Genetic factors play a key part in determining COVID-19 mortality rates, and, in south-east Asia, provide populations with a degree of protection.
The number of deaths per million people varies between countries, continents and ethnic groups. While this figure exceeds 3,000 for the worst-hit countries in Europe and the Americas, it remains below 300 in Cambodia, Laos, Myanmar, Thailand and Vietnam.
Even if there may be underestimates in poor countries with less developed administrative systems, the contrast remains striking. Geographic, climatic, demographic, economic and sociological factors, by themselves, are not enough to explain the gap. There must be specific genetic factors at work which are offering a degree of protection to populations in south-east Asia.
I formulated the hypothesis of a favourable effect from malaria and hemoglobin E in south-east Asia in two articles in The Geopolitics in 2020, “Why Southeast Asia is Relatively Spared by COVID-19” (May 13) and
The most recent scientific research supports this hypothesis. Human beings are not equal in the face of illness. In response to the question “Why does resistance to an illness appear in some people but not others?” Professor Jean Dausset, a Nobel Prize winner in medicine in 1980 for his work on the human genome, answers: “the answer is genetic. In every epidemic, part of the population is resistant, which leads to the extinction of the epidemic, because there is no-one else to kill …”. Dausset recalls the history the Black Plague and the saying: “They did not all die, but they were all affected …”. (1)
When COVID-19 became a global pandemic, I took the situation in my country of origin, Cambodia, as a starting point and extended my observations to neighbouring countries. All five countries on the Indo-China peninsula mentioned above seem to have been relatively protected from COVID-19. Until February 2021, the total number of deaths in these five countries was insignificant in statistical terms, while, during the same period, most of the rest of the world was suffering very large numbers of deaths.
Shared genetic traits
What could be the shared factor protecting these countries – at least in relative terms – from COVID-19?
The search for an answer took me in an unexpected direction: Geographic Hematology. That’s the title of a work published in 1966 by two leading French hematologists, professors Jean Bernard (considered as the father of modern hematology) and Jacques Ruffié. They combined their knowledge of history, geography, archaeology, hematology and genetics, and showed that many of the populations of south-east Asia carried hemoglobin E (HbE), a genetic characteristic of populations descended from the Khmer Empire, which was at its height in the twelfth and thirteenth centuries. This empire spread across part or all of the five countries in question. Modern Cambodia, which was at the heart of the Khmer Empire, is the country where the largest proportion of the population carries hemoglobin E (up to 62% of the population) versus 53% in Laos and Thailand, 42% in Myanmar and 35% in Vietnam.
Jean Bernard, who was president of France’s Académie de Médecine, wrote: “The geography of hemoglobin E and that of the monuments of Khmer art can be more or less superimposed. This correspondence is remarkable. The limits of the old Khmer Empire were until now defined by archaeology. They can be defined today by hematology. The limits are nearly the same.” (2)
Hemoglobin E and malaria
Two key factors are to bear in mind.
1- Hemoglobin E is a factor of natural selection which has protected populations carrying it against the worst forms of malaria which has been endemic in our region since the dawn of time.
2- There are striking pathogenetic similarities between malaria and COVID-19, especially in the most serious cases of the two illnesses: fatal sepsis stemming from a “cytokine storm”; formation of blood clots leading to thrombosis, pulmonary embolism and strokes; serious complications affecting multiple vital organs (brain, lungs, kidneys).
So the question becomes this: If hemoglobin E has been able to protect its carriers against the worst forms of malaria, could it also give protection against the worst cases of COVID-19 which present very similar symptoms?
Across the world, regions of endemic malaria seem to resist against COVID-19 better than other areas. This is notably the case in the malaria zones of central sub-Saharan Africa which are resisting COVID-19 better than the non-malaria areas in the continent’s north and south.
The case of Africa, (and of some regions in India), suggests that a form of immunity to malaria may also offer protection against the worst cases of COVID-19. This protection may be a form of hereditary immunity which shows itself by specific variants (HbE, HbC and HbS) of the hemoglobin present in the populations of malaria zones. These specific hereditary variants of hemoglobin contained in red blood cells allow better resistance to the pathogenic agent of malaria, a parasite of the Plasmodium genus which attacks precisely these red cells.
Scientific studies published this year seem to confirm these hypotheses, concerning both the protective role of hemoglobin E and the possibility of a partial cross-immunity between malaria and COVID-19.
The protective role of hemoglobin E
“Puzzling low incidence numbers and milder, non-fatal disease have been observed in Thailand and its Southeast (SE) Asian neighbors. Elusive genetic mechanisms might be operative, as a multitude of genetic factors are widely shared between the SE Asian populations, such as the more than 60 different thalassemia syndromes (principally dominated by the HbE trait). In this study, we have plotted COVID-19 infection and death rates in SE Asian (SEA) countries against heterozygote HbE and thalassemia carrier prevalence. COVID-19 infection and death incidence numbers appear inversely correlated with the prevalence of HbE and thalassemia heterozygote populations. We posit that the evolutionary protective effect of the HbE and other thalassemic variants against malaria and the dengue virus may extend its advantage to resistance to COVID-19 infection, as HbE heterozygote population prevalence appears to be positively correlated with immunity to COVID-19. Host immune system modulations induce antiviral interferon responses and alter structural protein integrity, thereby inhibiting cellular access and viral replication. These changes are possibly engendered by HbE carrier miRNAs. Proving this hypothesis is important, as it may shed light on the mechanism of viral resistance and lead to novel antiviral treatments. This development can thus guide decision-making and action to prevent COVID-19 infection.”
COVID-19 and malaria
“Starting from the evidence that in Italy, the areas with the lowest number of COVID-19 cases were those with the highest incidence of malaria in the early 1900’s, we explore possible inverse relationships between malaria and COVID-19. Indeed, some genetic variants, which have been demonstrated to give an advantage against malaria, can also play a role in the incidence and severity of SARS-CoV-2 infections (e.g., the ACE2 receptor). To verify this scientific hypothesis, we here use public data from whole-genome sequencing (WGS) experiments to extrapolate the genetic information of 46 world populations with matched COVID-19 data. In particular, we focus on 47 genes, including ACE2 and genes which have previously been reported to play a role in malaria.”
The study says that complex mechanisms of the immunity response involving the B and T lymphocytes draw malaria and COVID-19 together and suggest that resistance to the first may lead to partial immunity to the second.
“The shared immunodominant epitopes with cross-immunogenic reactivity between SARS-CoV-2 antigens S, N, ORF1ab and ORF3a to that of the P. falciparum antigens TRAP and SSP-2 . . . suggest an answer for the ambiguous reason why the lowest number of COVID-19 infections and mortality rates exist in malaria-endemic regions compared to the rest of the world. These results support other recently published data . . .”.
My observations and hypotheses on the protective role of hemoglobin E against COVID-19 and a possible cross-immunity between COVID-19 and malaria, are starting to gain scientific validation.
If future work supports these conclusions, we will have a basis to develop more effective treatments against COVID-19 and to adopt public health policies which will allow a faster end to the pandemic.
(1) “La Mosaïque Humaine”, Jean Bernard and Jean Dausset, Calmann-Lévy, January 2000, page 202.
Sam Rainsy, Cambodia’s finance minister from 1993 to 1994, is the co-founder and acting leader of the opposition Cambodia National Rescue Party (CNRP).