HbVar (http://globin.bx.psu.edu/hbvar) is one of the oldest and most appreciated locus-specific databases launched in 2001 by a multi-center academic effort to provide timely information on the genomic alterations leading to hemoglobin variants and all types of thalassemia and hemoglobinopathies. Database records include extensive phenotypic descriptions, biochemical and hematological effects, associated pathology and ethnic occurrence, accompanied by mutation frequencies and references. Here, we report updates to >600 HbVar entries, inclusion of population-specific data for 28 populations and 27 ethnic groups for α-, and β-thalassemias and additional querying options in the HbVar query page. HbVar content was also inter-connected with two other established genetic databases, namely FINDbase (http://www.findbase.org) and Leiden Open-Access Variation database (http://www.lovd.nl), which allows comparative data querying and analysis. HbVar data content has contributed to the realization of two collaborative projects to identify genomic variants that lie on different globin paralogs. Most importantly, HbVar data content has contributed to demonstrate the microattribution concept in practice. These updates significantly enriched the database content and querying potential, enhanced the database profile and data quality and broadened the inter-relation of HbVar with other databases, which should increase the already high impact of this resource to the globin and genetic database community.

Sjaak Philipsen and colleagues report that haploinsufficiency for KLF1 causes hereditary persistence of fetal hemoglobin in a large Maltese family. They further show that KLF1 is a key activator of BCL11A, which suppresses the expression of fetal hemoglobin. Hereditary persistence of fetal hemoglobin (HPFH) is characterized by persistent high levels of fetal hemoglobin (HbF) in adults. Several contributory factors, both genetic and environmental, have been identified1 but others remain elusive. HPFH was found in 10 of 27 members from a Maltese family. We used a genome-wide SNP scan followed by linkage analysis to identify a candidate region on chromosome 19p13.12–13. Sequencing revealed a nonsense mutation in the KLF1 gene, p.K288X, which ablated the DNA-binding domain of this key erythroid transcriptional regulator2. Only family members with HPFH were heterozygous carriers of this mutation. Expression profiling on primary erythroid progenitors showed that KLF1 target genes were downregulated in samples from individuals with HPFH. Functional assays suggested that, in addition to its established role in regulating adult globin expression, KLF1 is a key activator of the BCL11A gene, which encodes a suppressor of HbF expression3. These observations provide a rationale for the effects of KLF1 haploinsufficiency on HbF levels.

Background: The emergence of the novel coronavirus in Wuhan, Hubei Province, China, in December 2019 marked the synchronization of the world to a peculiar clock that is counting infected cases and deaths instead of hours and minutes. The pandemic, highly transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has indeed caused considerable morbidity and mortality and drastically changed our everyday lives. As we continue to become acquainted with the seventh coronavirus known to infect our species, a number of its characteristics keep surprising us. Among those is the wide spectrum of clinical manifestations of the resulting coronavirus disease 2019 (COVID-19), which ranges from asymptomatic or mildly symptomatic infections to severe pneumonia, respiratory failure, and death. Main body: Data, now from patient populations, are beginning to accumulate on human genetic factors that may contribute to the observed diversified disease severity. Therefore, we deemed it prudent to review the associations between specific human genetic variants and clinical disease severity or susceptibility to infection that have been reported in the literature to date (at the time of writing this article in early August 2020 with updates in mid-September). With this work, we hope (i) to assist the fast-paced biomedical research efforts to combat the virus by critically summarizing current knowledge on the potential role of host genetics, and (ii) to help guide current genetics and genomics research towards candidate gene variants that warrant further investigation in larger studies. We found that determinants of differing severity of COVID-19 predominantly include components of the immune response to the virus, while determinants of differing susceptibility to SARS-CoV-2 mostly entail genes related to the initial stages of infection (i.e., binding of the cell surface receptor and entry). Conclusion: Elucidating the genetic determinants of COVID-19 severity and susceptibility to SARS-CoV-2 infection would allow for the stratification of individuals according to risk so that those at high risk would be prioritized for immunization, for example, if or when safe and effective vaccines are developed. Our enhanced understanding of the underlying biological mechanisms could also guide personalized therapeutics. Such knowledge is already beginning to provide clues that help explain, at least in part, current epidemiologic observations regarding the typically more severe or benign disease course in older males and children, respectively.

Until recently our approach to analyzing human genetic diseases has been to accurately phenotype patients and sequence the genes known to be associated with those phenotypes; for example, in thalassemia, the globin loci are analyzed. Sequencing has become increasingly accessible, and thus a larger panel of genes can be analyzed and whole exome and/or whole genome sequencing can be used when no variants are found in the candidate genes. By using such approaches in patients with unexplained anemias, we have discovered that a broad range of hitherto unrelated human red cell disorders are caused by variants in KLF1, a master regulator of erythropoiesis, which were previously considered to be extremely rare causes of human genetic disease.

George Patrinos and colleagues report the first implementation of the microattribution approach to systematically document genetic variation associated with a disease, applied here to hemoglobinopathies and thalassemias. They developed a series of connected locus-specific databases that document genotype and phenotype information for genetic variation in 37 globin and erythroid protein genes in individuals with globin disorders, with reciprocal attribution to data contributors. We developed a series of interrelated locus-specific databases to store all published and unpublished genetic variation related to hemoglobinopathies and thalassemia and implemented microattribution to encourage submission of unpublished observations of genetic variation to these public repositories. A total of 1,941 unique genetic variants in 37 genes, encoding globins and other erythroid proteins, are currently documented in these databases, with reciprocal attribution of microcitations to data contributors. Our project provides the first example of implementing microattribution to incentivise submission of all known genetic variation in a defined system. It has demonstrably increased the reporting of human variants, leading to a comprehensive online resource for systematically describing human genetic variation in the globin genes and other genes contributing to hemoglobinopathies and thalassemias. The principles established here will serve as a model for other systems and for the analysis of other common and/or complex human genetic diseases.

The unique physiological and genetic characteristics of individuals influence their reactions to different dietary constituents and nutrients. This notion is the foundation of personalized nutrition. The field of nutrigenetics has witnessed significant progress in understanding the impact of genetic variants on macronutrient and micronutrient levels and the individual's responsiveness to dietary intake. These variants hold significant value in facilitating the development of personalized nutritional interventions, thereby enabling the effective translation from conventional dietary guidelines to genome-guided nutrition. Nevertheless, certain obstacles could impede the extensive implementation of individualized nutrition, which is still in its infancy, such as the polygenic nature of nutrition-related pathologies. Consequently, many disorders are susceptible to the collective influence of multiple genes and environmental interplay, wherein each gene exerts a moderate to modest effect. Furthermore, it is widely accepted that diseases emerge because of the intricate interplay between genetic predisposition and external environmental influences. In the context of this specific paradigm, the utilization of advanced "omic" technologies, including epigenomics, transcriptomics, proteomics, metabolomics, and microbiome analysis, in conjunction with comprehensive phenotyping, has the potential to unveil hitherto undisclosed hereditary elements and interactions between genes and the environment. This review aims to provide up-to-date information regarding the fundamentals of personalized nutrition, specifically emphasizing the complex triangulation interplay among microbiota, dietary metabolites, and genes. Furthermore, it highlights the intestinal microbiota's unique makeup, its influence on nutrigenomics, and the tailoring of dietary suggestions. Finally, this article provides an overview of genotyping versus microbiomics, focusing on investigating the potential applications of this knowledge in the context of tailored dietary plans that aim to improve human well-being and overall health.