Ethnic Inequality in Covid-19 Severity: Can We Blame the Neanderthal (Or Other) Genes?

Shin

Studies find if there are ethnic-specific genetic risk factors in Covid-19, but the answer is not as straightforward.

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Nadine D.

The BAME (Black, Asian, and Minority Ethnic) groups are at higher risks of Covid-19 infection, hospitalization, admission to intensive care unit (ICU), and death than White ethnicity, as a systematic review of 162 studies concluded. And such effects are more pronounced for the Black, even in young Covid-19 patients. While socioeconomic inequities are acknowledged as the driving force in the ethnic disparities in Covid-19 outcomes, genetic factors have not been entirely ruled out.

Ethnic-specific gene segment

First, a genomics study published in June in The New England Journal of Medicine (NEJM), “Genomewide Association Study of Severe Covid-19 with Respiratory Failure,” found that a set of six genes on chromosome 3— a gene segment— associates with a 60–70% increased odds of hospitalization and ventilation needs in a sample of 1,610 Covid-19 patients and 1,075 healthy controls. (Chromosomes carry genes.)

And in a more recent study published in Nature, “The major genetic risk factor for severe COVID-19 is inherited from Neanderthals,” researchers used a genome dataset that has been built up from the prior NEJM study —now totaling 3,199 Covid-19 patients and 897,488 population controls — to understand the origin of the chromosomal 3 gene segment.

Surprisingly, this gene segment is inherited from the Neanderthals (now extinct) about 60,000 years ago, the study discovered. It is now present in about 50% of South Asians and 16% of Europeans. It is especially widespread in Bangladesh, where 63% of people have it, and nearly absent in Africans. Indeed, people in the UK of Bangladeshi descent face two-times higher risk of death from Covid-19 than the general population.

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Geographic distribution of the Neanderthal gene segment (prevalence as indicated by pie charts) conferring risk for severe COVID-19.Source: Zeberg and Pääbo (2020). Nature.

But it remains a riddle why the Neanderthalian chromosomal 3 gene segment is a risk factor for greater Covid-19 severity. “It is currently not known what feature in the Neanderthal-derived region confers risk for severe Covid-19 and if the effects of any such feature are specific to SARS-CoV-2, to other coronaviruses or to other pathogens,” the Nature study concluded. “However, with respect to the current pandemic, it is clear that gene flow from Neanderthals has tragic consequences.”

Why then is this gene segment maintained to this day? “The genes in this region may well have protected the Neanderthals against some other infectious diseases that are not around today,” explained Dr. Svante Pääbo, senior co-author of the study and director of the Max Planck Institute of Evolutionary Anthropology.

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Ethnic-specific gene variants

A study titled “A survey of genetic variants in SARS-CoV-2 interacting domains of ACE2, TMPRSS2, and TLR3/7/8 across populations” published in the Infection, Genetics, and Evolution journal. Researchers at Harvard Medical School examined the prevalence of ACE2, TMPRSS2, CTSB/L, TLR3, TLR7, and TLR8 genetic variants in various ethnic populations.

(A gene can have multiple variants depending on its mutation rates. A gene segment, in contrast, is a set of multiple genes side-by-side.)

SARS-CoV-2 first binds to the ACE2 (angiotensin-converting enzyme 2) receptor on the cell surface. Its spike protein is then cleaved by two cellular enzymes — TMPRSS2 (transmembrane serine protease 2) and CTSB/L (cysteine proteases cathepsin B, L)— to complete cell infection.

Once the cell is infected, its toll-like receptors (TLR) detect parts of the invader — such as viral RNA — and then mount an immune response against it. Importantly, inherent genetic defects in TLR3 and TLR7 have been recognized as risk factors for more severe Covid-19 in young patients.

While the study did find gene variants for ACE2, CTSB/L, TLR7, TLR3, TLR7, and TLR8 — but none for TMPRSS2 — their global prevalence is only at <1% or <0.1%, which undermines their real-life importance. Further, only a few of these extraordinary genetic variants are ethnic-specific.

“We did not find genetic variation between populations while there is a significant difference in incidence and mortality between race and ethnic groups…,” the authors concluded. Thus, the ethnic disparities in Covid-19 health toll cannot be explained by gene variations related to SARS-CoV-2, but to other more mattering factors like socioeconomic status, as reflected by air pollution, living conditions, crowding, or access to healthcare.

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Short abstract and considerations

Recent data offer insights into the crucial question of whether genetics contribute to the ethnic inequalities in Covid-19. A gene segment in chromosome 3 that South Asians — particularly the Bangladeshi — inherited from Neanderthals is a risk factor for Covid-19 hospitalization and ventilation needs. Other studies looking into gene variants rather than segments, however, did not find any substantial ethnic-specific variations.

While we can rule out gene variants, the Neanderthalian gene segment qualifies as an ethnic-specific genetic risk factor for Covid-19. At the same time, this gene segment has just been identified in the NEJM and Nature papers by a genomic technique called genome-wide association studies (GWAS). But how reliable is GWAS?

The logic of GWAS is that provided sufficiently large samples of genes and human demographics are analyzed and mapped, hidden links between genes and diseases can be discovered. But the question of whys and hows is a gene related to a disease can only be answered with functional studies using cell, organoid, or animal models. Genetic risks in obesity, diabetes, and heart and autoimmune diseases, for example, have all been identified with GWAS and subsequent functional experiments.

And the latter has not been done with the Neanderthalain gene segment, although “this is something that we and others are now investigating as quickly as possible,” authors of the Nature study said in a news release.

Another point is that the NEJM and Nature GWAS studies only controlled for age and sex, which may not be enough since socioeconomic inequalities are the chief risk, or even causal, factor for ethnic disparities in Covid-19 infection, hospitalization, and death. Genes are regulated; obesity genetic risk factors, for instance, can be nullified with lifestyle changes. The same may apply to the Neaderthalian gene segment with socioeconomic or other health factors.

Also, recall that this segment leads to a 60–70% increased odds of Covid-19 hospitalization and ventilation needs, which is nowhere near, for example, the 40-times (40 x 100 = 4000%) increased odds of smoking in lung cancer in the U.S. When the risks are that high, then we can say it is causal.

Can we blame the genes? The answer exists on a spectrum: at this point, this Neanderthalian gene segment may contribute as a risk factor in the Covid-19 health disparities in certain ethnic groups, but definitely not a causal factor.

“We must avoid simplifying the causes and impact of Covid-19, as ultimately a person’s response to the disease is about contact and then the body’s immunity response,” Mark Maslin, a professor of Climatology at University College London, said in response to the study in Nature, “which is influenced by many environmental, health and genetic factors.”

This article was previously published in Microbial Instincts with minor changes.

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