Admixture mapping of coronary artery calcification in African Americans from the NHLBI family heart study

Objective.Urate may have effects on vascular remodeling and atherosclerosis. We had shown an association between serum uric acid (SUA) and carotid atherosclerotic plaques. Inflammation and vascular remodeling in atherosclerosis promote coronary artery calcification (CAC), a preclinical marker for atherosclerosis. Here, we examined whether SUA is associated with CAC, using the same study sample and methods as for our previous carotid atherosclerosis study.Methods.The National Heart, Lung, and Blood Institute Family Heart Study is a multicenter study designed to assess risk factors for heart disease. Participants were recruited from population-based cohorts in the US states of Massachusetts, North Carolina, Minnesota, Utah, and Alabama. CAC was assessed with helical computed tomography (CT). We conducted sex-specific and family-cluster analyses, as well as additional analyses among persons without risk factors related to both cardiovascular disease and hyperuricemia, adjusting for potential confounders as we had in the previous study of carotid atherosclerosis.Results.For the CAC study, 2412 subjects had both SUA and helical CT results available (55% women, age 58 ± 13 yrs, body mass index 27.6 ± 5.3). We found no association of SUA with CAC in men or women [OR in men: 1.0, 1.11, 0.86, 0.90; women: 1.0, 0.83, 1.00, 0.87 for increasing categories of SUA: < 5 (referent group), 5 to < 6, 6 to < 6.8, ≥ 6.8 mg/dl, respectively], nor in subgroup analyses.Conclusion.Replicating the methods used to demonstrate an association of SUA with carotid atherosclerosis did not reveal any association between SUA and CAC, suggesting that SUA likely does not contribute to atherosclerosis through effects on arterial calcification. The possibility that urate has divergent pathophysiologic effects on atherosclerosis and artery calcification merits further study.

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Abstract P109: Detection of Haplotypes Underlying a Coronary Artery Calcification Linkage Peak in the Family Heart Study

Circulation ◽

10.1161/circ.135.suppl_1.p109 ◽

2017 ◽

Vol 135 (suppl_1) ◽

Author(s):

James E Hicks ◽

Michael A Province

Keyword(s):

Coronary Artery ◽

Coronary Artery Calcification ◽

Chromosome 9 ◽

Genomic Feature ◽

Polygenic Effect ◽

Significant Evidence ◽

Family Heart Study ◽

Heart Study ◽

A Genome ◽

The Family

Coronary artery calcification (CAC) is the buildup of calcium deposits in the arteries leading to the heart, and is an indicator of atherosclerosis. CAC is known to have a genetic component, and a genome-wide linkage screen in the Family Heart Study identified significant evidence of linkage on chromosome 9 in the area near rs13293430, but no common variant in the linkage region showed significant evidence of association. Linkage screens attempt to identify covariance due to common ancestry at a genomic locus. This is robust to the presence of rare variation or multiple variants in a region, but is unable to identify the genomic feature causing the signal and additional research is needed to identify potential causative variants. Pairs of individuals who have inherited a locus from a common ancestor will share an identical sequence of alleles (a haplotype) within the region. To identify haplotypes influencing the trait in the region, a mixed effects model was used. CAC was modeled as a trait influenced by polygenic effects and locus-specific haplotype effects. This model has the benefit of jointly estimating the effect of each haplotype while separating the haplotype effect from the background polygenic effect. From the study, 2,687 individuals of European descent from 508 pedigrees with CAC scores were genotyped on the Illumina Human 1M-DuoV3 single nucleotide polymorphisms (SNP) array. Of these, 180 individuals from 23 pedigrees were for subsequent analysis due to membership in a pedigree contributing to the linkage signal. CAC scores were determined by cardiac CT scan and adjusted for age, sex, and principal components before analysis. Phased haplotypes were generated for 906,856 common SNPs across the genome using SHAPEIT. The region between 25Mb and 35Mb (3,500 SNPs) was divided into 250kb sections, and within each section haplotypes were created based on 24 evenly spaced SNPs. Statistical significance for each region was determined by likelihood ratio test. Haplotype analysis identified two regions showing strong evidence of association (p<10 -7 ) with CAC. The region 28-28.25Mb is located completely within the gene LINGO2, which has been associated with BMI and cholesterol. The region 27.5-27.75Mb contains MOBKL2B, IFNK and C9orf72. Additional work will be needed to validate haplotypes used in the model and identify the particular haplotype influencing the trait.

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Physical Activity, Inflammation, Coronary Artery Calcification, and Incident Coronary Heart Disease in African Americans: Insights From the Jackson Heart Study

Mayo Clinic Proceedings ◽

10.1016/j.mayocp.2020.09.042 ◽

2021 ◽

Vol 96 (4) ◽

pp. 901-911 ◽

Cited By ~ 1

Author(s):

Daisuke Kamimura ◽

Loretta R. Cain-Shields ◽

Donald Clark ◽

Adebamike A. Oshunbade ◽

Kellan E. Ashley ◽

...

