Community partnerships are fundamental to ethical ancient DNA research.

The ethics of the scientific study of Ancestors has long been debated by archaeologists, bioanthropologists, and, more recently, ancient DNA (aDNA) researchers. This article responds to the article "Ethics of DNA research on human remains: five globally applicable guidelines" published in 2021 in Nature by a large group of aDNA researchers and collaborators. We argue that these guidelines do not sufficiently consider the interests of community stakeholders, including descendant communities and communities with potential, but yet unestablished, ties to Ancestors. We focus on three main areas of concern with the guidelines. First is the false separation of "scientific" and "community" concerns and the consistent privileging of researcher perspectives over those of community members. Second, the commitment of the guidelines' authors to open data ignores the principles and practice of Indigenous Data Sovereignty. Further, the authors argue that involving community members in decisions about publication and data sharing is unethical. We argue that excluding community perspectives on "ethical" grounds is convenient for researchers, but it is not, in fact, ethical. Third, we stress the risks of not consulting communities that have established or potential ties to Ancestors, using two recent examples from the literature. Ancient DNA researchers cannot focus on the lowest common denominator of research practice, the bare minimum that is legally necessary. Instead, they should be leading multidisciplinary efforts to create processes to ensure communities from all regions of the globe are identified and engaged in research that affects them. This will often present challenges, but we see these challenges as part of the research, rather than a distraction from the scientific endeavor. If a research team does not have the capacity to meaningfully engage communities, questions must be asked about the value and benefit of their research.

Values and Practices to Strengthen Genetic Research Partnerships with Indigenous Communities.

Genetic datasets lack diversity and include very few data from Indigenous populations. Research models based on equitable partnership have the potential to increase Indigenous participation and have led to successful collaborations. We report here on a meeting of participants in four Indigenous community-university partnerships pursuing research on precision medicine. The goal of the meeting was to define values and practices that strengthen opportunities for genetic research. The group accorded the highest priority to developing trusting relationships, ensuring respect for Indigenous community authority, and pursuing research that has the potential to lead to community benefit. Supporting priorities included incorporation of Indigenous expertise in research planning, transparent communication, and development of community capacity, including capacity to participate in formulating research questions, informing research methodology, and leading research projects. Participants also noted the importance of attention to social determinants of health so that genetic contributors to health are evaluated in the appropriate context.

Recent shifts in the genomic ancestry of Mexican Americans may alter the genetic architecture of biomedical traits.

People in the Americas represent a diverse continuum of populations with varying degrees of admixture among African, European, and Amerindigenous ancestries. In the United States, populations with non-European ancestry remain understudied, and thus little is known about the genetic architecture of phenotypic variation in these populations. Using genotype data from the Hispanic Community Health Study/Study of Latinos, we find that Amerindigenous ancestry increased by an average of ~20% spanning 1940s-1990s in Mexican Americans. These patterns result from complex interactions between several population and cultural factors which shaped patterns of genetic variation and influenced the genetic architecture of complex traits in Mexican Americans. We show for height how polygenic risk scores based on summary statistics from a European-based genome-wide association study perform poorly in Mexican Americans. Our findings reveal temporal changes in population structure within Hispanics/Latinos that may influence biomedical traits, demonstrating a need to improve our understanding of admixed populations.

Fostering Ethical, Legal, and Social Implications Research in Tribal Communities: The Center for the Ethics of Indigenous Genomic Research.

Genomic research raises unique ethical concerns among Alaska Native and American Indian (AN/AI) people and their communities. The Center for the Ethics of Indigenous Genomic Research (CEIGR) was created to foster research that takes these concerns into account while considering the sovereign status of AN/AI tribal nations. Relationships developed within CEIGR have allowed for effective, collaborative research among individuals who come from diverse cultures, political and historical backgrounds, and academic disciplines, and who work for organizations with varying resources, capacities, and expectations. The CEIGR framework may inform other groups seeking to conduct social science research related to genomic research with tribal people and their communities.

Genetic analysis of hsCRP in American Indians: The Strong Heart Family Study.

BACKGROUND: Increased serum levels of C-reactive protein (CRP), an important component of the innate immune response, are associated with increased risk of cardiovascular disease (CVD). Multiple single nucleotide polymorphisms (SNP) have been identified which are associated with CRP levels, and Mendelian randomization studies have shown a positive association between SNPs increasing CRP expression and risk of colon cancer (but thus far not CVD). The effects of individual genetic variants often interact with the genetic background of a population and hence we sought to resolve the genetic determinants of serum CRP in a number of American Indian populations. METHODS: The Strong Heart Family Study (SHFS) has serum CRP measurements from 2428 tribal members, recruited as large families from three regions of the United States. Microsatellite markers and MetaboChip defined SNP genotypes were incorporated into variance components, decomposition-based linkage and association analyses. RESULTS: CRP levels exhibited significant heritability (h2 = 0.33 ± 0.05, p<1.3 X 10-20). A locus on chromosome (chr) 6, near marker D6S281 (approximately at 169.6 Mb, GRCh38/hg38) showed suggestive linkage (LOD = 1.9) to CRP levels. No individual SNPs were found associated with CRP levels after Bonferroni adjustment for multiple testing (threshold <7.77 x 10-7), however, we found nominal associations, many of which replicate previous findings at the CRP, HNF1A and 7 other loci. In addition, we report association of 46 SNPs located at 7 novel loci on chromosomes 2, 5, 6(2 loci), 9, 10 and 17, with an average of 15.3 Kb between SNPs and all with p-values less than 7.2 X 10-4. CONCLUSION: In agreement with evidence from other populations, these data show CRP serum levels are under considerable genetic influence; and include loci, such as near CRP and other genes, that replicate results from other ethnic groups. These findings also suggest possible novel loci on chr 6 and other chromosomes that warrant further investigation.

