Abstract 4401: Two Independent Genetic Variants in NOS1AP are Associated with QT interval in a Multi-Ethnic Population: the Dallas Heart Study

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Dan E Arking ◽  
Amit Khera ◽  
Chao Xing ◽  
Wen H Kao ◽  
Aravinda Chakravarti
Keyword(s):  
Heart Rate ◽  
Genetic Variants ◽  
Qt Interval ◽  
Genetic Model ◽  
Black Population ◽  
European Ancestry ◽  
Ethnic Population ◽  
Heart Study ◽  
Increased Risk ◽  
Dallas Heart Study

Extremes of QT interval are associated with increased risk for sudden cardiac death (SCD), and thus identification and characterization of genetic variants that modulate QT interval may elucidate the underlying etiology of SCD. Previous work revealed an association between a common genetic variant in NOS1AP and QT interval in populations of European ancestry, but this finding has not been extended to other ethnic populations. We thus sought to characterize the effects of NOS1AP genetic variants in the multi-ethnic population-based Dallas Heart Study (DHS). Among 3,557 participants in DHS with available DNA, those without QT interval, heart rate, age, and/or sex information, and those with QRS >120 or undetermined ethnicity were excluded, resulting in 2,949 samples available for analysis (501 Hispanic, 1,506 Black, 942 White). Sex- and ethnicity-stratified linear regression was used to correct QT interval for heart rate and age. Eight SNPs spanning the region previously associated with QT interval were genotyped, and ethnic-specific analyses were performed under an additive genetic model. The SNP most strongly associated with QT interval in previous samples of European ancestry, rs16847548, was the most strongly associated in the White participants (+2.6 ms, P<0.005) as well as in Blacks (+3.2 ms, P<3.6 × 10 –5), with the same direction of effect in Hispanics (+1.5 ms, P<0.17). A second SNP, rs16856785, which was uncorrelated with rs16847548 (r2 < 0.01 in Blacks) was also associated with QT interval in Blacks (+1.6 ms, P<0.01), with qualitatively similar results in Whites (+0.9 ms, P<0.33) and Hispanics (+0.6 ms, P<0.66). Adjusting for local and global ancestry using Ancestry Informative Markers did not significantly alter the results. Comparing Blacks homozygous at both SNPs for the QT lengthening allele to Blacks homozygous for the complementary alleles revealed a 13.9 ms difference in QT interval. These data extend the association of genetic variants in NOS1AP with QT interval to a Black population, with similar trends in Hispanics. Further, a second, independent site within NOS1AP has been implicated in modulating QT interval, highlighting the importance of NOS1AP genetic variants in regulating QT interval.

Abstract 2924: Association of NOS1AP Genetic Variants with QT Interval Duration in Families from the Diabetes Heart Study

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Allison B Lehtinen ◽  
Christopher Newton-Cheh ◽  
Julie T Ziegler ◽  
Carl D Langefeld ◽  
Barry I Freedman ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Qt Interval ◽  
Genetic Model ◽  
Additive Model ◽  
Adaptor Protein ◽  
European Ancestry ◽  
Nucleotide Polymorphisms ◽  
Interval Duration ◽  
Common Genetic Variants ◽  
Qt Interval Duration

