Maintenance of glycemic control during and after exercise remains a major challenge for individuals with type 1 diabetes. Glycemic responses to exercise may differ by exercise type (aerobic, ...interval, or resistance), and the effect of activity type on glycemic control after exercise remains unclear.
The Type 1 Diabetes Exercise Initiative (T1DEXI) was a real-world study of at-home exercise. Adult participants were randomly assigned to complete six structured aerobic, interval, or resistance exercise sessions over 4 weeks. Participants self-reported study and nonstudy exercise, food intake, and insulin dosing (multiple daily injection MDI users) using a custom smart phone application and provided pump (pump users), heart rate, and continuous glucose monitoring data.
A total of 497 adults with type 1 diabetes (mean age ± SD 37 ± 14 years; mean HbA1c ± SD 6.6 ± 0.8% 49 ± 8.7 mmol/mol) assigned to structured aerobic (n = 162), interval (n = 165), or resistance (n = 170) exercise were analyzed. The mean (± SD) change in glucose during assigned exercise was -18 ± 39, -14 ± 32, and -9 ± 36 mg/dL for aerobic, interval, and resistance, respectively (P < 0.001), with similar results for closed-loop, standard pump, and MDI users. Time in range 70-180 mg/dL (3.9-10.0 mmol/L) was higher during the 24 h after study exercise when compared with days without exercise (mean ± SD 76 ± 20% vs. 70 ± 23%; P < 0.001).
Adults with type 1 diabetes experienced the largest drop in glucose level with aerobic exercise, followed by interval and resistance exercise, regardless of insulin delivery modality. Even in adults with well-controlled type 1 diabetes, days with structured exercise sessions contributed to clinically meaningful improvement in glucose time in range but may have slightly increased time below range.
We conducted a genome-wide linkage scan for quantitative trait loci influencing total HDL-cholesterol (HDL-C) concentration in a sample of 1027 whites from 101 families participating in the NHLBI ...Family Heart Study. To maximize the relative contribution of genetic components of variance to the total variance of HDL-C, the HDL-C phenotype was adjusted for age, age, body mass index, and Family Heart Study field center, and standardized HDL-C residuals were created separately for men and women. All analyses were completed by the variance components method, as implemented in the program GENEHUNTER using 383 anonymous markers typed at the NHLBI Mammalian Genotyping Service in Marshfield, Wis. Evidence for linkage of residual HDL-C was detected near marker D5S1470 at location 39.9 cM from the p-terminal of chromosome 5 (LOD=3.64). Suggestive linkage was detected near marker D13S1493 at location 27.5 cM on chromosome 13 (LOD=2.36). We conclude that at least 1 genomic region is likely to harbor a gene that influences interindividual variation in HDL cholesterol.
Introduction Identifying contributors to accelerated aging may elucidate risks and mechanisms for age-related diseases and mortality. A DNA methylation (DNAm)-based marker of fast biological aging, ...epigenetic age acceleration, is associated with modifiable lifestyle factors. Sleep disordered breathing (SDB) is a common disorder that results in oxidative stress and inflammation and is associated with multiple age-related health disorders; however, SBD has not been well studied with respect to epigenetic aging. We examined the association of SDB traits with epigenetic age acceleration, and whether the association differed by sex. Methods A diverse sample (N = 622) had blood DNA methylation measured and underwent Type 2 in-home polysomnography, which assessed apnea-hypopnea index (AHI), percentage of sleep time that oxygen saturation is lower than 90% (Per90), and arousal index. Using DNA methylation, two validated epigenetic age measures were computed: DNAm PhenoAge and DNAm age. Age acceleration measures were calculated as residuals from the regression of each epigenetic age on chronological age. The association of each SDB trait with age acceleration was estimated using linear regression, controlling for socio-demographics, health behaviors, BMI, and study site. Results Participants were 53.2% female with a mean age of 68.7 (SD: 9.2) years. AHI was associated with greater DNAm PhenoAge acceleration (β = 0.03; 95% CI 0.00, 0.06), equivalent to 215 days of DNAm PhenoAge acceleration for 1-SD increase in AHI. Arousal index was associated with greater DNAm age acceleration (β = 0.04; 95% CI 0.01, 0.07), equivalent to 321 days of DNAm age acceleration for 1-SD increase in arousal index. Both associations were stronger in women compared to men. There was no evidence that Per90 was associated with epigenetic age acceleration or exhibited sex differences. Conclusion Increasing SDB severity and sleep disruption was associated with epigenetic age acceleration, independent of measured confounders. These associations were stronger in women than in men, suggesting that women may be particularly vulnerable to the adverse effects of SDB. Future work should study whether treatment reduces epigenetic age acceleration among those individuals with SBD. Support (If Any) None.
