Genetic and hormonal influence on SARS-CoV-2-infection susceptibility: Re: The potential influence of human Y-chromosome haplogroup on COVID-19 prevalence and mortality.

We read with interest the correspondence by Delanghe et al., suggesting that genetic variants, and in particular Y chromosome polymorphisms, might explain outcome variations between genders. During the coronavirus disease 2019 (COVID-19) pandemic one prominent difference became apparent: men are more vulnerable to severe outcomes than women. We recently published an observational study putting forward the hypothesis that male hormones may explain the increased male susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Our analysis was focused on SARS-CoV-2-infected prostate cancer patients of the Italian region of Veneto.

Importantly, as highlighted by Delanghe et al., the spread of the pandemic shows a marked geographical heterogeneity in the prevalence and mortality. Several factors can contribute to this phenomenon; the geographical distribution of genetic variants is one of them. Indeed, Delanghe et al. reported a positive correlation between COVID-19 prevalence and mortality frequency and the frequency of the R1b-S116 haplotype in Europe. Noteworthy, several genes located on the Y chromosome have been associated with human diseases such as hypertension, coronary artery disease, and also infections. Indeed, several immune-related genes are on the Y chromosome and might modulate the immune response.

Data from our study suggest that male hormones may be associated with increased SARS-CoV-2 susceptibility. It is important to highlight that the androgen receptor (AR) gene locus is located on the X chromosome, and that AR polymorphisms exist, which are linked to variable AR transcriptional activity. However, the association between AR genetic variants and COVID-19 severity has not been demonstrated yet.

Other studies have investigated the influence of genetic factors in the spreading of SARS-CoV-2. ACE2 and TMPRSS2 are interesting target genes, as they are crucial for SARS-CoV-2 entry in infected cells. Importantly, ACE2 is located on the X chromosome and TMPRSS2 is regulated by androgen levels. Asselta et al. analyzed genetic variants of ACE2 and TMPRSS2 genes in the Italian population, looking for genetic factors underlying COVID-19 severity. According to their analysis, specific TMPRSS2 genetic variants (one exonic variant and two distinct haplotypes) might be associated with more severe disease manifestations, and could also explain sex-related differences.

Nevertheless, available data on the COVID-19 pandemic are not sufficient to confirm the existence of genetic modulators of SARS-CoV-2 infection outcomes. For this reason, there is an urgent need for large studies linking genetic variants with disease susceptibility and outcomes.