Background: Prolongation of the electrocardiographic QT interval is a risk factor for sudden cardiac death (SCD) in unselected samples as well as in post-myocardial infarction patients or those with diabetes. Common genetic variants in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene have been reported to be associated with QT interval duration in individuals of European ancestry. We sought to replicate the association of NOS1AP variants with QT interval duration in pedigrees enriched for type 2 diabetes mellitus (T2DM). Methods and Results: Two single nucleotide polymorphisms (SNPs) in the NOS1AP gene, rs10494366 and rs10918594, were genotyped in a collection of 937 European Americans (EAs) and 177 African Americans (AAs) in 450 pedigrees containing at least two siblings with T2DM. An additive genetic model was tested for each SNP in ancestry-specific analyses using SOLAR in the total sample and in the diabetic subset (EA n=778, AA n=159), with and without exclusion of QT-altering medications. In the EA individuals, rs10494366 minor allele homozygotes had an 8.9 msec longer mean QT interval compared to major homozygotes (additive model p=4.4x10 -3 ); rs10918594 minor homozygotes had a 12.9 msec longer mean QT interval compared to major homozygotes (p=9.9x10 -5 ). Excluding users of QT-altering medications in the diabetic-only EA sample (n=514) strengthened the association despite the reduction in sample size (20.6 msec difference, p=2.0x10 -5 ; 23.4 msec difference, p=8.9x10 -7 , respectively). No association between the NOS1AP SNPs and QT interval duration was observed in the limited number of AA individuals examined. Conclusions: Two NOS1AP SNPs are strongly associated with QT interval duration in a predominately diabetic EA sample. Stronger effects of NOS1AP variants in diabetic individuals compared to previously reported unselected samples suggest that this patient subset may be particularly susceptible to genetic variants that influence myocardial depolarization and repolarization as manifest in the QT interval.

Abstract 187: Electrocardiographic Heart Rate-corrected Qt Interval And Risk Of Stroke In The REasons For Geographic And Racial Differences In Stroke (REGARDS) Study

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Elsayed Z Soliman ◽  
George Howard ◽  
George Howard ◽  
Mary Cushman ◽  
Brett Kissela ◽  
...  
Keyword(s):  
Heart Rate ◽  
Racial Differences ◽  
Qt Interval ◽  
Proportional Hazards ◽  
Left Ventricular ◽  
Cox Proportional Hazards ◽  
Corrected Qt Interval ◽  
Cardiovascular Morbidity And Mortality ◽  
Increased Risk ◽  
Regards Study

Background: Prolongation of heart rate-corrected QT interval (QTc) is a well established predictor of cardiovascular morbidity and mortality. Little is known, however, about the relationship between this simple electrocardiographic (ECG) marker and risk of stroke. Methods: A total of 27,411 participants aged > 45 years without prior stroke from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study were included in this analysis. QTc was calculated using Framingham formula (QTcFram). Stroke cases were identified and adjudicated during an up to 7 years of follow-up (median 2.7 years). Cox proportional hazards analysis was used to estimate the hazard ratios for incident stroke associated with prolonged QTcFram interval (vs. normal) and per 1 standard deviation (SD) increase, separately, in a series of incremental models. Results: The risk of incident stroke in the study participants with baseline prolonged QTcFram was almost 3 times the risk in those with normal QTcFram [HR (95% CI): 2.88 (2.12, 3.92), p<0.0001]. After adjustment for age, race, sex, antihypertensive medication use, systolic blood pressure, current smoking, diabetes, left ventricular hypertrophy, atrial fibrillation, prior cardiovascular disease, QRS duration, warfarin use, and QT-prolonging drugs (full model), the risk of stroke remained significantly high [HR (95% CI): 1.67 (1.16, 2.41), p=0.0060)], and was consistent across several subgroups of REGARDS participants. When the risk of stroke was estimated per 1 SD increase in QTcFram, a 24% increased risk was observed [HR (95% CI): 1.24 (1.16, 1.33), p<0.0001)]. This risk remained significant in the fully adjusted model [HR (95% CI): 1.12 (1.03, 1.21), p=0.0055]. Similar results were obtained when other QTc correction formulas including Hodge’s, Bazett’s and Fridericia’s were used. Conclusions: QTc prolongation is associated with a significantly increased risk of incident stroke independently from known stroke risk factors. In light of our results, examining the risk of stroke associated with QT-prolonging drugs may be warranted.

scholarly journals Genetic underpinnings of regional adiposity distribution in African Americans: Assessments from the Jackson Heart Study

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0255609
Author(s):  
Mohammad Y. Anwar ◽  
Laura M. Raffield ◽  
Leslie A. Lange ◽  
Adolfo Correa ◽  
Kira C. Taylor
Keyword(s):  
Waist Circumference ◽  
Genetic Variants ◽  
African Ancestry ◽  
Visceral Adiposity ◽  
European Ancestry ◽  
Risk Scores ◽  
Jackson Heart Study ◽  
Anthropometric Measures ◽  
Heart Study ◽  
Common Genetic Variants