Keyword(s):

Physical Activity ◽

Coronary Heart Disease ◽

Heart Disease ◽

Coronary Artery ◽

African Americans ◽

Coronary Artery Calcification ◽

Jackson Heart Study ◽

Incident Coronary Heart Disease ◽

Heart Study

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Abstract P257: Between-pedigree Genome-wide Linkage Screen Identifies a Locus on Chromosome 9 Influencing Coronary Artery Calcification in the Family Heart Study

Circulation ◽

10.1161/circ.133.suppl_1.p257 ◽

2016 ◽

Vol 133 (suppl_1) ◽

Author(s):

James E Hicks ◽

Michael A Province

Keyword(s):

Coronary Artery ◽

Coronary Artery Calcification ◽

Chromosome 9 ◽

Genome Wide Association ◽

Ratio Test ◽

Family Heart Study ◽

Genome Wide ◽

Heart Study ◽

A Genome ◽

The Family

Coronary artery calcification (CAC) is the buildup of calcium deposits in the arteries leading to the heart, and is an indicator of atherosclerosis. CAC is known to have a genetic component. To identify the genes underlying CAC, a genome-wide linkage screen was performed in the Family Heart Study. There are two established loci influencing CAC identified by genome-wide association scans, at chromosome 9p21 and 6p24. However, there may be rare variants on haplotypes in the population that influence CAC. These would not be able to be identified by genome-wide association scans, but linkage scans could detect them. From the study, 2,687 individuals of European descent from 508 pedigrees with CAC scores were genotyped on the Illumina Human 1M-DuoV3 single nucleotide polymorphisms (SNP) array. CAC scores were determined by cardiac CT scan and adjusted for age, sex, and principal components before analysis. Using 484,358 common SNPs (minor allele frequency greater than 5%), common ancestry across the genome was determined for all pairs of individuals in the study. A segment of the genome was considered to be inherited from a common ancestor (identical-by-descent, IBD) if it contained more than 1,000 matching SNP genotypes over a length of at least one megabase. To test the influence of IBD at a locus on CAC, a linear mixed effects model was fit, including random effects to account for covariance due to relatedness and IBD states at each locus. All pedigrees were considered jointly in the model. Statistical significance was determined by comparing this model to one without IBD covariance via the likelihood ratio test. This model was evaluated approximately every megabase across all 22 pairs of autosomes. Since IBD states are determined solely by dense genotype data, IBD can be detected both within and between pedigrees in the study. This allows the inclusion covariance due to IBD in individuals in different pedigrees. If there is a haplotype shared across pedigrees, power to detect linkage is increased. CAC was found to have a narrow-sense heritability of 37.4% in this sample. Significant evidence of linkage was encountered at rs13293430 (chromosome 9, 31,050,747bp, LOD=3.042). When considering IBD between pedigrees, 914 pairs of individuals from different pedigrees were IBD at this position. This locus is near DDX58. Mutations in DDX58 cause Singleton-Merton syndrome, a disease characterized by calcification of blood vessels, making it an intriguing candidate gene for influence on CAC.

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Sugar-Sweetened Beverage Consumption and Calcified Atherosclerotic Plaques in the Coronary Arteries: The NHLBI Family Heart Study

Nutrients ◽

10.3390/nu13061775 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1775

Author(s):

Yash R. Patel ◽

Tasnim F. Imran ◽

R. Curtis Ellison ◽

Steven C. Hunt ◽

John Jeffrey Carr ◽

...

Keyword(s):

Sensitivity Analysis ◽

Coronary Arteries ◽

Subclinical Atherosclerosis ◽

Agatston Score ◽

Sugar Sweetened Beverage ◽

Cut Points ◽

Sweetened Beverage ◽

Family Heart Study ◽

Heart Study ◽

Nhlbi Family Heart Study

Background: Sugar-sweetened beverage (SSB) intake is associated with higher risk of weight gain, diabetes, hypertension, cardiovascular disease, and cardiovascular mortality. However, the association of SSB with subclinical atherosclerosis in the general population is unknown. Objective: Our primary objective was to investigate the association between SSB intake and prevalence of atherosclerotic plaque in the coronary arteries in The National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study. Methods: We studied 1991 participants of the NHLBI Family Heart Study without known coronary heart disease. Intake of SSB was assessed through a semi-quantitative food frequency questionnaire. Coronary artery calcium (CAC) was measured by cardiac Computed Tomography (CT) and prevalent CAC was defined as an Agatston score ≥100. We used generalized estimating equations to calculate adjusted prevalence ratios of CAC. A sensitivity analysis was also performed at different ranges of cut points for CAC. Results: Mean age and body mass index (BMI) were 55.0 years and 29.5 kg/m2, respectively, and 60% were female. In analysis adjusted for age, sex, BMI, smoking, alcohol use, physical activity, energy intake, and field center, higher SSB consumption was not associated with higher prevalence of CAC [prevalence ratio (95% confidence interval) of: 1.0 (reference), 1.36 (0.70–2.63), 1.69 (0.93–3.09), 1.21 (0.69–2.12), 1.05 (0.60–1.84), and 1.58 (0.85–2.94) for SSB consumption of almost never, 1–3/month, 1/week, 2–6/week, 1/day, and ≥2/day, respectively (p for linear trend 0.32)]. In a sensitivity analysis, there was no evidence of association between SSB and prevalent CAC when different CAC cut points of 0, 50, 150, 200, and 300 were used. Conclusions: These data do not provide evidence for an association between SSB consumption and prevalent CAC in adult men and women.

