We read with interest the paper by Montopoli et al. about the association between androgen deprivation therapies (ADT) in prostate cancer patients and protection against coronavirus disease 2019 (COVID-19). The TMPRSS2 regulated expression by the androgen receptor (AR) in non-prostatic tissues might explain the increased susceptibility of men to develop severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. ADT, based on luteinizing hormone-releasing hormone (LHRH) agonist/antagonists or AR inhibitors, might reduce SARS-CoV-2 infections or complications in high-risk male populations.1 The outbreak of the pandemic shows a marked geographical variation in the prevalence and mortality of COVID-19. Some Western European regions (e.g. Bergamo in Italy, Noord-Brabant in the Netherlands, Limburg in Belgium) were severely affected. As a potentially protective role of the double X chromosome in females was suggested,2 we postulated that Y-chromosome polymorphisms might also partly explain the variable prevalence and mortality.
The phylogenetic resolution of the Y-chromosome haplogroup (YHG) tree is now sufficiently high to be able to detect geographic patterns on a micro-regional scale.3 , 4 A critical role for genetic variation in chromosome Y in regulating susceptibility to influenza A virus infection and in augmenting pathogenic immune responses in the lung has been demonstrated in a murine model.5 We have compared the prevalence of Y-chromosome haplotypes in the Netherlands and Dutch-speaking Belgium (Flanders) with the prevalence and mortality of COVID-19 using individualized data of 12 Dutch and 5 Flemish provinces. In parallel, prevalence and mortality of COVID-19 were compared with epidemiological data on Y-chromosome haplotypes and several polymorphisms [angiotensin-converting enzyme 1 (ACE1), human homeostatic iron regulator protein (HFE), and complement component C3] in 28 (mainly European) countries. Infection-related data reported on 30 April 2020 by Belgian and Dutch health authorities, as well as Johns Hopkins, were analyzed. COVID-19 prevalence (Figure 1 A) and mortality frequency in the Dutch and Flemish provinces strongly correlated with the R1b-S116 haplotype frequency (r 2 = 0.601 and 0.453, respectively). Similarly, in European countries, a marked correlation was noted: COVID-19 prevalence (Figure 1B) and mortality showed a strong correlation with the R1b-S116 haplotype frequency (r 2 = 0.390 and 0.493, respectively). Even in separate multivariate regression models for COVID-19 prevalence and mortality frequency including the listed candidate markers, R1b-S116 remained a significant factor (next to ACE1 polymorphism for COVID-19 prevalence). Remarkably, among Italians, the heavily affected Bergamo area is characterized by a very high R1b-S116 haplotype frequency (0.179). Among European countries, a linear positive correlation was found between R1b-S116 allele frequency and basic reproduction numbers [calculated from a susceptible-infectious-recovered COVID-19 model (r 2 = 0.281)].
Figure 1.
R1b-S116 haplotype frequency versus COVID-19 prevalence (30 April 2020) in the Netherlands and Flanders (A) [log (prevalence) = 2.8684 + 7.543 X (R1b-S116 haplotype frequency), r2 = 0.601] and in a group of 28 countries (B) [log (prevalence) = 2.848 + 5.561 X (R1b-S116 haplotype frequency), r2 = 0.390].
On the one hand, the Y-chromosome influences immune and inflammatory responses, resulting in a genetically programmed susceptibility to diseases with a strong immune component. On the other hand, the R1b-S116 haplotype frequency might also be regarded as a population marker, which stands for cosegregated genes and associated epigenetic control. Further research should focus on the interaction between the AR, TMPRSS2, and the pattern of Y-chromosome haplotype distribution in different COVID-19 patient population groups.
Acknowledgments
Funding
None declared.
Disclosure
The authors have declared no conflicts of interest.
References
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