Citations

Background— Massively parallel, high-throughput sequencing technology is helping to generate new insights into the genetic basis of human diseases. We used whole exome sequencing to identify the mutation underlying a syndrome affecting 2 siblings with aortic hypoplasia, calcific atherosclerosis, systolic hypertension, and premature cataract. Methods and Results— Exonic regions were captured and sequenced using a next-generation sequencing platform to generate 100 bases paired-end reads. A computational genomic data analysis pipeline was used to perform quality control, align reads to a reference genome, and identify genetic variants; findings were confirmed using a different exome analyses pipeline. The 2 siblings were homozygous for a rare missense mutation (Ser818Cys) in INO80D , a subunit of the human INO80 chromatin remodeling complex. Homozygosity mapping and Sanger sequencing confirmed that the mutation is located in one of the runs of homozygosity on chromosome 2. INO80D encodes a key subunit of the human IN080 complex, a multiprotein complex involved in DNA binding, chromatin modification, organization of chromosome structure, and ATP-dependent nucleosome sliding. By introducing a new disulphide-bond in the protein product and also disrupting the composition of low-complexity regions, the Ser818Cys mutation may affect INO80D function, protein–protein interactions, and chromatin remodeling. Conclusions— Our findings suggest a link between the Ser818Cys mutation in INO80D , a subunit of the human INO80 chromatin remodeling complex, and accelerated arterial aging.

Background and Purpose— We investigated whether family history of stroke or coronary heart disease (CHD) is associated with presence of carotid artery stenosis (CAS). Methods— The study cohort included 864 patients (72±8 years; 68% men) with CAS and 1698 controls (61±11 years; 55% men) referred for noninvasive vascular testing. CAS was defined as ≥70% stenosis in the internal carotid artery on ultrasound or history of carotid revascularization. Controls did not have CAS or history of cerebrovascular disease or CHD. Family history of stroke and CHD was defined as having ≥1 first-degree relative who had stroke or CHD before age 65 years. Logistic regression analysis was used to evaluate whether family history of stroke or CHD was associated with presence of CAS, independent of conventional risk factors. Results— Family history of stroke and CHD was present more often in patients with CAS than in controls, with a resulting odds ratios (95% confidence interval) of 2.02 (1.61–2.53) and 2.01 (1.70–2.37), respectively. The associations remained significant after adjustment for age, sex, body mass index, smoking, diabetes mellitus, hypertension, and dyslipidemia; odds ratios: 1.41 (1.06–1.90) and 1.69 (1.35–2.10), respectively. A greater number of affected relatives with stroke or CHD was associated with higher odds of CAS; adjusted odds ratios: 1.25 (0.91–1.72) and 1.46 (1.14–1.89) versus 2.65 (1.35–5.40) and 2.13 (1.57–2.90) for patients with 1 and ≥2 affected relatives with stroke and CHD, respectively. Conclusions— Family history of stroke and of CHD were each associated with CAS, suggesting that shared genetic and environmental factors contribute to the risk of CAS.

Background: Coronary heart disease (CHD) poses a major health burden in the Gulf countries. Knowledge of novel genetic and proteomic markers of CHD will provide more precise estimates of risk while defining the pathways important in individual patients, revealing new targets for intervention, and ultimately enabling an individualized approach to care. We describe design of a biorepository with linkage to medical records to facilitate discovery of biomarkers for CHD. Methods: The goal of the Qatar Cardiovascular Biorepository (QCBio) is to archive plasma and DNA of 1000 Qatari patients with CHD and 1000 age, gender, and ethnicity-matched controls who have no history of CHD. Cases will include patients needing percutaneous intervention for symptomatic CHD or admitted with an acute coronary syndrome (myocardial infarction or unstable angina). Controls will be identified from the blood bank as adults who have no history of CHD. Relevant risk factors and comorbid conditions will be ascertained by electronic medical record (EMR)-based electronic phenotyping algorithms that included diagnosis and procedure codes, medication use and laboratory data. We will include processes to promote use of the biorepository by Qatari investigators by facilitating access to the repository for biomarker research, while maintaining the highest ethical standards with emphasis on patient confidentiality and stewardship of the biospecimens. Results: Thus far, we have a) created a patient questionnaire in Arabic to obtain information on demographic factors, cardiovascular disease risk factors, and family history; b) hired the technologist for sample processing, aliquoting, and DNA extraction; c) hired and trained the study coordinators who will recruit patients; d) developed consent forms in Arabic; e) put in place a Laboratory Information Management System (LIMS) for sample tracking; and f) set up a website for the study. We have obtained approval from the Hamad Medical Center IRB and recruitment is about to begin. We will present the progress made at various seminars and conferences of the Cardiology Department to increase awareness of QCBio.

