Early human migration determines the risk of being attacked by wolves: ethnic gene diversity on the development of systemic lupus erythematosus

Abstract

The prevalence of systemic lupus erythematosus (SLE) varies significantly based on ethnicity rather than geographic distribution; thus, the prevalence is higher in Asian, Hispanic, and Black African populations than in European populations. The risk of developing lupus nephritis (LN) is the highest among Asian populations. Therefore, we hypothesize that human genetic diversity between races has occurred through the early human migration and human genetic adaptation to various environments, with a particular focus on pathogens. Additionally, we compile the currently available evidence on the ethnic gene diversity of SLE and how it relates to disease severity. The human leukocyte antigen (HLA) locus is well established as associated with susceptibility to SLE; specific allele distributions have been observed across diverse populations. Notably, specific amino acid residues within these HLA loci demonstrate significant associations with SLE risk. The non-HLA genetic loci associated with SLE risk also varies across diverse ancestries, implicating distinct immunological pathways, such as the type-I interferon and janus kinase-signal transducers and activators of transcription (JAK-STAT) pathways in Asians, the type-II interferon signaling pathway in Europeans, and B cell activation pathway in Africans. Furthermore, assessing individual genetic susceptibility using genetic risk scores (GRS) for SLE helps to reveal the diverse prevalence, age of onset, and clinical phenotypes across different ethnicities. A higher GRS increases the risk of LN and the severity of SLE. Therefore, understanding ethnic gene diversity is crucial for elucidating disease mechanisms and SLE severity, which could enable the development of novel drugs specific to each race.

Keywords: Ethnicity; Genetics; Systemic lupus erythematosus.

Figure 1

Early human migration throughout the history of the Earth. The Earth was created around 4.54 billion (B) years ago. The geological timeline represents deep time based on events throughout the Earth's history. The Precambrian is the earliest part of the Earth's history. Fossils of bacteria older than 3.46 B years have been found. Bacteria may have appeared 3 B years ago, followed by viruses 1.5 B years ago, with animals potentially appearing 1 B years ago. The succeeding eon is the current Phanerozoic Eon, which is divided into three eras: the Paleozoic, the Mesozoic, and the Cenozoic, which are split into three periods; the Paleogene, in which the HERV may have appeared, the Neogene, and the Quaternary, whose first epoch is the Pleistocene, which is divided into three sub-epochs; the Gelasian, from which the fossils of homo erectus were found, with its earliest occurrence about 2 million years ago, the Calabrian, and the Chibanian in which homo Neanderthalensis appeared around 300,000 years ago, followed by Homo sapiens who migrated from Africa to Europe and Asia where the fossils of homo Denisova were found. HERV: Human endogenous retrovirus.

Figure 2

Ancestry-driven pathways for SLE-risk SNP-associated genes. The ancestry-driven key signaling pathways in Asians, Europeans, and African Americans were analyzed by enrichr (https://maayanlab.cloud/Enrichr/#libraries) using non-HLA SNP-associated genes. SLE: systemic lupus erythematosus, SNP: single-nucleotide polymorphism, JAK–STAT: janus kinase–signal transducers and activators of transcription, IFN: interferon gamma.

Figure 3

Three ways to increase variation in natural evolution. Natural selection is a central mechanism responsible for the evolution of adaptive features. Darwin tried to establish the fundamental requirement for evolutionary change, which is variation among individuals. Speciation is the generation of distinct species by splitting a single lineage into two or more genetically independent ones. Geographic specification, also called allopatric specification, is a speciation mode that occurs when populations are geographically separated, i.e., where gene flow is disrupted. Traits that alter life expectancy are only evolutionarily relevant when they affect reproductive output. Therefore, characteristics that increase reproduction may increase frequency through generations even though they shorten overall life expectancy. The relative fitness of different traits depends on the current environment. Indeed, currently, fit traits may become unfit should the environment change. Adapted from the article of Darwin C. On the origin of species by means of natural selection, or the preservation of favored races in the struggle for life. London, John Murray, 1859 [94].