Background African ancestry individuals with comparable overall anthropometric measures to Europeans have lower abdominal adiposity. To explore the genetic underpinning of different adiposity patterns, we investigated whether genetic risk scores for well-studied adiposity phenotypes like body mass index (BMI) and waist circumference (WC) also predict other, less commonly measured adiposity measures in 2420 African American individuals from the Jackson Heart Study. Methods Polygenic risk scores (PRS) were calculated using GWAS-significant variants extracted from published studies mostly representing European ancestry populations for BMI, waist-hip ratio (WHR) adjusted for BMI (WHRBMIadj), waist circumference adjusted for BMI (WCBMIadj), and body fat percentage (BF%). Associations between each PRS and adiposity measures including BF%, subcutaneous adiposity tissue (SAT), visceral adiposity tissue (VAT) and VAT:SAT ratio (VSR) were examined using multivariable linear regression, with or without BMI adjustment. Results In non-BMI adjusted models, all phenotype-PRS were found to be positive predictors of BF%, SAT and VAT. WHR-PRS was a positive predictor of VSR, but BF% and BMI-PRS were negative predictors of VSR. After adjusting for BMI, WHR-PRS remained a positive predictor of BF%, VAT and VSR but not SAT. WC-PRS was a positive predictor of SAT and VAT; BF%-PRS was a positive predictor of BF% and SAT only. Conclusion These analyses suggest that genetically driven increases in BF% strongly associate with subcutaneous rather than visceral adiposity and BF% is strongly associated with BMI but not central adiposity-associated genetic variants. How common genetic variants may contribute to observed differences in adiposity patterns between African and European ancestry individuals requires further study.

scholarly journals GWAS of Post-Orthodontic Aggressive External Apical Root Resorption Identified Multiple Putative Loci at X-Y Chromosomes

2020 ◽  
Vol 10 (4) ◽  
pp. 169
Author(s):  
Paula Iber-Díaz ◽  
Raquel Senen-Carramolino ◽  
Alejandro Iglesias-Linares ◽  
Pablo Fernández-Navarro ◽  
Carlos Flores-Mir ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Root Resorption ◽  
Genetic Model ◽  
Nucleotide Polymorphisms ◽  
Apical Root Resorption ◽  
A Genome ◽  
Increased Risk ◽  
External Apical Root Resorption

Personalized dental medicine requires from precise and customized genomic diagnostic. To conduct an association analysis over multiple putative loci and genes located at chromosomes 2, 4, 8, 12, 18, X, and Y, potentially implicated in an extreme type of external apical root resorption secondary to orthodontic forces (aEARR). A genome-wide association study of aEARR was conducted with 480 patients [ratio~1:3 case/control]. Genomic DNA was extracted and analyzed using the high-throughput Axiom platform with the GeneTitan® MC Instrument. Up to 14,377 single nucleotide polymorphisms (SNPs) were selected at candidate regions and clinical/diagnostic data were recorded. A descriptive analysis of the data along with a backward conditional binary logistic regression was used to calculate odds ratios, with 95% confidence intervals [p < 0.05]. To select the best SNP candidates, a logistic regression model was fitted assuming a log-additive genetic model using R software [p < 0.0001]. In this sample the top lead genetic variants associated with aEARR were two novel putative genes located in the X chromosome, specifically, STAG 2 gene, rs151184635 and RP1-30E17.2 gene, rs55839915. These variants were found to be associated with an increased risk of aEARR, particularly restricted to men [OR: 6.09; 95%CI: 2.6–14.23 and OR: 6.86; 95%CI: 2.65–17.81, respectively]. Marginal associations were found at previously studied variants such as SSP1: rs11730582 [OR: 0.54; 95%CI: 0.34–0.86; p = 0.008], P2RX7: rs1718119 [OR: 0.6; 95%CI: 0.36–1.01; p = 0.047], and TNFRSF11A: rs8086340 [OR: 0.6; 95%CI: 0.38–0.95; p = 0.024]), found solely in females. Multiple putative genetic variants located at chromosomes X and Y are potentially implicated in an extreme phenotype of aEARR. A gender-linked association was noted.

