Advancing genomics to improve health equity.

Health equity is the state in which everyone has fair and just opportunities to attain their highest level of health. The field of human genomics has fallen short in increasing health equity, largely because the diversity of the human population has been inadequately reflected among participants of genomics research. This lack of diversity leads to disparities that can have scientific and clinical consequences. Achieving health equity related to genomics will require greater effort in addressing inequities within the field. As part of the commitment of the National Human Genome Research Institute (NHGRI) to advancing health equity, it convened experts in genomics and health equity research to make recommendations and performed a review of current literature to identify the landscape of gaps and opportunities at the interface between human genomics and health equity research. This Perspective describes these findings and examines health equity within the context of human genomics and genomic medicine.

A virtual randomized controlled trial of an alcohol-exposed pregnancy prevention mobile app with urban American Indian and Alaska Native young women: Native WYSE CHOICES rationale, design, and methods.

BACKGROUND: Fetal Alcohol Spectrum Disorders (FASD) result in lifelong disability and are a leading cause of preventable birth defects in the US, including for American Indian and Alaska Natives (AIANs). Prevention of alcohol exposed pregnancies (AEPs), which can cause FASD, is typically aimed at adult women who are risky drinkers and have unprotected sex. Among AIANs, AEP prevention research has been primarily conducted in reservation communities, even though over 70% of AIANs live in urban areas. Culturally appropriate AEP prevention for urban AIAN young women, regardless of current drinking or sexual behaviors, may maximize the potential for primary prevention at the beginning of the reproductive years for this underserved population. METHODS: We developed a virtual randomized controlled trial (RCT) - fully implemented through technology - to evaluate Native WYSE CHOICES, a culturally tailored mobile app, with urban AIAN young women ages 16-20 nationally. While virtual RCTs are not new, this is the first engaging a solely urban AIAN population, historically excluded from research. Participants are recruited on a rolling basis through the project social media community, organizational partnerships, and in-person events. Eligible participants complete a baseline survey and are randomized to either the app's intervention or comparison arm - each of which provide about 3 h of content. Follow-up data are collected at 1-, 6-, and 12-months post-baseline. RESULTS: Our study offers a template for building trust and extending reach to this underserved population while also providing important lessons and insights on advances in virtual or hybrid research approaches.

A scoping review of veteran suicide prevention programs in Native American communities and in the general population.

Suicide is a major public health problem that disproportionately impacts veterans in the general U.S. population. Recent analyses indicate that American Indian and Alaska Native (AI/AN) veterans may be two to three times as likely as non-Hispanic White veterans to experience suicidal ideation. Although suicide prevention programs have been successfully implemented for many at-risk populations, to our knowledge, none have been designed or implemented for AI/AN veterans. To address this gap, we conducted a scoping review of suicide prevention programs with the objective of identifying promising strategies and lessons learned to identify promising practices for preventing suicide among AI/AN veterans. We conducted two parallel literature searches-a review of suicide prevention programs for the general U.S. adult population and AI/AN communities. We rated programs on 16 criteria, covering five domains-best practices in suicide prevention, U.S. Department of Veterans Affairs (VA) Office of Rural Health Promising Practice criteria, cultural fit, care coordination, and outcomes. Our findings indicate that many of the VA evidence-based or best practice programs are available system-wide, but none have been tailored for AI/AN veterans or the communities in which they live. Conversely, we found that many culturally specific programs implemented in AI/AN communities were rarely disseminated beyond tribal land and none were specifically developed for veterans. Based upon these findings, and to advance suicide prevention programs for AI/AN veterans, we propose a suicide prevention model that builds upon existing VA infrastructure to disseminate best practices to AI/AN communities and integrate tribal-specific cultural approaches to suicide prevention. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Diabetes Prevention and Care Capacity at Urban Indian Health Organizations.