Different Risk for Hypertension, Diabetes, Dyslipidemia, and Hyperuricemia According to Level of Body Mass Index in Japanese and American Subjects.

Obesity is a risk factor for hypertension, diabetes mellitus (DM), dyslipidemia, and hyperuricemia. Here, we evaluated whether the same body mass index (BMI) for the U.S. population conferred similar metabolic risk in Japan. This was a cross-sectional analysis involving 90,047 Japanese adults (18⁻85 years) from St. Luke's International Hospital, Tokyo, Japan and 14,734 adults from National Health and Nutrition Examination Survey (NHANES) collected in the U.S. We compared the prevalence of hypertension, DM, dyslipidemia, and hyperuricemia according to BMI in Japan and the U.S. The prevalence of hypertension, DM, and dyslipidemia were significantly higher in the U.S. than Japan, whereas the prevalence of hyperuricemia did not differ between countries. Higher BMI was an independent risk factor for hypertension, DM, dyslipidemia, and hyperuricemia both in Japan and in the U.S. after adjusting for age, sex, smoking and drinking habits, chronic kidney disease, and other cardiovascular risk factors. The BMI cut-off above which the prevalence of these cardio-metabolic risk factors increased was significantly higher in the U.S. than in Japan (27 vs. 23 kg/m² for hypertension, 29 vs. 23 kg/m² for DM, 26 vs. 22 kg/m² for dyslipidemia, and 27 vs. 23 kg/m² for hyperuricemia). Higher BMI is associated with an increased prevalence of hypertension, DM, dyslipidemia, and hyperuricemia both in Japan and U.S. The BMI cut-off above which the prevalence of cardio-metabolic risk factors increases is significantly lower in Japan than the U.S., suggesting that the same definition of overweight/obesity may not be similarly applicable in both countries.

Genetic variants and risk of asthma in an American Indian population.

BACKGROUND: Asthma is recognized as a complex, multifactorial disease with a genetic component that is well recognized. Certain genetic variants are associated with asthma in a number of populations. OBJECTIVE: To determine whether the same variants increase the risk of asthma among American Indian children. METHODS: The electronic medical records of an Indian Health Service facility identified all children between 6 and 17 years of age with case-defining criteria for asthma (n = 108). Control children (n = 216), matched for age, were also identified. Real-time polymerase chain reaction assays were used to genotype 10 single-nucleotide polymorphisms (SNPs) at 6 genetic loci. Genotypic distributions among cases and controls were evaluated by χ2 and logistic regression methods. RESULTS: A variant at 5q22.1 revealed a statistically significant imbalance in the distribution of genotypes between case-control pairs (rs10056340, P < .001). In logistic regression analyses, the same variant at 5q22.1 and a variant at 17q21 were associated with asthma at P < .05 (rs10056340 and rs9303277). Inclusions of age, body mass index, and atopy in multivariate models revealed significant associations between rs10056340 (odds ratio, 2.020; 95% confidence interval, 1.283-3.180; P = .002) and all 5 17q21 SNPs and asthma in this population. In analyses restricted to atopic individuals, the association of rs10056340 was essentially unchanged, whereas among nonatopic individuals the trend was in the same direction but nonsignificant. The reverse was true for the 17q21 SNPs. CONCLUSION: These findings demonstrate that many variants commonly associated with asthma in other populations also accompany this condition among American Indian children. American Indian children also appear to have an increased risk of asthma associated with obesity.

Chaco Canyon Dig Unearths Ethical Concerns.

The field of paleogenomics (the study of ancient genomes) is rapidly advancing, with more robust methods of isolating ancient DNA and increasing access to next-generation DNA sequencing technology. As these studies progress, many important ethical issues have emerged that should be considered when ancient Native American remains, whom we refer to as ancestors, are used in research. We highlight a 2017 article by Kennett et al., "Archaeogenomic evidence reveals prehistoric matrilineal dynasty," that brings to light several ethical issues that should be addressed in paleogenomics research. The study helps elucidate the matrilineal relationships in ancient Chacoan society through ancient DNA analysis. However, we, as Indigenous researchers and allies, raise ethical concerns with the study's scientific conclusions that can be problematic for Native American communities: (1) the lack of tribal consultation, (2) the use of culturally insensitive descriptions, and (3) the potential impact on marginalized groups. Further, we explore the limitations of the Native American Graves Protection and Repatriation Act, which addresses repatriation but not research, because clear ethical guidelines have not been established for research involving Native American ancestors, especially those deemed "culturally unaffiliated." Multiple studies of "culturally unaffiliated" remains have been initiated recently, so it is imperative that researchers consider the ethical ramifications of paleogenomics research. Past research indiscretions have created a history of mistrust and exploitation in many Native American communities. To promote ethical engagement of Native American communities in research, we therefore suggest careful attention to ethical considerations, strong tribal consultation requirements, and greater collaborations among museums, federal agencies, researchers, scientific journals, and granting agencies.