Abstract 273: HDL Particle Concentration Inversely Associates with Incident Metabolic Syndrome in the Multiethnic Dallas Heart Study

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Preethi Mani ◽  
Ian J Neeland ◽  
Darren K McGuire ◽  
Colby Ayers ◽  
Amit Khera ◽  
...  
Keyword(s):  
Risk Factors ◽  
Metabolic Syndrome ◽  
Visceral Fat ◽  
Particle Concentration ◽  
Atherosclerotic Cardiovascular Disease ◽  
Heart Study ◽  
Increased Risk ◽  
Ascvd Risk ◽  
Dallas Heart Study

Objective: Metabolic syndrome (MetS) increases atherosclerotic cardiovascular disease (ASCVD) risk. Low HDL cholesterol (HDL-C) is a diagnostic criterion of MetS and a major ASCVD risk factor. HDL particle concentration (HDL-P) associates with incident ASCVD independent of HDL-C, but its association with incident MetS has not been studied. We hypothesized that HDL-P would be inversely associated with incident metabolic syndrome independent of HDL-C and other recognized risk factors. Methods: HDL-P was measured by NMR and visceral fat by MRI in participants of the Dallas Heart Study, a probability-based population sample of adults age 30-65. Participants with prevalent MetS, DM, CVD, cirrhosis, cancer, HIV, or renal failure were excluded. Incident MetS as defined by NCEP ATPIII criteria was determined in all participants after median follow-up period of 9.4 years. Results: Among a cohort of 1120 participants without DM or MetS at baseline (57% women, 45% Black, mean age 43), 22.8% had incident MetS at follow-up. HDL-P and HDL-C were modestly correlated (r=0.54, p<0.0001). The lowest quartile of HDL-P was associated with younger age, men, Hispanic ethnicity, lower total, HDL, and LDL cholesterol levels and particle sizes, and less reported alcohol intake. Participants in the lowest sex and race stratified quartile of HDL-P had the highest incidence of MetS (Figure). In models adjusted for traditional risk factors, HDL-C, visceral fat, HOMA-IR, and hs-CRP, the lowest quartile of HDL-P was associated with 65% increased risk of incident MetS (Figure). Conclusion: HDL-P is independently associated with incident MetS after adjustment for HDL-C, adiposity, inflammation, and markers of insulin sensitivity. Further studies are warranted to validate these findings and elucidate the mechanisms underpinning this association.

Abstract P151: Neighborhood-Level Socioeconomic Deprivation Is Associated with Diabetes Mellitus in a Multi-Ethnic Population: The Dallas Heart Study

Circulation ◽  
2014 ◽  
Vol 129 (suppl_1) ◽  
Author(s):  
Michael McClurkin ◽  
Colby Ayers ◽  
Tammy Leonard ◽  
Rebecca Cooper-McCann ◽  
Christine Hoehner ◽  
...  
Keyword(s):  
Socioeconomic Deprivation ◽  
Self Report ◽  
Metabolic Risk Factor ◽  
Metabolic Risk ◽  
Ethnic Population ◽  
Dallas County ◽  
Heart Study ◽  
Dallas Heart Study ◽  
The Relationship ◽  
Neighborhood Level