Spirometric measures of pulmonary function exhibited high heritability in the National Heart, Lung, and Blood Institute Family Heart Study. A genome scan of FEV1, FVC, and the ratio of FEV1/FVC was ...performed to identify chromosomal regions influencing these measures. The pulmonary traits were adjusted through multiple linear regression techniques for the effects of age, age2, body mass index, height, smoking status, and pack-years of smoking. The distribution of FEV1/FVC was transformed to account for nonnormality, and standardized residuals were used as the quantitative trait for variance component linkage analysis in GENEHUNTER (Whitehead Institute, Cambridge, MA). The genome scan identified regions on chromosomes 4 and 18 with logarithm of the odds favoring linkage (LOD) scores above 2.5, and these two chromosomes were further evaluated by incorporating additional marker genotyping. The FEV1/FVC ratio was linked to chromosome 4 around 28 centimorgans (cM; D4S1511) with a LOD score of 3.5, and the transformed ratio was linked to the same region with a LOD of 2.0. FEV1 and FVC were suggestively linked to regions on chromosome 18 with multipoint LOD scores of 2.4 for FEV1 and 1.5 for FVC at 31 cM (D18S843) and a LOD of 2.9 for FVC at 79 cM (D18S858).
Association of the tissue kallikrein gene promoter with ESRD and hypertension.
Kallikreins have long been implicated in human essential hypertension and associated complications. In particular, low ...urinary kallikrein excretion has been associated with hypertension and renal disease in African Americans. In an effort to identify the source of differential kallikrein excretion, we investigated the promoter of KLK1, the tissue kallikrein gene. The KLK1 promoter is uniquely polymorphic with a poly-G length polymorphism coupled with multiple single base substitutions. In this report, we genetically evaluated the association of KLK1 gene promoter alleles with end-stage renal disease (ESRD) in African Americans.
A total of 15 haplotypes were identified in the KLK1 promoter region through detailed DNA sequence analysis. This polymorphic region was then genetically evaluated for association with ESRD in African Americans with diabetic and non-diabetic etiologies of ESRD.
The complex polymorphic nature of the promoter presents challenges to determining the alleles. We have redefined the region as six separate loci: five substitution loci and one length locus. The length locus was defined as G repeats starting at position -130 and ending at -121 on the gene. Among four relevant substitution loci for this study, one at position -131, just outside the G repeats, is an A-to-G substitution. The other three variant positions are -129, -128, and -127, all G-to-C substitutions within the G repeats. This region was genotyped in African American subjects with and without ESRD using semiautomated sequencing. Four different G repeat alleles ranging from 11.8% for 12 Gs to 52.3% for 10 Gs were observed in 86 control subjects. The C substitution of Gs ranges from 2.9% at position -127 to 8.2% at -129. When affected probands from each of 76 hypertensive ESRD families were genotyped, an association for the 12G allele, the longest of the length locus alleles, was detected (allele specific P = 0.004 and locus total P = 0.02). When all ESRD affected individuals with hypertension from each family (107 patients in total) were used in the analysis, an even stronger association was observed for this allele (allele specific P = 0.003, locus total P = 0.01). This allele was more frequent in the hypertensive (non-diabetic) patients (0.20 in probands and 0.19 in all ESRD cases) than in the controls (0.12). No evidence of association in diabetic ESRD patients was observed (P = 0.93).
The KLK1 promoter is uniquely polymorphic. The observed genetic association suggests an etiologic effect of the KLK1 promoter on hypertension and/or hypertension associated ESRD.
Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated ...glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.
Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been ...limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants.
Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics).
We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10
. These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the
gene locus including ZAP70 (sentinel single nucleotide polymorphism SNP rs7412-T, β=0.61±0.05,
=3.27×10
) and MMP-3 (β=-0.60±0.05,
=1.67×10
), as well as a completely novel pleiotropic locus at the
gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β=0.34±0.04,
=1.34×10
) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure.
Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.
Abstract only
Background:
Traditional cardiovascular (CV) risk factors and the underlying genetic risk of elevated blood pressure (BP) determine an individual’s composite risk of developing adverse ...CV events. We evaluated the relative contributions of the traditional CV risk factors to the development of adverse CV events in the context of varying BP polygenic risk score (PRS) profiles among multiethnic population-based cohorts (ARIC, MESA, JHS, FHS, CARDIA, and CHS cohort).
Methods:
Multiethnic genome-wide BP PRS was constructed among participants with WGS data through TOPMed program and were stratified into high, intermediate, and low genetic risk (>80
th
, 20-80
th
, <20
th
centile). Based on the ACC/AHA Pooled Cohorts Equation (PCE), participants were stratified into low and high (10y-ASCVD risk: <10% or ≥10%) CV risk factor profile groups. Cox regression was used to assess the risk of adverse CV events (incident HF, CHD, and stroke) and its components.