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A QTL on 12q Influencing an Inflammation Marker and Obesity in White Women: The NHLBI Family Heart Study

Obesity ◽

10.1038/oby.2008.556 ◽

2009 ◽

Vol 17 (3) ◽

pp. 525-531 ◽

Cited By ~ 8

Author(s):

Jun Wu ◽

James S. Pankow ◽

Russell P. Tracy ◽

Kari E. North ◽

Richard H. Myers ◽

...

Keyword(s):

White Women ◽

Inflammation Marker ◽

Family Heart Study ◽

Heart Study ◽

Nhlbi Family Heart Study

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Association of Coronary Artery Calcified Plaque With Clinical Coronary Heart Disease in the National Heart, Lung, and Blood Institute’s Family Heart Study

The American Journal of Cardiology ◽

10.1016/j.amjcard.2005.12.043 ◽

2006 ◽

Vol 97 (11) ◽

pp. 1564-1569 ◽

Cited By ~ 14

Author(s):

Paul N. Hopkins ◽

R. Curtis Ellison ◽

Michael A. Province ◽

James S. Pankow ◽

J. Jeffrey Carr ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Coronary Artery ◽

Family Heart Study ◽

National Heart ◽

Coronary Artery Calcified Plaque ◽

Heart Study ◽

Calcified Plaque ◽

National Heart Lung

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Abstract P159: Coronary Artery Calcium Score Improves the Net Reclassification Index of Prevalent Cardiovascular Disease In African Americans: The Jackson Heart Study

Circulation ◽

10.1161/circ.125.suppl_10.ap159 ◽

2012 ◽

Vol 125 (suppl_10) ◽

Author(s):

Joseph Yeboah ◽

Che L Smith ◽

Mario Sims ◽

Ervin Fox ◽

Yaorong Ge ◽

...

Keyword(s):

Cardiovascular Disease ◽

Coronary Artery ◽

High Risk ◽

African Americans ◽

Diagnostic Accuracy ◽

Coronary Artery Calcium ◽

Smoking Status ◽

Jackson Heart Study ◽

Net Reclassification Improvement ◽

Heart Study

Background: Prior studies suggest that African Americans (AA) have lower prevalence of coronary artery calcium (CAC) compared to whites, yet CAC has similar ability to predict coronary heart disease (CHD) events. The role of CAC as a screening tool for CHD risk in AA is unclear. We compared the diagnostic accuracy for CHD prevalence using the CAC score and the Framingham Risk Score (FRS) in an adult population of AA. Methods: CAC was measured in 2944 participants in the Jackson Heart Study, an NHLBI funded study of AA based in Jackson, MS. Approximately 8% of this cohort had known cardiovascular disease (CVD) defined as prior MI, angina, stroke, PTCA, CABG or PVD. Logistic regression, ROC and net reclassification index (NRI) analysis were used adjusting for age, gender, SBP, total and HDL cholesterol, smoking status, DM and BMI. FRS was calculated and those with DM were classified as high risk. Results: The mean age was 60, 65% were females, 26% had DM, 50% were obese and 30% were current or former smokers. Prevalent CVD was associated with older age, higher SBP, lower HDL and total cholesterol, and higher CAC. CAC was independently associated with prevalent CVD in our multivariable model [OR (95% CI): 1.26 (1.17, 1.35), p< 0.0001]. In ROC analysis, CAC improved the diagnostic accuracy (c statistic) of the FRS from 0.617 to 0.757 (p < 0.0001) for prevalent CVD. The FRS classified 30% of the cohort as high risk, 38.5% as intermediate risk and 31.5% as low risk. FRS classfied 51% of subjects with prevalent CVD as high risk. Addition of CAC to FRS resulted in net reclassification improvement of 4% for subjects with known CVD and 28.5% in those without CVD (see figure). Conclusion: In AA, the CAC is independently associated with prevalent CVD and improves the diagnostic accuracy of FRS for prevalent CVD by 14%. Addition of CAC improves the NRI of those with prevalent CVD by 4% and the NRI of individuals without CVD by 28.5%. Determination of CAC in AA may be useful in identifying individuals at risk of CVD and reclassifying individuals with low and intermediate FRS.

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