Background: Although neighborhood-level socioeconomic deprivation has been associated with obesity, its relationship with diabetes, a cardio-metabolic risk factor and determinant of cardiovascular health, is poorly understood. Methods and Results: We examined the relationship between neighborhood-level socioeconomic deprivation and prevalent diabetes in the Dallas Heart Study (DHS), a multi-ethnic, population-based sample of Dallas County residents aged 18-65 (N=1621). Participants underwent detailed examination between 2000-2002. Geo-coded home addresses defined neighborhood block groups; a neighborhood-level deprivation index (NDI) for Dallas County was created using factor analysis based on 21 Census block-group characteristics (higher scores=greater neighborhood-level deprivation). Diabetes was defined by self-report, use of anti-hyperglycemic medication, or fasting glucose≥126 mg/dl. Logistic regression modeling was used to determine odds of prevalent diabetes for those in highest vs. lowest NDI tertile. In DHS, diabetes prevalence was 5%, 13%, and 16% across NDI tertiles (p<0.001). In modeling diabetes, we found a significant interaction between race and NDI (p=0.03); therefore, models were race-stratified. White, Hispanic, and black DHS participants in neighborhoods in the highest NDI tertile were up to seven times more likely to have diabetes than those living in the lowest tertile (Table). In whites and Hispanics, higher deprivation remained associated with a greater likelihood of diabetes after adjustment for age, sex, smoking, and education and was only attenuated after adjusting for income. In contrast, adjustment for confounders attenuated the relationship between NDI and diabetes among blacks. Conclusions: Residing in socioeconomically deprived neighborhoods is associated with prevalent diabetes among whites and Hispanics in DHS. These data suggest racial/ethnic disparities in cardio-metabolic risk within areas of higher socioeconomic deprivation in Dallas County.

Antipsychotics and lengthening QT / QTc

2011 ◽  
Vol 26 (S2) ◽  
pp. 887-887
Author(s):  
L. Tarricone
Keyword(s):  
Heart Rate ◽  
Antipsychotic Medication ◽  
Qt Interval ◽  
First Generation ◽  
Second Generation ◽  
Pathophysiological Mechanism ◽  
Increased Risk ◽  
Second Generation Antipsychotics ◽  
Effective Drugs ◽  
Typical Antipsychotics

Serious arrhythmias and / or sudden deaths related to the use of first-generation or typical antipsychotics have been observed for about thirty years. It is considered that the pathophysiological mechanism that causes these events may to be block the potassium and calcium channels with abnormal ventricular repolarization. The assessment of QT, QTc corrected for heart rate, is a predictor of risk for TdP. The introduction of second generation antipsychotics raised the question if these molecules can induce prolongation of the QT interval on the increased risk of arrhythmia and / or TdP. Controlled studies also argue that second-generation antipsychotics may lead to prolongation of QT / QTc. by introducing into the routine ECG and laboratory evaluations The purpose of this study is to analyze any change in ECG QTc observed in patients admitted to the SPDC, and possible correlation with antipsychotic medication.AscoltaThe ECGs of 300 patients admitted during the period January 2009/January 2010 with QTc assessment the first day and fifteen days after the treatment with second generation antipsychotics were examined. Changes were evaluated in relation to gender, age, diagnosis, antipsychotic taken in single or co-therapy QTc value divided into three classes: 440 ≤; 441 ≥ 500 ; 501≥;). There were no significant changes in QTc in relation to medication. It is believed that second-generation antipsychotics are considered safe and effective drugs at the time and that psychiatrists should pay more attention, however, by introducing into the routine ECG and laboratory evaluations.

scholarly journals Common Genetic Variants in Trypsin Regulating Genes Are Associated with AsparAginase-Associated Pancreatitis in Children with Acute Lymphoblastic Leukemia: A Ponte Di Legno Toxicity Working Group Study

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 885-885
Author(s):  
Benjamin Ole Wolthers ◽  
Thomas Leth Frandsen ◽  
Andishe Attarbaschi ◽  
Shlomit Barzilai ◽  
Antonella Colombini ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Genetic Variants ◽  
Working Group ◽  
Risk Allele ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Minor Allele ◽  
European Ancestry ◽  
Common Genetic Variants ◽  
Increased Risk