Results:
Among 21,899 American adults (mean age: 56 years; 56% women; 36% non-White race), 1 SD increase in the BP PRS computed using 1.1 million variants was associated with systolic BP (β: 4.7, 95% CI: 4.5-5.0) and HTN (OR: 1.09, 95% CI: 1.09-1.10), respectively. This association was robustly seen across racial/ethnic groups. Each SD increase in BP PRS was associated with a higher risk of the primary outcome (HR: 1.08 1.05-1.11) after controlling for ACC/AHA PCE risk score. Among individuals with a high BP PRS, low ASCVD risk was associated with a 69% lower hazard for the primary outcome (HR: 0.31, 0.27-0.35) compared with those with high ASCVD risk. A similar pattern was noted in intermediate and low BP PRS groups. Comparable results were noted for all the secondary outcomes.
Conclusions:
In a multiethnic cohort of >21,000 US adults, genome-wide BP PRS was associated with BP traits and adverse CV events. Adequate CV risk factor control may reduce this increased predisposition to adverse CV events by 69% in those with high BP PRS.
Abstract only
Introduction:
Genome-wide association studies have identified common genetic variants associated with hypertrophic (HCM) and dilated cardiomyopathy (DCM) and left ventricular (LV) ...characteristics. However, the association of these variants with myocardial fibrosis (MF), an important pathophysiological mediator of cardiomyopathy, is unknown.
Hypothesis:
We used the Multi-Ethnic Study of Atherosclerosis (MESA), to evaluate the association of these loci with interstitial MF measured by cardiac MRI (CMR).
Methods:
Unrelated MESA participants with T1-mapping CMR and no history of MI or heart failure were included (n=1,235). We used the extracellular volume (ECV) fraction as a well-established surrogate of interstitial MF. Genotyping was performed by Affymetrix Human SNP array 6.0, and imputation was performed using the TOPMED reference panel. Log ECV(%) was regressed on 50 candidate SNPs, in each ethnicity/race group, adjusting for age, sex, and population stratification principal component. The race-specific results were pooled by fixed-effect meta-analyses using METASOFT.
Results:
The
SMARCB1
rs2186370 intronic variant, previously identified as a risk variant for DCM and HCM, was associated with ECV (p=0.0004). The rs2186370 A allele (frequency: 0.18 in Whites, and 0.50 in African Americans) was associated with a 1.6% increase in ECV. The rs2070458 A allele (another
SMARCB1
intronic variant), in complete linkage disequilibrium with rs2186370, was known previously to be associated with increased LV wall thickness, mass, and concentricity. The direction of effect was similar in all four ancestry groups, but the effect was strongest in African Americans. These variants are strong expression quantitative loci (eQTLs) in human LV tissue and are associated with genotype-dependent expression of
SMARCB1
(
p
=7.3х10
-22
) and
MMP11
(
p
=2.5х10
-24
).
Conclusions:
In conclusion, variants in two linked
SMARCB1
loci previously associated with HCM, DCM and LV traits, are associated with CMR-based interstitial MF. These loci are eQTL not only for SMARCB1 but also for MMP11 an important mediator of MF
.
These findings underscore the important link between MF and CM, and potentially provide novel mechanistic targets in understanding the development of CM.
In addition to rare genetic variants and the
locus, common genetic variants contribute to idiopathic pulmonary fibrosis (IPF) risk. The predictive power of common variants outside the
locus for IPF ...and interstitial lung abnormalities (ILAs) is unknown.
We tested the predictive value of IPF polygenic risk scores (PRSs) with and without the
region on IPF, ILA, and ILA progression.
We developed PRSs that included (PRS-M5B) and excluded (PRS-NO-M5B) the
region (500-kb window around rs35705950-T) using an IPF genome-wide association study. We assessed PRS associations with area under the receiver operating characteristic curve (AUC) metrics for IPF, ILA, and ILA progression.
We included 14,650 participants (1,970 IPF; 1,068 ILA) from six multi-ancestry population-based and case-control cohorts. In cases excluded from genome-wide association study, the PRS-M5B (odds ratio OR per SD of the score, 3.1;
= 7.1 × 10
) and PRS-NO-M5B (OR per SD, 2.8;
= 2.5 × 10
) were associated with IPF. Participants in the top PRS-NO-M5B quintile had ∼sevenfold odds for IPF compared with those in the first quintile. A clinical model predicted IPF (AUC, 0.61); rs35705950-T and PRS-NO-M5B demonstrated higher AUCs (0.73 and 0.7, respectively), and adding both genetic predictors to a clinical model yielded the highest performance (AUC, 0.81). The PRS-NO-M5B was associated with ILA (OR, 1.25) and ILA progression (OR, 1.16) in European ancestry participants.
A common genetic variant risk score complements the
variant to identify individuals at high risk of interstitial lung abnormalities and pulmonary fibrosis.
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