Genetic research and reduction of health disparities

A unique genetic history and make-up of a population may make it an attractive research target for population geneticists and pharmaco-genomic investors. The promise of pharmaceutical profits and advances in medical knowledge attracted Harvard researchers and the company Millennium Pharmaceuticals to remote areas in Anhui Province, Central China, leading to international diplomatic disagreements about issues such as the ownership of genetic material and informed consent (IC). This article discusses the role of genomics and genetic sampling in China, the way it is related to population policies (the new eugenics), the national importance of genetic materials and the conflicts it led to between the Chinese government and Harvard University. Here many consider the Xu Xiping case as a textbook example of ruthless Western exploitation of development countries, illustrating the cold rationality of science in the process of globalisation. Ten perspectives on this case show that this view is simplistic and contributes little to an understanding of bioethical issues important to the population actually donating the samples. Viewing the Xu Xiping case as the nexus of the intertwinement of international, transnational, national, and local interest groups shows how different interest groups make use of different units of analysis. It also clarifies why the same practice of genetic sampling continues under a different regime, and why the discussion about genetic sampling has shifted from a concern with health care of the poor to an issue of international exploitation, terrorism and development.     

Leveraging genetic ancestry to study health disparities

Research to understand human genomic variation and its implications in health has great potential to contribute in the reduction of health disparities. Biological anthropology can play important roles in genomics and health disparities research using a biocultural approach. This paper argues that racial/ethnic categories should not be used as a surrogate for sociocultural factors or global genomic clusters in biomedical research or clinical settings, because of the high genetic heterogeneity that exists within traditional racial/ethnic groups. Genetic ancestry is used to show variation in ancestral genomic contributions to recently admixed populations in the United States, such as African Americans and Hispanic/Latino Americans. Genetic ancestry estimates are also used to examine the relationship between ancestry-related biological and sociocultural factors affecting health disparities. To localize areas of genomes that contribute to health disparities, admixture mapping and genome-wide association studies (GWAS) are often used. Recent GWAS have identified many genetic variants that are highly differentiated among human populations that are associated with disease risk. Some of these are population-specific variants. Many of these variants may impact disease risk and help explain a portion of the difference in disease burden among racial/ethnic groups. Genetic ancestry is also of particular interest in precision medicine and disparities in drug efficacy and outcomes. By using genetic ancestry, we can learn about potential biological differences that may contribute to the heterogeneity observed across self-reported racial groups.     

HIV research in Australia: linking basic research findings with clinical and public health outcomes

H9-T-cells do not support the replication of mutant HIV-1 encoding Env protein lacking its long cytoplasmic C-terminal domain (Env-CT). Here we describe the generation of a H9-T-cell population constitutively expressing the HIV-1 Env-CT protein domain anchored in the cellular membrane by it homologous membrane-spanning domain (TMD). We confirmed that the Env-TMD-CT protein was associated with cellular membranes, that its expression did not have any obvious cytotoxic effects on the cells and that it did not affect wild-type HIV-1 replication. However, as measured in both a single-round assay as well as in spreading infections, replication competence of mutant pNL-Tr712, lacking the Env-CT, was not restored in this H9 T-cell population. This means that the Env-CT per se cannot transcomplement the replication block of HIV-1 virions encoding C-terminally truncated Env proteins and suggests that the Env-CT likely exerts its function only in the context of the complete Env protein.     

Mendelian randomization in health research: Using appropriate genetic variants and avoiding biased estimates

Mendelian randomization methods, which use genetic variants as instrumental variables for exposures of interest to overcome problems of confounding and reverse causality, are becoming widespread for assessing causal relationships in epidemiological studies. The main purpose of this paper is to demonstrate how results can be biased if researchers select genetic variants on the basis of their association with the exposure in their own dataset, as often happens in candidate gene analyses. This can lead to estimates that indicate apparent “causal” relationships, despite there being no true effect of the exposure. In addition, we discuss the potential bias in estimates of magnitudes of effect from Mendelian randomization analyses when the measured exposure is a poor proxy for the true underlying exposure. We illustrate these points with specific reference to tobacco research.     

Anthropological insights into the use of race/ethnicity to explore genetic contributions to disparities in health

Anthropological insights into the use of race/ethnicity to explore genetic contributions to disparities in health were developed using in-depth qualitative interviews with editorial staff from nineteen genetics journals, focusing on the methodological and conceptual mechanisms required to make race/ethnicity a genetic variable. As such, these analyses explore how and why race/ethnicity comes to be used in the context of genetic research, set against the background of continuing critiques from anthropology and related human sciences that focus on the social construction, structural correlates and limited genetic validity of racial/ethnic categories. The analyses demonstrate how these critiques have failed to engage geneticists, and how geneticists use a range of essentially cultural devices to protect and separate their use of race/ethnicity as a genetic construct from its use as a societal and social science resource. Given its multidisciplinary, biosocial nature and the cultural gaze of its ethnographic methodologies, anthropology is well placed to explore the cultural separation of science and society, and of natural and social science disciplines. Anthropological insights into the use of race/ethnicity to explore disparities in health suggest that moving beyond genetic explanations of innate difference might benefit from a more even-handed critique of how both the natural and social sciences tend to essentialize selective elements of race/ethnicity. Drawing on the example of HIV/AIDS, this paper demonstrates how public health has been undermined by the use of race/ethnicity as an analytical variable, both as a cipher for innate genetic differences in susceptibility and response to treatment, and in its use to identify 'core groups' at greater risk of becoming infected and infecting others. Clearly, a tendency for biological reductionism can place many biomedical issues beyond the scope of public health interventions, while socio-cultural essentialization has tended to stigmatize 'unhealthy behaviours' and the communities where these are more prevalent.     