American Indian and Alaska Native (AI/AN) people suffer a disproportionate burden of diabetes and cardiovascular disease. Urban Indian Health Organizations (UIHOs) are an important source of diabetes services for urban AI/AN people. Two evidence-based interventions-diabetes prevention (DP) and healthy heart (HH)-have been implemented and evaluated primarily in rural, reservation settings. This work examines the capacity, challenges and strengths of UIHOs in implementing diabetes programs. Methods: We applied an original survey, supplemented with publicly-available data, to assess eight organizational capacity domains, strengths and challenges of UIHOs with respect to diabetes prevention and care. We summarized and compared (Fisher's and Kruskal-Wallis exact tests) items in each organizational capacity domain for DP and HH implementers vs. non-implementers and conducted a thematic analysis of strengths and challenges. Results: Of the 33 UIHOs providing services in 2017, individuals from 30 sites (91% of UIHOs) replied to the survey. Eight UIHOs (27%) had participated in either DP (n = 6) or HH (n = 2). Implementers reported having more staff than non-implementers (117.0 vs. 53.5; p = 0.02). Implementers had larger budgets, ~$10 million of total revenue compared to $2.5 million for non-implementers (p = 0.01). UIHO strengths included: physical infrastructure, dedicated leadership and staff, and community relationships. Areas to strengthen included: staff training and retention, ensuring sufficient and consistent funding, and data infrastructure. Conclusions: Strengthening UIHOs across organizational capacity domains will be important for implementing evidence-based diabetes interventions, increasing their uptake, and sustaining these interventions for AI/AN people living in urban areas of the U.S.

Perspectives on Genetic Research: Results From a Survey of Navajo Community Members.

The Navajo Nation placed a moratorium on genetic research studies in 2002, in part due to concerns about historical distrust, exploitation, limited expertise and resources, and the lack of a genetics policy. Navajo tribal leaders, scientists, and policy experts are exploring the possibility of lifting the moratorium, developing a genetic research policy, and discussing its potential health implications. This study aimed to identify the key concerns, needs, and desires of Navajo people regarding genetic research. We conducted a survey of Navajo individuals to assess knowledge of the moratorium and research, gauge interest in genetic research, and quantify appropriate genetic research topics to understand broad views and concerns. We performed descriptive statistics and tested associations between relevant categorical variables using Chi-square tests. We hypothesized that individuals with more knowledge about the moratorium and health research increased the likelihood of supporting and participating in genetic research. A total of 690 surveys from Navajo respondents were analyzed. Of these, 63% of respondents reported being unaware of the Navajo Nation's moratorium on genetic research. There were positive associations between those who knew about the moratorium and willingness to donate biospecimens for research under certain conditions, such as community involvement, review and approval by community leaders, research on diseases affecting the community, and support for lifting the moratorium (p-values < 0.001). We found no significant differences between age, gender, religious/spiritual beliefs, or agency affiliation with knowledge levels of genetics and related topics, participation in relation to beliefs, and donation of biospecimens. Interestingly, respondents who resided off the Navajo Nation were positively associated with having knowledge of the moratorium, having heard of discussions of genetics on the Navajo Nation, and the lawsuit filed by the Havasupai Tribe. Most respondents agreed that it was very important to develop a policy that incorporates cultural knowledge (56%), is beneficial (56%), and has data sharing protections (59%) before allowing genetic research on the Navajo Nation. Overall, a large proportion of respondents (46%) were unsure about lifting the moratorium and instead wanted more genetics education to assess its potential implications. The study results can inform the direction of future guidelines and policies.

Multi-level Diabetes Prevention and Treatment Interventions for Native People in the USA and Canada: a Scoping Review.

PURPOSE OF REVIEW: This scoping literature review seeks to answer the question "What is known in the existing literature about multi-level diabetes prevention and treatment interventions for Native people living in the United States and Canada?" RECENT FINDINGS: Multi-level interventions to prevent and/or treat chronic diseases, such as diabetes, promise to help individuals who experience health disparities related to social determinants of health. As described by the socio-ecological model, such interventions mobilize support through a combination of individual, interpersonal, organizational, community, and policy levels of activity. This review revealed little literature about multi-level diabetes prevention and/or treatment programs for US and Canada-based Native peoples. Ten interventions were identified; all focused on diabetes prevention; eight were specific to youth. Multi-level intervention design elements were largely individual-, school-, and community-based. Only three interventions included environmental or policy-level components.

Designing Inclusive HPV Cancer Vaccines and Increasing Uptake among Native Americans-A Cultural Perspective Review.

Despite a global and nationwide decrease, Native Americans continue to experience high rates of cancer morbidity and mortality. Vaccination is one approach to decrease cancer incidence such as the case of cervical cancer. However, the availability of vaccines does not guarantee uptake, as evident in the Coronavirus 2019 pandemic. Therefore, as we consider current and future cancer vaccines, there are certain considerations to be mindful of to increase uptake among Native Americans such as the incidence of disease, social determinants of health, vaccine hesitancy, and historical exclusion in clinical trials. This paper primarily focuses on human papillomavirus (HPV) and potential vaccines for Native Americans. However, we also aim to inform researchers on factors that influence Native American choices surrounding vaccination and interventions including cancer therapies. We begin by providing an overview of the historical distrust and trauma Native Americans experience, both past and present. In addition, we offer guidance and considerations when engaging with sovereign Tribal Nations in vaccine development and clinical trials in order to increase trust and encourage vaccine uptake.

