Citations

Background: Abdominal aortic aneurysm (AAA) is an important cause of cardiovascular mortality; however, its genetic determinants remain incompletely defined. In total, 10 previously identified risk loci explain a small fraction of AAA heritability. Methods: We performed a genome-wide association study in the Million Veteran Program testing ≈18 million DNA sequence variants with AAA (7642 cases and 172 172 controls) in veterans of European ancestry with independent replication in up to 4972 cases and 99 858 controls. We then used mendelian randomization to examine the causal effects of blood pressure on AAA. We examined the association of AAA risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and derived a genome-wide polygenic risk score (PRS) to identify a subset of the population at greater risk for disease. Results: Through a genome-wide association study, we identified 14 novel loci, bringing the total number of known significant AAA loci to 24. In our mendelian randomization analysis, we demonstrate that a genetic increase of 10 mm Hg in diastolic blood pressure (odds ratio, 1.43 [95% CI, 1.24–1.66]; P =1.6×10 −6 ), as opposed to systolic blood pressure (odds ratio, 1.06 [95% CI, 0.97–1.15]; P =0.2), likely has a causal relationship with AAA development. We observed that 19 of 24 AAA risk variants associate with aneurysms in at least 1 other vascular territory. A 29-variant PRS was strongly associated with AAA (odds ratio PRS , 1.26 [95% CI, 1.18–1.36]; P PRS =2.7×10 −11 per SD increase in PRS), independent of family history and smoking risk factors (odds ratio PRS+family history+smoking , 1.24 [95% CI, 1.14–1.35]; P PRS =1.27×10 −6 ). Using this PRS, we identified a subset of the population with AAA prevalence greater than that observed in screening trials informing current guidelines. Conclusions: We identify novel AAA genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of AAA independent of family history. Our data suggest that extending current screening guidelines to include testing to identify those with high polygenic AAA risk, once the cost of genotyping becomes comparable with that of screening ultrasound, would significantly increase the yield of current screening at reasonable cost.

As applications of genomic sequencing have expanded, offering genetic counseling support to all patients is arguably no longer practical. Additionally, whether individuals desire and value genetic counseling services for genomic screening is unclear. We offered elective genetic counseling to 5110 individuals prior to undergoing sequencing and 2310 participants who received neutral results to assess demand. A total of 0.2% of the study participants accessed genetic counseling services prior to sequencing, and 0.3% reached out after receiving neutral results. We later conducted 50 interviews with participants to understand why they did not access these services. Many interviewees did not recall the availability of genetic counseling and were unfamiliar with the profession. Interviewees described not needing counseling before sequencing because they understood the study and felt that they could cope with any result. Counseling was considered equally unnecessary after learning neutral results. Although the participants had questions about their results, they did not feel that speaking with a genetic counselor would be helpful. Genomic screening efforts that employ opt-in models of genetic counseling may need to clarify the potential value of genetic counseling support from the outset and feature genetic counseling services more prominently in program materials.

AbstractCarotid artery atherosclerotic disease (CAAD) is a risk factor for stroke. We used a genome‐wide association (GWAS) approach to discover genetic variants associated with CAAD in participants in the electronic Medical Records and Genomics (eMERGE) Network. We identified adult CAAD cases with unilateral or bilateral carotid artery stenosis and controls without evidence of stenosis from electronic health records at eight eMERGE sites. We performed GWAS with a model adjusting for age, sex, study site, and genetic principal components of ancestry. In eMERGE we found 1793 CAAD cases and 17,958 controls. Two loci reached genome‐wide significance, on chr6 in LPA (rs10455872, odds ratio [OR] (95% confidence interval [CI]) = 1.50 (1.30–1.73), p = 2.1 × 10−8) and on chr7, an intergenic single nucleotide variant (SNV; rs6952610, OR (95% CI) = 1.25 (1.16–1.36), p = 4.3 × 10−8). The chr7 association remained significant in the presence of the LPA SNV as a covariate. The LPA SNV was also associated with coronary heart disease (CHD; 4199 cases and 11,679 controls) in this study (OR (95% CI) = 1.27 (1.13–1.43), p = 5 × 10−5) but the chr7 SNV was not (OR (95% CI) = 1.03 (0.97–1.09), p = .37). Both variants replicated in UK Biobank. Elevated lipoprotein(a) concentrations ([Lp(a)]) and LPA variants associated with elevated [Lp(a)] have previously been associated with CAAD and CHD, including rs10455872. With electronic health record phenotypes in eMERGE and UKB, we replicated a previously known association and identified a novel locus associated with CAAD.