Abstract Background: Asparaginase-associated pancreatitis (AAP) is a well-known toxicity of childhood acute lymphoblastic leukemia (ALL) therapy. Recent multi-trial group phenotyping of 465AAP caseshas documented severe complications to AAP, including 8% risk of needing assisted mechanical ventilation, 26% risk of developing pancreatic pseudocysts and 9% risk of developing persisting diabetes (Wolthers et al. Lancet Oncology, 2017) . Investigation of host genome variation associated with AAP has been limited by varying phenotype definition, inclusion criteria and small study sizes. Objectives and Methods: To investigate genetic variants associated with risk of developing AAP, this genome-wide association study reports data on 1544 children (1.0−17.9 years) from 10 ALL trial groups treated with ALL from January 2000−January 2016. The Ponte di Legno toxicity working group consensus definition (Schmiegelow et al. Lancet Oncology, 2016) was used to diagnose AAP: At least two of i) amylase, pancreatic amylase, or pancreatic lipase &gt;3x upper normal limit (UNL), ii) abdominal pain, iii) imaging compatible with AAP. Controls included children treated for ALL with verified completion of intended asparaginase therapy, 78% of whom (1024/1320) received at least 8 injections of PEG-asparaginase without developing AAP. Germline DNA obtained after clinical remission was genotyped on Illumina Infinium Omni2.5exome-8 BeadChip arrays. Association analyses were done in PLINK and annotation in Ensembl. Results: Of 1564 patients passing genotype quality control, 244 had AAP. 205 of 244 (84%) of cases and 1185/1320 (90%) of controls were of European ancestry. Median age was 8.1 years (IQR 4.3−13.1) and 5 (IQR: 3−9) for cases and controls, respectively. After filtering, 1401908 single nucleotide polymorphisms (SNPs) with a minor allele frequency above 1% were analyzed. In logistic regression analysis, adjusting for age and ancestry, the variant rs62228256 (reference allele=C, minor allele=T (C&gt;T)) on 20q13.2 had the strongest association to AAP (OR=3.75; 95% CI 2.33−6.04; p=5.2∙10-8). rs62228256 is located in a non-coding region without known regulatory effects. rs13228878 (A&gt;G; OR=0.61; 95% CI 0.5−0.76; p=7.1∙10-6) and rs10273639 (C&gt;T; OR=0.62; 95% CI 0.5−0.77; p =1.1∙10-5) were among the top 30 SNPs most significantly associated to AAP. They are in high linkage disequilibrium (R2=0.94) and located in the PRSS1-PRSS2 locus on chromosome 7. The rs13228878 A risk allele was not associated with level of amylase (p=0.1) or lipase (p=0,68) at diagnosis of AAP, age at diagnosis of AAP (p=0.63), or risk of pseudocysts (p=0.78). Using identical diagnostic criteria for pancreatitis, the major C allele in rs10273639 has been associated with pancreatitis risk in adults (Whitcomb et al. Nature Genetics, 2012; Masson et al. Gut, 2017) with identical risk allele and similar odds ratios. PRSS1 and PRSS2 encode cationic and anionic trypsinogen, respectively. rs10273639 is an expressive quantitative locus for PRSS1 and the C risk-variant is associated with elevated expression of trypsinogen in pancreatic tissue. Gain of function mutations in PRSS1, known from hereditary pancreatitis, lead to increased autoactivation, increased intra-acinar trypsin levels, and increased risk of auto-digestion leading to pancreatitis. Further investigation of previously validated SNPs known to regulate trypsin activation gave the following results for associations with AAP; rs17107315 in pancreatic secretory trypsin inhibitor (SPINK1; OR=2.87; 95% CI 1.36−5.8; p=4∙10-3), rs10436957 in chymotrypsin C (CTRC ; OR=0.69; 95% CI 0.53−0.89; p=5∙10-3) and rs4409525 in Claudin-2 (CLDN2 ; OR=1.41; 95% CI 1.08−1.83; p=1∙10-2). In total, 207 out of 244 cases were homozygous for the risk allele in rs13228878 (n=104), rs17107315 (n=1), rs10436957 (n=165) and/or rs4409525 (n=16). However, no significant additive effect of having more than one risk allele was found. Conclusion: Children who develop AAP possess the same pancreatitis risk variants as adults with non-asparaginase associated pancreatitis. This shared genetic disposition may facilitate research into pathogenesis and identification of effective interventions towards AAP. Disclosures No relevant conflicts of interest to declare.

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