Generations of genomes: advances in paleogenomics technology and engagement for Indigenous people of the Americas.

For decades, scientists have collected genomic information from Indigenous peoples and their ancestors with the goal of elucidating human migration events, understanding ancestral origins, and identifying ancestral variants contributing to disease. However, such studies may not have offered much benefit to the Indigenous groups who contributed DNA, and many have instead perpetuated stereotypes and other harms. With recent advances in genomic technology facilitating the study of both ancient and present-day DNA, researchers and Indigenous communities have new opportunities to begin collaboratively addressing important questions about human health and history. Yet, while there are increased efforts to ethically engage Indigenous communities, more work is still needed as the discipline struggles to absolve itself of the racialized science and extractive biocolonialism that defined its past.

Weaving the Strands of Life (Iiná Bitl'ool): History of Genetic Research Involving Navajo People.

To date, some genetic studies offer medical benefits but lack a clear pathway to benefit for people from underrepresented backgrounds. Historically, Indigenous people, including the Diné (Navajo people), have raised concerns about the lack of benefits, misuse of DNA samples, lack of consultation, and ignoring of cultural and traditional ways of knowing. Shortly after the Navajo Nation Human Research Review Board was established in 1996, the Navajo Nation recognized growing concerns about genetic research, and in 2002 they established a moratorium on human genetic research studies. The moratorium effectively has protected their citizens from potential genetic research harms. Despite the placement of the moratorium, some genetic research studies have continued using blood and DNA samples from Navajo people. To understand the history of genetic research involving Navajo people, the authors conducted a literature review of genetic or genetics-related research publications that involved Navajo people, identifying 79 articles from the years 1926 to 2018. To their knowledge, no known literature review has comprehensively examined the history of genetic research in the Navajo community. This review divides the genetic research articles into the following general classifications: bacteria or virus genetics, blood and human leukocyte antigens, complex diseases, forensics, hereditary diseases, and population genetics and migration. The authors evaluated the methods reported in each article, described the number of Navajo individuals reported, recorded the academic and tribal approval statements, and noted whether the study considered Diné cultural values. Several studies focused on severe combined immunodeficiency disease, population history, neuropathy, albinism, and eye and skin disorders that affect Navajo people. The authors contextualize Diné ways of knowing related to genetics and health with Western scientific concepts to acknowledge the complex philosophy and belief system that guides Diné people and recognizes Indigenous science. They also encourage researchers to consider cultural perspectives and traditional knowledge that has the potential to create stronger conclusions and better-informed, ethical, and respectful science.

Filamin C Truncation Mutations Are Associated With Arrhythmogenic Dilated Cardiomyopathy and Changes in the Cell-Cell Adhesion Structures.

OBJECTIVES: The purpose of this study was to assess the phenotype of Filamin C (FLNC) truncating variants in dilated cardiomyopathy (DCM) and understand the mechanism leading to an arrhythmogenic phenotype. BACKGROUND: Mutations in FLNC are known to lead to skeletal myopathies, which may have an associated cardiac component. Recently, the clinical spectrum of FLNC mutations has been recognized to include a cardiac-restricted presentation in the absence of skeletal muscle involvement. METHODS: A population of 319 U.S. and European DCM cardiomyopathy families was evaluated using whole-exome and targeted next-generation sequencing. FLNC truncation probands were identified and evaluated by clinical examination, histology, transmission electron microscopy, and immunohistochemistry. RESULTS: A total of 13 individuals in 7 families (2.2%) were found to harbor 6 different FLNC truncation variants (2 stopgain, 1 frameshift, and 3 splicing). Of the 13 FLNC truncation carriers, 11 (85%) had either ventricular arrhythmias or sudden cardiac death, and 5 (38%) presented with evidence of right ventricular dilation. Pathology analysis of 2 explanted hearts from affected FLNC truncation carriers showed interstitial fibrosis in the right ventricle and epicardial fibrofatty infiltration in the left ventricle. Ultrastructural findings included occasional disarray of Z-discs within the sarcomere. Immunohistochemistry showed normal plakoglobin signal at cell-cell junctions, but decreased signals for desmoplakin and synapse-associated protein 97 in the myocardium and buccal mucosa. CONCLUSIONS: We found FLNC truncating variants, present in 2.2% of DCM families, to be associated with a cardiac-restricted arrhythmogenic DCM phenotype characterized by a high risk of life-threatening ventricular arrhythmias and a pathological cellular phenotype partially overlapping with arrhythmogenic right ventricular cardiomyopathy.