The mitochondrion in cell death control: certainties and incognita

Apoptosis research has recently experienced a change from a paradigm in which the nucleus determined the apoptotic process to a paradigm in which caspases and, more recently, mitochondria constitute the center of death control. Mitochondria undergo major changes in membrane integrity before classical signs of cell death become manifest. These changes concern both the inner and the outer mitochondrial membranes, leading to the dissipation of the inner transmembrane potential (DeltaPsi(m)) and/or the release of intermembrane proteins through the outer membrane. An ever-increasing number of endogenous, viral, or xenogeneic effectors directly act on mitochondria to trigger permeabilization. At least in some cases, this is achieved by a direct action on the permeability transition pore complex (PTPC), a multiprotein ensemble containing proteins from both mitochondrial membranes, which interact with pro- and antiapoptotic members of the Bcl-2 family. At present, it is elusive whether opening of the PTPC is the only physiological mechanism leading to mitochondrial membrane permeabilization. Proteins released from mitochondria during apoptosis include caspases (mainly caspases 2, 3, and 9), caspase activators (cytochrome c, hsp 10), as well as a caspase-independent death effector, AIF (apoptosis inducing factor). The functional hierarchy among these proteins and their actual impact on the decision between death and life is elusive.     

Prader-Willi syndrome: genetic tests and clinical findings

Here we describe the genetic studies performed in 53 patients with the suspected diagnosis of Prader-Willi syndrome (PWS). PWS is characterized by neonatal hypotonia, hypogonadism, delayed psychomotor development, hyperphagia, obesity, short stature, small hands and feet, learning disabilities, and obsessive-compulsive behavior. Through the methylation analysis of the SNRPN gene, microsatellite studies of loci mapped within and outside the PWS/AS region, and fluorescence in situ hybridization (FISH) study, we confirmed the diagnosis in 35 patients: 27 with a paternal deletion, and 8 with maternal uniparental disomy (UPD). The clinical comparisons between deleted and UPD patients indicated that there were no major phenotype differences, except for a lower birth length observed in the UPD children. Our sample was composed of more girls than boys; UPD patients were diagnosed earlier than the deleted cohort (2(10/12) s. 7(9/12) years); and, in the deleted group, the boys were diagnosed earlier than the girls (5(2/12) vs. 7(8/12) years, respectively).     

Inter‐ and intrasexual genetic correlations of exaggerated traits and locomotor activity

Exaggerated traits in males can be costly and therefore can negatively affect fitness. Although these costs are thought to be male specific, traits that have a negative effect due to exaggeration are often shared between the sexes as life‐history traits. When there are genetic intersexual correlations for these shared characters, the evolution of the exaggerated traits can impose these costs on nonadorned females through the intersexual correlation. Thus, the exaggerated traits can constrain optimum development of female characters, even if the females lack these exaggerations completely. However, investigation of this pattern has been largely ignored, and thus, it is necessary to investigate genetic architectures of these traits within and across the sexes. Male flour beetles, Gnatocerus cornutus, have enlarged mandibles that are used in male–male competition, but females lack this character completely. Using a traditional full‐sib/half‐sib breeding design, we detected a negative intrasexual genetic correlation between male weapon size and locomotor activity, but not an intersexual genetic correlation for locomotor activity. After subjecting this weapon to 17 generations of bidirectional selection, we found a correlated response to locomotor activity in the male, whereas there was no correlated response in the female. Our results suggest that the costs of exaggerated traits to locomotion are not imposed on females and would be male specific. This is partly explained by genetic decoupling of locomotor activities across the sexes.     

Meta-analysis: synthesizing research findings in ecology and evolution

The growing number of empirical studies performed in ecology and evolution creates a need for quantitative summaries of research domains to generate higher-order conclusions about general trends and patterns. Recent developments In meta-analysis (the area of statistics that is designed for summarizing and analyzing multiple independent studies) have opened up new and exciting possibilities. Unlike more traditional qualitative and narrative reviews, meta-analysis allows powerful quantitative analyses of the magnitude of effects and has a high degree of objectivity because it is based on a standardized set of statistical procedures. The first pioneering applications in ecology and evolution demonstrate that meta-analysis is both tractable and powerful.