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

Circulation ◽  
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.

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

Circulation ◽  
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.

scholarly journals Serum Urate Is Not Associated with Coronary Artery Calcification: The NHLBI Family Heart Study

2010 ◽  
Vol 38 (1) ◽  
pp. 111-117 ◽  
Author(s):  
TUHINA NEOGI ◽  
ROBERT TERKELTAUB ◽  
R. CURTIS ELLISON ◽  
STEVEN HUNT ◽  
YUQING ZHANG
Keyword(s):  
Risk Factors ◽  
Coronary Artery ◽  
Vascular Remodeling ◽  
Coronary Artery Calcification ◽  
Carotid Atherosclerosis ◽  
Helical Ct ◽  
Arterial Calcification ◽  
Helical Computed Tomography ◽  
Family Heart Study ◽  
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.

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

BMC Genetics ◽  
2015 ◽  
Vol 16 (1) ◽  
Author(s):  
Felicia Gomez ◽  
Lihua Wang ◽  
Haley Abel ◽  
Qunyuan Zhang ◽  
Michael A Province ◽  
...  
Keyword(s):  
Coronary Artery ◽  
African Americans ◽  
Coronary Artery Calcification ◽  
Admixture Mapping ◽  
Family Heart Study ◽  
Heart Study ◽  
Nhlbi Family Heart Study

Genome-wide admixture mapping for coronary artery calcification in African Americans: the NHLBI Family Heart Study

2008 ◽  
Vol 32 (3) ◽  
pp. 264-272 ◽  
Author(s):  
Qunyuan Zhang ◽  
Cora E. Lewis ◽  
Lynne E. Wagenknecht ◽  
Richard H. Myers ◽  
James S. Pankow ◽  
...  
Keyword(s):  
Coronary Artery ◽  
African Americans ◽  
Coronary Artery Calcification ◽  
Admixture Mapping ◽  
Family Heart Study ◽  
Genome Wide ◽  
Heart Study ◽  
Nhlbi Family Heart Study

scholarly journals SEDENTARY BEHAVIOR IS ASSOCIATED WITH CORONARY ARTERY CALCIFICATION IN THE DALLAS HEART STUDY

2015 ◽  
Vol 65 (10) ◽  
pp. A1446
Author(s):  
Jacquelyn Kulinski ◽  
Julia Kozlitina ◽  
Jarett Berry ◽  
James de Lemos ◽  
Amit Khera
Keyword(s):  
Coronary Artery ◽  
Sedentary Behavior ◽  
Coronary Artery Calcification ◽  
Heart Study ◽  
Dallas Heart Study

Abstract 002: Race and Sex Influence the Associations of Subcutaneous and Visceral Adipose Tissues with Calcified Plaque of the Coronary and Abdominal Aortic Arteries: The Family Heart Study

Circulation ◽  
2012 ◽  
Vol 125 (suppl_10) ◽  
Author(s):  
J G Terry ◽  
Sean L Simpson ◽  
Che Smith ◽  
J J Carr ◽  
Kristen G Hairston ◽  
...  
Keyword(s):  
Regression Models ◽  
Abdominal Fat ◽  
Arterial Calcification ◽  
Logistic Regression Models ◽  
Family Heart Study ◽  
Heart Study ◽  
Calcified Plaque ◽  
The Family ◽  
Multivariable Models ◽  
Visceral Adipose