Background We investigated whether disease location influences survival in patients with peripheral arterial disease. Methods and Results Patients (n=12 731; mean age, 67.5±12.7 years; 57.4% male) who underwent outpatient noninvasive lower extremity arterial evaluation were followed up for 5.9±3.1 years for all‐cause mortality. Peripheral arterial disease (n=8930) was defined as a resting or postexercise ankle‐brachial index ( ABI ) ≤0.90, and normal ABI (n=3 801) was defined as a resting and postexercise ABI of 1.00 to 1.30. Presence or absence of disease at the proximal location or distal location was determined on the basis of D oppler signals in leg arteries; 42% had no PD or DD , 45% had proximal (14% postexercise PD only), 30% had distal disease, 17% had both proximal and distal disease, 28% had proximal only and 14% had distal only. We performed multivariable logistic regression to identify factors associated with disease location, and C ox proportional hazard regression to assess the respective effects of proximal or distal disease on survival. Older age, male sex, diabetes, heart failure, and critical limb ischemia were associated with distal disease, whereas female sex, smoking, hypertension, dyslipidemia, coronary heart disease, cerebrovascular disease, chronic obstructive pulmonary disease, and critical limb ischemia were associated with proximal disease. Over a mean follow‐up of 5.9±3.1 years, 3039 patients (23.9%) died. After adjustment for potential confounders, the hazard ratios ( HR s) of death associated with PD only and DD only were 1.3 (1.3 to 1.4) and 1.5 (1.4 to 1.6), respectively. After additional adjustment for resting ABI , there was no significant association between proximal disease and death, whereas the association of distal disease with death remained significant ( HR , 1.2; 95% CI , 1.1 to 1.3). Conclusions In patients with peripheral arterial disease, proximal and distal disease locations were associated with distinctive risk factor and comorbidity profiles. Distal disease was associated with worse survival even after adjustment for risk factors, comorbidities, and resting ABI .

Although mosaic autosomal chromosomal abnormalities are being increasingly detected as part of high-density genotyping studies, the clinical correlates are unclear. From an electronic medical record (EMR)–based genome-wide association study (GWAS) of peripheral arterial disease, log-R-ratio and B-allele-frequency data were used to identify mosaic autosomal chromosomal abnormalities including copy number variation and loss of heterozygosity. The EMRs of patients with chromosomal abnormalities and those without chromosomal abnormalities were reviewed to compare clinical characteristics. Among 3336 study participants, 0.75% (n = 25, mean age = 74.8 ± 10.7 years, 64% men) had abnormal intensity plots indicative of autosomal chromosomal abnormalities. A hematologic malignancy was present in 8 patients (32%), of whom 4 also had a solid organ malignancy while 2 patients had a solid organ malignancy only. In 50 age- and sex-matched participants without chromosomal abnormalities, there was a lower rate of hematologic malignancies (2% vs 32%, P < .001) but not solid organ malignancies (20% vs 24%, P = .69). We also report the clinical characteristics of each patient with the observed chromosomal abnormalities. Interestingly, among 5 patients with 20q deletions, 4 had a myeloproliferative disorder while all 3 men in this group had prostate cancer. In summary, in a GWAS of 3336 adults, 0.75% had autosomal chromosomal abnormalities and nearly a third of them had hematologic malignancies. A potential novel association between 20q deletions, myeloproliferative disorders, and prostate cancer was also noted.

Abstract To identify novel genetic loci influencing interindividual variation in red blood cell (RBC) traits in African-Americans, we conducted a genome-wide association study (GWAS) in 2315 individuals, divided into discovery (n = 1904) and replication (n = 411) cohorts. The traits included hemoglobin concentration (HGB), hematocrit (HCT), RBC count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC). Patients were participants in the electronic MEdical Records and GEnomics (eMERGE) network and underwent genotyping of ~1.2 million single-nucleotide polymorphisms on the Illumina Human1M-Duo array. Association analyses were performed adjusting for age, sex, site, and population stratification. Three loci previously associated with resistance to malaria—HBB (11p15.4), HBA1/HBA2 (16p13.3), and G6PD (Xq28)—were associated (P ≤ 1 × 10−6) with RBC traits in the discovery cohort. The loci replicated in the replication cohort (P ≤ 0.02), and were significant at a genome-wide significance level (P &lt; 5 × 10−8) in the combined cohort. The proportions of variance in RBC traits explained by significant variants at these loci were as follows: rs7120391 (near HBB) 1.3% of MCHC, rs9924561 (near HBA1/A2) 5.5% of MCV, 6.9% of MCH and 2.9% of MCHC, and rs1050828 (in G6PD) 2.4% of RBC count, 2.9% of MCV, and 1.4% of MCH, respectively. We were not able to replicate loci identified by a previous GWAS of RBC traits in a European ancestry cohort of similar sample size, suggesting that the genetic architecture of RBC traits differs by race. In conclusion, genetic variants that confer resistance to malaria are associated with RBC traits in African-Americans.