Na+channel (ENaC) can cause early onset familial hypertension, demonstrating the importance of this channel in modulating blood pressure. It remains unclear whether other genetic variants resulting in subtler alterations of channel function result in hypertension or altered sensitivity of blood pressure to dietary salt. This study sought to identify functional human ENaC variants to examine how these variants alter channel activity and to explore whether these variants are associated with altered sensitivity of blood pressure to dietary salt. Six-hundred participants of the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study with salt-sensitive or salt-resistant blood pressure underwent sequencing of the genes encoding ENaC subunits. Functional effects of identified variants were examined in a Xenopusoocyte expression system. Variants that increased channel activity included three in the gene encoding the α-subunit (αS115N, αR476W, and αV481M), one in the β-subunit (βS635N), and one in the γ-subunit (γL438Q). One α-subunit variant (αA334T) and one γ-subunit variant (βD31N) decreased channel activity. Several α-subunit extracellular domain variants altered channel inhibition by extracellular Na+(Na+self-inhibition). One variant (αA334T) decreased and one (αV481M) increased cell surface expression. Association between these variants and salt sensitivity did not reach statistical significance. This study identifies novel functional human ENaC variants and demonstrates that some variants alter channel cell surface expression and/or Na+self-inhibition.

Introduction:In the Protein and Blood Pressure (ProBP) trial, milk and soy protein supplements reduced blood pressure (BP) compared to carbohydrate intervention. We investigated the underlying mechanisms influencing the effects.Methods:Serum metabolites were profiled at pre-trial baseline and after supplementation with carbohydrate, soy protein, and milk protein, respectively, among 80 ProBP participants. We tested the mediating and modifying effects of metabolites on BP-lowering effects of soy and milk protein interventions.Results:Dietary interventions significantly (P<6.49х10-4) changed 40 metabolites, of which 29 had reduced levels. Two clusters of metabolites mediated 45.5% and 100% of the effects of soy and milk protein interventions, respectively. Within the clusters, lipid 4-cholesten-3-onehad the largest effect and mediated 12.7% (P=0.03) and 16.3% (P=0.045) of the effects of soy and milk protein interventions, respectively. At baseline, amino acids 5-oxoprolineand taurine,lysophospholipid 1-arachidonoyl-GPA(20:4), and acylcholines oleoylcholine, dihomo-linolenoyl-choline, and arachidonoylcholinepredicted BP increase during carbohydrate intervention; while lipids N-stearoyl-sphinganine(d18:0/18:0)and isoursodeoxycholateand peptide gamma-glutamylserinepredicted less reduction of BP during soy protein and milk protein supplements (P<6.49х10-4). Finally, effects of soy and milk protein interventions on systolic and diastolic BP were influenced by changes of isobutyrylglycine(Pfor interaction=0.02 and 9.12х10-5, respectively). In the bottom tertile of isobutyrylglycinechanges, soy and milk protein reduced 5.10 (P=0.03) and 4.43 (P=0.01) mmHg systolic BP and 3.22 (P=0.03) and 3.12 (P=0.04) mmHg diastolic BP, respectively; while in the top tertile, the two interventions had no or increasing effects on systolic (βsoy protein=-0.04, P=0.98; βmilk protein=-2.34, P=0.25) and diastolic BP (βsoy protein=3.19, P=0.02; βmilk protein=1.08, P=0.43).Conclusions:We documented serum metabolites altered by dietary carbohydrate, milk protein, and soy protein interventions, and identified important metabolites mediating or modifying the BP-lowering effect of milk and soy protein interventions.

We conducted a genome-wide linkage scan and positional association study to identify genes and variants influencing blood lipid levels among participants of the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study. The GenSalt study was conducted among 1906 participants from 633 Han Chinese families. Lipids were measured from overnight fasting blood samples using standard methods. Multipoint quantitative trait genome-wide linkage scans were performed on the high-density lipoprotein, low-density lipoprotein, and log-transformed triglyceride phenotypes. Using dense panels of single nucleotide polymorphisms (SNPs), single-marker and gene-based association analyses were conducted to follow-up on promising linkage signals. Additive associations between each SNP and lipid phenotypes were tested using mixed linear regression models. Gene-based analyses were performed by combining P-values from single-marker analyses within each gene using the truncated product method (TPM). Significant associations were assessed for replication among 777 Asian participants of the Multi-ethnic Study of Atherosclerosis (MESA). Bonferroni correction was used to adjust for multiple testing. In the GenSalt study, suggestive linkage signals were identified at 2p11.2‒2q12.1 [maximum multipoint LOD score (MML) = 2.18 at 2q11.2] and 11q24.3‒11q25 (MML = 2.29 at 11q25) for the log-transformed triglyceride phenotype. Follow-up analyses of these two regions revealed gene-based associations of charged multivesicular body protein 3 (CHMP3), ring finger protein 103 (RNF103), AF4/FMR2 family, member 3 (AFF3), and neurotrimin (NTM) with triglycerides (P = 4 × 10−4, 1.00 × 10−5, 2.00 × 10−5, and 1.00 × 10−7, respectively). Both the AFF3and NTMtriglyceride associations were replicated among MESA study participants (P = 1.00 × 10−7and 8.00 × 10−5, respectively). Furthermore, NTMexplained the linkage signal on chromosome 11. In conclusion, we identified novel genes associated with lipid phenotypes in linkage regions on chromosomes 2 and 11.

Blood pressure (BP) response to cold pressor test (CPT) is associated with increased risk of cardiovascular disease. We performed a genome-wide linkage scan and regional association analysis to identify genetic determinants of BP response to CPT.

Blood pressure (BP) responses to dietary sodium and potassium intervention and cold pressor test vary considerably among individuals. We aimed to identify novel genetic variants influencing individuals’ BP responses to dietary intervention and cold pressor test.

Diabetes mellitus is associated with an increased incidence of colorectal cancer, but the impact of diabetes mellitus on colorectal cancer prognosis is not clear.

High blood pressure (BP) is a complex trait determined by genetic and environmental factors, as well as their interactions. Over the past few decades, there has been substantial progress elucidating the genetic determinants underlying BP response to sodium intake, or BP salt sensitivity. Research of monogenic BP disorders has highlighted the importance of renal salt handling in BP regulation, implicating genes and biological pathways subsequently identified in candidate gene studies of salt sensitivity. Despite these advancements, certain candidate gene findings await replication evidence, and some biological pathways warrant further investigation. Furthermore, results from genome-wide association studies (GWASs) and sequencing work have yet to be reported. GWAS will be valuable for uncovering novel mechanisms underlying salt sensitivity, whereas future sequencing efforts promise the discovery of functional variants related to this complex trait. Delineating the genetic architecture of salt sensitivity will be critical to understanding how genes and dietary sodium interact to influence BP.

Observational epidemiologic studies and clinical trials have documented that dietary potassium intake lowers blood pressure (BP). We examined the association between genetic variants in the renin–angiotensin–aldosterone system and BP responses to potassium intervention.