Kullo, Iftikhar J.

As genomic sequencing expands to screen larger numbers of individuals, offering genetic counseling to everyone may not be possible. One approach to managing this limitation is for a genetic counselor to communicate clinically actionable results in person or by telephone, but report other results by mail. We employed this approach in a large genomic implementation study. In this paper, we describe participants’ experiences receiving genomic screening results by mail. We conducted 50 semi-structured telephone interviews with individuals who received neutral genomic screening results by mail. Most participants were satisfied receiving neutral results by mail. Participants generally had a good understanding of results; however, a few participants had misunderstandings about their genomic screening results, including mistaken beliefs about their disease risk and the comprehensiveness of the test. No one reported plans to alter health behaviors, defer medical evaluations, or take other actions that might be considered medically problematic. Reporting neutral results by mail is unlikely to cause recipients distress or generate misunderstandings that may result in reduced vigilance in following recommended preventive health strategies. Nonetheless, some individuals may benefit from additional genetic counseling support to help situate their results in the context of personal concerns and illness experiences.

Abstract Objective: Fibromuscular dysplasia (FMD) is an arteriopathy that presents mainly by hypertension, stroke or dissection. Diagnosis is often made in middle-aged women with few cardiovascular risk factors. We aim at identifying common genetic variants associated to FMD. Design and method: We tested ∼6.5 million common genetic variants (MAF > 0.01) in 1962 cases and 7100 controls from 6 studies using variants and gene-based association analyses. Participants were of European ancestry, with similar characteristics (91% multifocal, 88% women), diagnosis methods and inclusion/exclusion criteria. Transcriptome-wide association (TWAS), eQTL, gene expression by sex and colocalization analyses used expression data in arteries from GTEx and/or FMD patients and matched controls. Open chromatin regions were defined using ATAC-Seq on primary human fibroblasts, smooth muscle and endothelial cells. Genetic correlations were assessed using summary statistics from UKBiobank and/or published studies by linkage disequilibrium score regression and multi-trait-based conditional and joint analyses (mtCOJO). Results: We confirmed the previously identified PHACTR1 locus and identified three new loci (LRP1, ATP2B1, and LIMA1) associated with FMD. TWAS in arteries identified one additional locus (SLC24A3). Through integration of annotation datasets, we provided prioritization of variants and genes. These are consistently and specifically expressed in fibroblasts, smooth muscle cells, and arterial tissues. PHACTR1 and SLC24A3 showed sex differences in gene expressions consistent with the direction of effects of FMD risk alleles. FMD genes are involved in regulatory mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, two mechanisms central to vascular contraction. We found significant genetic overlaps between FMD and blood pressure traits, for the associated loci and globally at the genome level, but demonstrated that hypertension is not driving the genetic association with FMD. We also found positive genetic correlations with migraine and intracranial aneurysm, and an inverse correlation with coronary artery disease, independently from the genetics of blood pressure. Conclusions: We describe robustly associated loci and genes with FMD and provide several new leads toward understanding biological mechanisms of stenosis and dissection in young women in the absence of atherosclerosis, which shares part of its genetic basis with more common cardiovascular and neurovascular diseases.

Introduction: Minority communities have had limited access to advances in genomic medicine. Mayo Clinic and Mountain Park Health Center, a Federally Qualified Health Center in Phoenix, Arizona, partnered to assess the feasibility of offering genomic screening to Latino patients receiving care at a community-based health center. We examined primary care provider (PCP) experiences reporting genomic screening results and integrating those results into patient care. Methods: We conducted open-ended, semi-structured interviews with PCPs and other members of the health care team charged with supporting patients who received positive genomic screening results. Interviews were recorded, transcribed, and analyzed thematically. Results: Of the 500 patients who pursued genomic screening, 10 received results indicating a genetic variant that warranted clinical management. PCPs felt genomic screening was valuable to patients and their families, and that genomic research should strive to include underrepresented minorities. Providers identified multiple challenges integrating genomic sequencing into patient care, including difficulties maintaining patient contact over time; arranging follow-up medical care; and managing results in an environment with limited genetics expertise. Providers also reflected on the ethics of offering genomic sequencing to patients who may not be able to pursue diagnostic testing or follow-up care due to financial constraints. Conclusions: Our results highlight the potential benefits and challenges of bringing advances in precision medicine to community-based health centers serving under-resourced populations. By proactively considering patient support needs, and identifying financial assistance programs and patient-referral mechanisms to support patients who may need specialized medical care, PCPs and other health care providers can help to ensure that precision medicine lives up to its full potential as a tool for improving patient care.