A framework for enhancing ethical genomic research with Indigenous communities.

Integration of genomic technology into healthcare settings establishes new capabilities to predict disease susceptibility and optimize treatment regimes. Yet, Indigenous peoples remain starkly underrepresented in genetic and clinical health research and are unlikely to benefit from such efforts. To foster collaboration with Indigenous communities, we propose six principles for ethical engagement in genomic research: understand existing regulations, foster collaboration, build cultural competency, improve research transparency, support capacity building, and disseminate research findings. Inclusion of underrepresented communities in genomic research has the potential to expand our understanding of genomic influences on health and improve clinical approaches for all populations.

FLNC Gene Splice Mutations Cause Dilated Cardiomyopathy.

OBJECTIVE: To identify novel dilated cardiomyopathy (DCM) causing genes, and to elucidate the pathological mechanism leading to DCM by utilizing zebrafish as a model organism. BACKGROUND: DCM, a major cause of heart failure, is frequently familial and caused by a genetic defect. However, only 50% of DCM cases can be attributed to a known DCM gene variant, motivating the ongoing search for novel disease genes. METHODS: We performed whole exome sequencing (WES) in two multigenerational Italian families and one US family with arrhythmogenic DCM without skeletal muscle defects, in whom prior genetic testing had been unrevealing. Pathogenic variants were sought by a combination of bioinformatic filtering and cosegregation testing among affected individuals within the families. We performed function assays and generated a zebrafish morpholino knockdown model. RESULTS: A novel filamin C gene splicing variant (FLNC c.7251+1 G>A) was identified by WES in all affected family members in the two Italian families. A separate novel splicing mutation (FLNC c.5669-1delG) was identified in the US family. Western blot analysis of cardiac heart tissue from an affected individual showed decreased FLNC protein, supporting a haploinsufficiency model of pathogenesis. To further analyze this model, a morpholino knockdown of the ortholog filamin Cb in zebrafish was created which resulted in abnormal cardiac function and ultrastructure. CONCLUSIONS: Using WES, we identified two novel FLNC splicing variants as the likely cause of DCM in three families. We provided protein expression and in vivo zebrafish data supporting haploinsufficiency as the pathogenic mechanism leading to DCM.

A Review of the Giant Protein Titin in Clinical Molecular Diagnostics of Cardiomyopathies.

Titin (TTN) is known as the largest sarcomeric protein that resides within the heart muscle. Due to alternative splicing of TTN, the heart expresses two major isoforms (N2B and N2BA) that incorporate four distinct regions termed the Z-line, I-band, A-band, and M-line. Next-generation sequencing allows a large number of genes to be sequenced simultaneously and provides the opportunity to easily analyze giant genes such as TTN. Mutations in the TTN gene can cause cardiomyopathies, in particular dilated cardiomyopathy (DCM). DCM is the most common form of cardiomyopathy, and it is characterized by systolic dysfunction and dilation of the left ventricle. TTN truncating variants have been described as the most common cause of DCM, while the real impact of TTN missense variants in the pathogenesis of DCM is still unclear. In a recent population screening study, rare missense variants potentially pathogenic based on bioinformatic filtering represented only 12.6% of the several hundred rare TTN missense variants found, suggesting that missense variants are very common in TTN and are frequently benign. The aim of this review is to understand the clinical role of TTN mutations in DCM and in other cardiomyopathies. Whereas TTN truncations are common in DCM, there is evidence that TTN truncations are rare in the hypertrophic cardiomyopathy (HCM) phenotype. Furthermore, TTN mutations can also cause arrhythmogenic right ventricular cardiomyopathy (ARVC) with distinct clinical features and outcomes. Finally, the identification of a rare TTN missense variant cosegregating with the restrictive cardiomyopathy (RCM) phenotype suggests that TTN is a novel disease-causing gene in this disease. Clinical diagnostic testing is currently able to analyze over 100 cardiomyopathy genes, including TTN; however, the size and presence of extensive genetic variation in TTN presents clinical challenges in determining significant disease-causing mutations. This review discusses the current knowledge of TTN genetic variations in cardiomyopathies and the impact of the diagnosis of TTN pathogenic mutations in the clinical setting.