Humoral immune factors and asthma among American Indian children: a case-control study.

BACKGROUND: Asthma is recognized as intimately related to immunologic factors and inflammation, although there are likely multiple phenotypes and pathophysiologic pathways. Biomarkers of inflammation may shed light on causal factors and have potential clinical utility. Individual and population genetic factors are correlated with risk for asthma and improved understanding of these contributions could improve treatment and prevention of this serious condition. METHODS: A population-based sample of 108 children with clinically defined asthma and 216 control children were recruited from a small community in the northern plains of the United States. A complete blood count, high sensitivity C-reactive protein, total IgE and specific antibodies to 5 common airborne antigens (CAA), in addition to basic demographic and anthropomorphic data were obtained. Logistic regression was primarily used to determine the association between these humoral factors and risk of asthma. RESULTS: The body mass index (BMI) of those with asthma and their total leukocyte counts, percentage of eosinophils, and levels of total IgE were all greater than corresponding control values in univariate analysis. The presence of detectable, specific IgE antibodies to five common airborne antigens was more likely among cases compared with controls. In multivariate analysis, total IgE was independently associated with asthma; but not after inclusion of a cumulative measure of specific IgE sensitization. CONCLUSION: Many previously reported associations between anthropomorphic and immune factors and increased risk of asthma appear to be also present in this American Indian population. In this community, asthma is strongly associated with sensitization to CAA.

Diabetes and Kidney Disease in American Indians: Potential Role of Sugar-Sweetened Beverages.

Since the early 20th century, a marked increase in obesity, diabetes, and chronic kidney disease has occurred in the American Indian population, especially the Pima Indians of the Southwest. Here, we review the current epidemic and attempt to identify remediable causes. A search was performed using PubMed and the search terms American Indian and obesity, American Indian and diabetes, American Indian and chronic kidney disease, and American Indian and sugar or fructose, Native American, Alaska Native, First Nations, Aboriginal, Amerind, and Amerindian for American Indian for articles linking American Indians with diabetes, obesity, chronic kidney disease, and sugar; additional references were identified in these publications traced to 1900 and articles were reviewed if they were directly discussing these topics. Multiple factors are involved in the increased risk for diabetes and kidney disease in the American Indian population, including poverty, overnutrition, poor health care, high intake of sugar, and genetic mechanisms. Genetic factors may be especially important in the Pima, as historical records suggest that this group was predisposed to obesity before exposure to Western culture and diet. Exposure to sugar-sweetened beverages may also be involved in the increased risk for chronic kidney disease. In these small populations in severe health crisis, we recommend further studies to investigate the role of excess added sugar, especially sugar-sweetened beverages, as a potentially remediable risk factor.

Hispanic Americans living in the United States and their risk for obesity, diabetes and kidney disease: Genetic and environmental considerations.

The Hispanic American, the largest minority population in the United States, is at increased risk for obesity, diabetes and end-stage renal disease. Here we review genetic and environmental factors that might account for their increased risk for these conditions. Whereas many environmental and genetic factors have important roles in driving the increased risk for obesity and kidney disease in this population, a case is made that excessive intake of sugary beverages is a contributory cause. Studies focusing on decreasing intake of sugary beverages among the Hispanic American could potentially reduce renal and cardiovascular complications in this population.

New insights on the risk for cardiovascular disease in African Americans: the role of added sugars.

African Americans are at increased risk for cardiovascular and metabolic diseases, including obesity, high BP, diabetes, CKD, myocardial infarction, and stroke. Here we summarize the current risks and provide an overview of the underlying risk factors that may account for these associations. By reviewing the relationship between cardiovascular and renal diseases and the African-American population during the early 20th century, the historic and recent associations of African heritage with cardiovascular disease, and modern population genetics, it is possible to assemble strong hypotheses for the primary underlying mechanisms driving the increased frequency of disease in African Americans. Our studies suggest that underlying genetic mechanisms may be responsible for the increased frequency of high BP and kidney disease in African Americans, with particular emphasis on the role of APOL1 polymorphisms in causing kidney disease. In contrast, the Western diet, particularly the relatively high intake of fructose-containing sugars and sweetened beverages, appears to be the dominant force driving the increased risk of diabetes, obesity, and downstream complications. Given that intake of added sugars is a remediable risk factor, we recommend clinical trials to examine the reduction of sweetened beverages as a primary means for reducing cardiovascular risk in African Americans.