Abstract Coronary artery disease (CAD) is a leading cause of death, yet its genetic determinants are not fully elucidated. We report a multi-ethnic genome-wide association study of CAD involving nearly a quarter of a million cases, incorporating the largest cohorts to date of Whites, Blacks, and Hispanics from the Million Veteran Program with existing studies including CARDIoGRAMplusC4D, UK Biobank, and Biobank Japan. We verify substantial and nearly equivalent heritability of CAD across multiple ancestral groups, discover 107 novel loci including the first nine on the X-chromosome, identify the first eight genome-wide significant loci among Blacks and Hispanics, and demonstrate that two common haplotypes are largely responsible for the risk stratification at the well-known 9p21 locus in most populations except those of African origin where both haplotypes are virtually absent. We identify 15 loci for angiographically derived burden of coronary atherosclerosis, which robustly overlap with the strongest and earliest loci reported to date for clinical CAD. Phenome-wide association analyses of novel loci and externally validated polygenic risk scores (PRS) augment signals from the insulin resistance cluster of risk factors and consequences, extend previously established pleiotropic associations of loci with traditional risk factors to include smoking and family history, and confirm a substantially reduced transferability of existing PRS to Blacks. Downstream integrative genomic analyses reinforce the critical role of endothelial, fibroblast, and smooth muscle cells within the coronary vessel wall in CAD susceptibility. Our study highlights the value of a multi-ethnic design in efficiently characterizing the genetic architecture of CAD across all human populations.

AbstractObjective Familial hypercholesterolemia (FH), a prevalent genomic disorder that increases risk of coronary heart disease, remains significantly underdiagnosed. Clinical decision support (CDS) tools have the potential to increase FH detection. We describe our experience in the development and implementation of a genomic CDS for FH at a large academic medical center.Methods CDS development and implementation were conducted in four phases: (1) development and validation of an algorithm to identify “possible FH”; (2) obtaining approvals from institutional committees to develop the CDS; (3) development of the initial prototype; and (4) use of an implementation science framework to evaluate the CDS.Results The timeline for this work was approximately 4 years; algorithm development and validation occurred from August 2018 to February 2020. During this 4-year period, we engaged with 15 stakeholder groups to build and integrate the CDS, including health care providers who gave feedback at each stage of development. During CDS implementation six main challenges were identified: (1) need for multiple institutional committee approvals; (2) need to align the CDS with institutional knowledge resources; (3) need to adapt the CDS to differing workflows; (4) lack of institutional guidelines for CDS implementation; (5) transition to a new institutional electronic health record (EHR) system; and (6) limitations of the EHR related to genomic medicine.Conclusion We identified multiple challenges in different domains while developing CDS for FH and integrating it with the EHR. The lessons learned herein may be helpful in streamlining the development and deployment of CDS to facilitate genomic medicine implementation.

Advances in genomics have the potential to improve human health [...]

Background Atherosclerosis in >1 vascular bed (ie, polyvascular disease), often a feature of peripheral artery disease (PAD), is associated with high morbidity and mortality. We sought to identify risk factors for polyvascular involvement in patients with PAD. Methods and Results We performed 2‐sample Mendelian randomization using an inverse‐variance‐weighted approach, to assess 60 exposures including size and lipid content of atherogenic lipoproteins, blood pressure, glycated hemoglobin, and smoking as causal mediators for polyvascular disease in patients with PAD. Genetic instruments for these exposures were obtained from prior genome‐wide association studies. Patients with PAD were from the Mayo Vascular Disease Biorepository, and polyvascular disease (ie, concomitant coronary heart disease, cerebrovascular disease, and/or abdominal aortic aneurysm) was ascertained by validated phenotyping algorithms. Of 3279 patients with PAD, 61% had polyvascular disease. Genetically predicted levels of the lipid content and/or particle measures of very small and small size very low‐density lipoprotein, intermediate‐density lipoprotein, and large low‐density lipoprotein were associated with polyvascular disease: odds ratios (OR) of 1.80 (95% CI, 1.23–2.61), 1.70 (95% CI, 1.17–2.61), and 1.40 (95% CI, 1.09–1.80) per 1 SD increase in genetically determined levels, respectively. Both genetically predicted diastolic and systolic blood pressure were associated with polyvascular disease; OR per 10 mm Hg genetic increase in diastolic and systolic blood pressure were 1.66 (95% CI, 1.19–2.33) and 1.31 (95% CI, 1.07–1.60), respectively. Conclusions Lifetime exposure to increased lipid content and levels of very small and small very low‐density lipoprotein, intermediate‐density lipoprotein, and large low‐density lipoprotein particles as well as elevated blood pressure are associated with polyvascular involvement in patients with PAD. Reduction in levels of such exposures may limit progression of atherosclerosis in patients with PAD.

AbstractPopulation‐based genomic screening has the potential to improve health outcomes by identifying genetic causes of disease before they occur. While much attention has been paid to supporting the needs of the small percentage of patients who will receive a life‐altering positive genomic screening result that requires medical attention, little attention has been given to the communication of negative screening results. As there are currently no best practices for returning negative genomic screening results, we drew on experiences across the electronic medical records and genomics (eMERGE) III Network to highlight the diversity of reporting methods employed, challenges encountered in reporting negative test results, and “lessons learned” across institutions. A 60‐item survey that consisted of both multiple choice and open‐ended questions was created to gather data across institutions. Even though institutions independently developed procedures for reporting negative results, and had very different study populations, we identified several similarities of approach, including but not limited to: returning results by mail, placing results in the electronic health record via an automated process, reporting results to participants' primary care provider, and providing genetic counseling to interested patients at no cost. Differences in procedures for reporting negative results included: differences in terminology used to describe negative results, definitions of negative results, guidance regarding the meaning of negative results for participants and their family members, and recommendations for clinical follow up. Our findings highlight emerging practices for reporting negative genomic screening results and highlight the need to create patient education and clinical support tools for reporting negative screening results.