Genetic risks and association with severe COVID-19 among global populations

The worldwide pandemic caused by the novel coronavirus infection (COVID-19) has continued unabated as multiple factors have influenced its transmission, morbidity, and mortality. Infected older adults and those with preexisting health conditions are at risk of increased disease severity. Progression to acute respiratory failure accompanies prolonged hospitalization and poor prognosis. COVID-19 transmission differs vastly among countries. The European Center for Disease Prevention and Control reports significant differences in mortality rates among regions as of 21 November 2020, from 725 per million in North America to 558 per million in the European Union, with lowest rates in East Asia (4 per million) [1].

While population demographics and healthcare infrastructure influence mortality, genetic predisposition may also influence clinical severity of COVID-19. Recent genome-wide association studies identified multiple host genetic factors associated with disease susceptibility and severity [2–4]. These studies examined mostly European populations, which prompted us to examine these disease-modifying loci in the Asian population. We examined variabilities in the frequencies of risk alleles among the global population from the gnomAD, GenomeAsia 100k, and Southeast Asia database [5].

Chromosomal locus 3p21.31 was highly correlated with disease severity in hospitalized Italian and Spanish COVID-19 patients (rs11385942; 95% confidence interval (CI), p = 1.15x10⁻¹⁰) [2], which was confirmed in the United Kingdom (rs13078854; 95% CI, p = 1.6x10⁻¹⁸) [3] and in a multi-ethnic study (rs73064425; 95% CI, p = 4.77x10⁻³⁰) [4]. This gene-rich locus includes SLC6A20 (encoding sodium-imino acid transporter 1, which interacts with COVID-19 ACE2 receptor) and multiple chemokine receptors (CCR9, CXCR6, CCR1, and CCR2). Our analysis found that the frequency of the risk allele rs11385942 at this locus differs vastly among Southeast Asians, ranging from 0.21 in the Filipino population to 0.06 in the Thai population, but it was rare in Northeast Asians (Figure 1). Surprisingly, frequencies of risk alleles at 19p13.2 (rs74956615) and 19p13.3 (rs2109069) were also low among Northeast Asians relative to other populations. Collectively, these three loci encode inflammatory response genes (CCR2, TYK2, and DPP9) and are hypothesized to influence COVID-19 severity through hyper-inflammatory response and subsequent organ injury [3].

Figure 1. Analysis of the different frequencies of risk alleles known to be associated with the susceptibility and severity of COVID-19 in different populations. Allele frequencies available from the gnomAD database, which include East Asia, Africa, Ashkenazi Jewish, European(non-Finnish), European(Finnish) and Latino, GenomeAsia 100k database, which includes South Asia, Philippines, Indonesia, Malaysia, China, South Korea, and Japan, and from a control Thai population (n = 236) [5] were analyzed

The frequency of the risk allele at rs657152 located on 9q34.2 (linked to ABO blood group locus) varies from 0.25 in Indonesians to 0.48 in South Koreans. This locus found to be associated with European patients with respiratory failure (rs657152; 95% CI, p = 4.95x10⁻⁸) [2]. In addition, another study found the same locus to be associated with COVID-19-infected individuals when compare to those uninfected at lower p-value (95% CI, p = 5.3x10⁻²⁰) [3]. On chromosome 21q22.1 where the interferon receptor gene IFNAR2 is located, the frequencies of the risk allele rs2236757 is 0.56 in Southeast and 0.46 in Northeast Asians (higher than 0.29 found in non-Finnish Europeans).

Along with other factors, lower COVID-19 mortality in East Asian countries may be attributed to lower frequencies of risk alleles. The impact of known risk alleles may not be universal among the different human populations in predicting COVID-19 severity and susceptibility due to differences in the patterns of linkage disequilibrium in some loci. Supplementary studies in Latin America, Africa, and Asia may provide further explanation in the observed unequal disease severity in different populations.

Acknowledgments

This work was supported by The National Research Council of Thailand, The Center of Excellence in Clinical Virology of Chulalongkorn University & Hospital and MK restaurant group pcl. Support for John Mauleekoonphairoj was provided by the Second Century Fund of Chulalongkorn University, PhD program.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the The Center of Excellence in Clinical Virology of Chulalongkorn University & Hospital ; Second Century Fund of Chulalongkorn University, PhD program; The National Research Council of Thailand; MK restaurant group pcl.