Role of Titin Missense Variants in Dilated Cardiomyopathy.

BACKGROUND: The titin gene (TTN) encodes the largest human protein, which plays a central role in sarcomere organization and passive myocyte stiffness. TTN truncating mutations cause dilated cardiomyopathy (DCM); however, the role of TTN missense variants in DCM has been difficult to elucidate because of the presence of background TTN variation. METHODS AND RESULTS: A cohort of 147 DCM index subjects underwent DNA sequencing for 313 TTN exons covering the N2B and N2BA cardiac isoforms of TTN. Of the 348 missense variants, we identified 44 "severe" rare variants by using a bioinformatic filtering process in 37 probands. Of these, 5 probands were double heterozygotes (additional variant in another DCM gene) and 7 were compound heterozygotes (2 TTN "severe" variants). Segregation analysis allowed the classification of the "severe" variants into 5 "likely" (cosegregating), 5 "unlikely" (noncosegregating), and 34 "possibly" (where family structure precluded segregation analysis) disease-causing variants. Patients with DCM carrying "likely" or "possibly" pathogenic TTN "severe" variants did not show a different outcome compared with "unlikely" and noncarriers of a "severe" TTN variant. However, the "likely" and "possibly" disease-causing variants were overrepresented in the C-zone of the A-band region of the sarcomere. CONCLUSIONS: TTN missense variants are common and present a challenge for bioinformatic classification, especially when informative families are not available. Although DCM patients carrying bioinformatically "severe" TTN variants do not appear to have a worse clinical course than noncarriers, the nonrandom distribution of "likely" and "possibly" disease-causing variants suggests a potential biological role for some TTN missense variants.

Pharmacogenetics of heart failure.

PURPOSE OF REVIEW: Novel medical approaches and personalized medicine seek to use genetic information to 'individualize' and improve diagnosis, prevention, and therapy. The personalized management of cardiovascular disease involves a large spectrum of potential applications, from diagnostics of monogenic disorders, to prevention and management strategies based on modifier genes, to pharmacogenetics, in which individual genetic information is used to optimize the pharmacological treatments. RECENT FINDINGS: Evidence suggests that the common polymorphic variants of modifier genes could influence drug response in cardiovascular disease in a variety of areas, including heart failure, arrhythmias, dyslipidemia, and hypertension. In heart failure, common genetic variants of ß-adrenergic receptors, α-adrenergic receptors, and endothelin receptors (among others) have been associated with variable response to heart failure therapies. The challenge remains to develop strategies to leverage this information in ways that personalize and optimize cardiovascular therapy based on a patient's genetic profile. SUMMARY: Although advances in technologies will continue to transition personalized medicine from the research to the clinical setting, healthcare providers will need to reshape the clinical diagnostic paradigms. Ultimately, pharmacogenetics will give providers the options for improving patient management on the basis of pharmacogenetic data.

Decreased levels of BAG3 in a family with a rare variant and in idiopathic dilated cardiomyopathy.

The most common cause of dilated cardiomyopathy and heart failure (HF) is ischemic heart disease; however, in a third of all patients the cause remains undefined and patients are diagnosed as having idiopathic dilated cardiomyopathy (IDC). Recent studies suggest that many patients with IDC have a family history of HF and rare genetic variants in over 35 genes have been shown to be causative of disease. We employed whole-exome sequencing to identify the causative variant in a large family with autosomal dominant transmission of dilated cardiomyopathy. Sequencing and subsequent informatics revealed a novel 10-nucleotide deletion in the BCL2-associated athanogene 3 (BAG3) gene (Ch10:del 121436332_12143641: del. 1266_1275 [NM 004281]) that segregated with all affected individuals. The deletion predicted a shift in the reading frame with the resultant deletion of 135 amino acids from the C-terminal end of the protein. Consistent with genetic variants in genes encoding other sarcomeric proteins there was a considerable amount of genetic heterogeneity in the affected family members. Interestingly, we also found that the levels of BAG3 protein were significantly reduced in the hearts from unrelated patients with end-stage HF undergoing cardiac transplantation when compared with non-failing controls. Diminished levels of BAG3 protein may be associated with both familial and non-familial forms of dilated cardiomyopathy.