Abstract Background It is unclear how the Health Insurance Portability and Accountability Act (HIPAA) should be interpreted in the context of sharing of genomic information between family members. Methods The authors analyzed the HIPAA Privacy Rule, reviewed the literature and constructed a clinical scenario to inform how HIPAA can be interpreted for multiple forms of patient- and provider-mediated genetic risk notification. Results Under HIPAA, healthcare providers can lawfully notify relatives to recommend genetic risk assessment using multiple approaches, including supporting the patient telling their own relatives, contacting relatives directly with the patient’s authorization, or contacting a relative’s provider directly. Conclusions Multiple forms of patient- or provider-mediated contact of relatives are already legally permissible under HIPAA, are consistent with ethical obligations of care to patients and their families, and could result in improved population health through identification of clinically actionable disease risk. Unanswered questions remain about implementation and impacts of provider-mediated programs.

Electronic health record (EHR)-based clinical decision support (CDS) can address the low awareness and undertreatment of familial hypercholesterolemia (FH), a disorder associated with a markedly increased risk of coronary heart disease. We aimed to incorporate provider perspectives into the development and implementation of a CDS tool for FH. An implementation science framework and a user-centered design process were used to create a CDS tool for FH. Primary care physicians and specialist physicians participated in qualitative interviews, usability testing and an implementation survey. The CDS was configured in two formats—a best practice alert (BPA) and an in-basket message and subsequently deployed in the EHR in silent mode. The key themes that emerged from the analysis of interview transcripts included understanding and awareness of FH, clinical workflow, physician preferences and value of CDS tools, perspectives on patient needs and values and dissemination and implementation. Recommendations related to usability included preferred CDS format and placement, content, timing and frequency, and level of alert urgency/prioritization. In response to the survey, 84.6% of physicians agreed that the CDS would improve early FH diagnosis and 92.3% agreed that it would help them identify and manage FH patients. Physician feedback led to iterative CDS refinement. In summary, we developed a CDS tool for FH using an implementation science framework and physician feedback. Initial deployment revealed a significant burden of FH and the potential for the CDS tool to have a large impact.

A challenge in returning genomic test results to research participants is how best to communicate complex and clinically nuanced findings to participants in a manner that is scalable to the large numbers of participants enrolled. The purpose of this study was to examine the features of genetic results letters produced at each Electronic Medical Records and Genomics (eMERGE3) Network site to assess their readability and content. Letters were collected from each site, and a qualitative analysis of letter content and a quantitative analysis of readability statistics were performed. Because letters were produced independently at each eMERGE site, significant heterogeneity in readability and content was found. The content of letters varied widely from a baseline of notifying participants that results existed to more detailed information about positive or negative results, as well as materials for sharing with family members. Most letters were significantly above the Centers for Disease Control-suggested reading level for health communication. While continued effort should be applied to make letters easier to understand, the ongoing challenge of explaining complex genomic information, the implications of negative test results, and the uncertainty that comes with some types of test and result makes simplifying letter text challenging.