Previous research suggests that visceral adipose tissue (VAT) increases risk for atherosclerosis and specifically arterial calcification, yet the association of subcutaneous adipose tissue (SAT) with calcification is less substantiated. Studies have also noted important race and sex differences in risk of atherosclerosis. In the Family Heart Study, we examined race and sex differences in the pattern of associations of abdominal fat depots with coronary (CAC) and abdominal aorto-iliac (AAC) calcified plaque measured using computed tomography (CT). Methods- We used CT to measure abdominal fat volume and arterial calcified plaque in 2,748 participants of European American descent (EA; n=1512 females) and 626 participants of African American descent (AA; n=412 females) in the Family Heart Study. CAC and AAC were defined as present (≥1) or absent (0) based on Agatston scores. Odds ratios (OR) and 95% confidence intervals (95% CI) were determined using logistic regression models adjusted for age, field center, family pedigree, race, and history of coronary heart disease (CHD), diabetes, hypertension, hypercholesterolemia, and smoking. Results- The association of SAT and VAT with prevalent CAC and AAC varied with sex and race in multivariable logistic regression models. In males, SAT was strongly associated with both CAC (p=0.001) and AAC (p<0.001) in multivariable models and there was evidence that the associations of SAT with CAC and AAC differed by race (each p interaction SAT*race p<0.01). The associations of SAT with CAC and AAC appeared to be stronger in EA males than in AA males. In EA, the OR for CAC for a single SD increase in SAT was 2.17 (95% CI 1.37-3.45) whereas for AA the OR was 1.42 (95% CI 1.17-1.72) per SD increase in SAT. Also, in EA males the OR for AAC per SD increase in SAT was 2.69 (95% CI 1.61-4.50) compared to 1.39 (95% CI 1.11-1.73) in AA males. VAT was significantly associated with prevalent CAC in both EA males (OR=1.96 per SD increase, p=0.02) and AA males (OR=1.26 per SD increase, p=0.02) though there were no significant associations of VAT with AAC among males. In females, both SAT (OR=1.18 per SD increase, p=0.004) and VAT (OR=1.21 per SD increase, p=0.003) were associated with prevalent CAC, but not AAC, in multivariable models and associations did not vary by race. Conclusions- Abdominal SAT was associated with both CAC and AAC prevalence in males, and associations appeared to be stronger in EA compared to AA participants. VAT was predictive of CAC in both EA and AA males. In contrast, SAT and VAT were only associated with CAC in females and no differences by race were noted. Our findings suggest that SAT, and by inference obesity, along with VAT may be an important contributors to prevalence of arterial calcification and that race plays a role in associations among males.

scholarly journals A Quantitative Trait Locus on Chromosome 5p Influences D-Dimer Levels in the San Antonio Family Heart Study

2010 ◽  
Vol 2010 ◽  
pp. 1-6
Author(s):  
V. P. Diego ◽  
L. Almasy ◽  
D. L. Rainwater ◽  
M. C. Mahaney ◽  
A. G. Comuzzie ◽  
...  
Keyword(s):  
Quantitative Trait ◽  
Mexican Americans ◽  
San Antonio ◽  
Lod Score ◽  
Family Heart Study ◽  
Heart Study ◽  
A Genome ◽  
Increased Risk ◽  
Chromosome 5P ◽  
D Dimer

Background. D-dimer is associated with increasing severity of atherosclerosis and with increased risk of a cardiovascular disease (CVD).Methods and Results. To better understand this risk factor, we performed a genome scan on 803 (301 males and 502 females) Mexican Americans in the San Antonio Family Heart Study (SAFHS). The SAFHS is ideal for the discovery of quantitative trait loci (QTLs) influencing CVD because CVD risk factors are prevalent in Mexican Americans of San Antonio and because the study design involves large families, which is optimal for QTL discovery. D-dimer levels were normalized in our study. We found that D-dimer levels were heritable, at about 23% heritability (P≈.00001). In a linkage analysis employing 432 microsatellite markers, we found strong evidence of a QTL on chromosome 5p with a lod score of 3.32 at 21 centiMorgans (cM). We also found suggestive evidence of a QTL on chromosome 2q with a lod score of 2.33 at 207 cM.Conclusions. To our knowledge, the putative QTL on chromosome 5p is novel. The possible QTL on chromosome 2q is discussed in relation to a recent report of linkage of a related hemostatic factor to the same location. These results warrant further investigation.

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