A goal of the 3rd phase of the Electronic Medical Records and Genomics (eMERGE3) Network was to examine the return of results (RoR) of actionable variants in more than 100 genes to consenting participants and their healthcare providers. Each of the 10 eMERGE sites developed plans for three essential elements of the RoR process: Disclosure to the participant, notification of the health care provider, and integration of results into the electronic health record (EHR). Procedures and protocols around these three elements were adapted as appropriate to individual site requirements and limitations. Detailed information about the RoR procedures at each site was obtained through structured telephone interviews and follow-up surveys with the clinical investigator leading or participating in the RoR process at each eMERGE3 institution. Because RoR processes at each of the 10 sites allowed for taking into account differences in population, disease focus and institutional requirements, significant heterogeneity of process was identified, including variability in the order in which patients and clinicians were notified and results were placed in the EHR. This heterogeneity in the process flow for eMERGE3 RoR reflects the “real world” of genomic medicine in which RoR procedures must be shaped by the needs of the patients and institutional environments.

AbstractBackgroundA 61‐year‐old woman underwent direct to consumer genetic testing and was found to be homozygous for the C282Y HFE variant (c.845G>A :p.Cys282Tyr) which is classified as pathogenic/likely pathogenic for hereditary hemochromatosis. However, no action was taken by the individual.MethodsThe individual took part in the Mayo Clinic Return of Actionable Variants Empiric (RAVE) study and the actionable finding was confirmed and results disclosed in person by a genetic counselor with subsequent referral to a hepatologist.ResultsFurther testing revealed iron overload with an elevated ferritin level (560 ng/ml) and increased ferritin saturation (74%). Phlebotomy was initiated with subsequent normalization of the ferritin levels (252 ng/ml).ConclusionThis case highlights that actionable genetic results may not be acted on after direct to consumer testing and the need for effective genetic counseling after such testing.

Most individuals who undergo genomic screening will receive negative results or results not sufficient to warrant a clinical response. Even though a majority of individuals receive negative results, little is known about how negative results may impact individuals’ perception of disease risk. Changes in risk perception (specifically reductions in perceived risk) may affect both probands and their family members if inaccurate information is communicated to family members. We surveyed patients who received negative results as part of their participation in a genomic screening study and assessed their perceptions of disease risk following receipt of results. Participants had either hyperlipidemia or colon polyps (or both) and received their negative genomic screening results by mail. Of 1712 total individuals recruited, 1442 completed the survey (84.2% completion rate). Approximately one quarter of individuals believed their risk for heart disease to be lower and approximately one third of individuals believed their risk for colon cancer to be lower after receiving and evaluating their negative genomic screening result. 78% of those who believed their risk for one or both diseases had declined had already shared or intended to share their result with family members. Our study suggests patients may interpret a negative genomic screening result as implying a reduction in their overall disease risk.

Background: The prevalence of familial hypercholesterolemia is 1 in 250, but <10% of patients are diagnosed. Cascade testing enables early detection of cases through systematic family tracing. Establishment of familial hypercholesterolemia cascade testing programs in the US could be informed by approaches used elsewhere. Methods: We conducted a systematic review of published studies in the English language of cascade testing for familial hypercholesterolemia, which reported the number of index cases and number of relatives tested and specified methods of contacting relatives and testing modalities methods utilized. For each study, we calculated yield (proportion of relatives who test positive) and new cases per index case, to facilitate comparison. Results: We identified 10 studies from the literature that met inclusion criteria; the mean number of probands and relatives per study was 242 and 826, respectively. The average yield was 44.76% with a range of 30% to 60.5%, and the mean new cases per index case was 1.65 with a range of 0.22 to 8.0. New cases per index case tended to be greater in studies that used direct contact versus indirect contact (2.06 versus 0.86), tested beyond first-degree relatives versus only first-degree relatives (3.65 versus 0.80), used active sample collection versus collection at clinic (4.11 versus 1.06), and utilized genetic testing versus biochemical testing (2.47 versus 0.42). Conclusions: New case detection in familial hypercholesterolemia cascade testing programs tended to be higher with direct contact of relatives, testing beyond first-degree relatives, in-home–based sample collection, and genetic testing. These findings should be helpful for establishing cascade testing programs in the United States.