Complement genetics as a potential clue to race differences in COVID-10 severity
One of the current obstacles in COVID-19 infection is the racial difference in patients developing severe illness. As outlined above, highly pathogenic coronaviruses are recognized by MBL. Several polymorphisms have been described for MBL in exon 1 at codon positions 52, 54, and 57 (Steffensen, Thiel, Varming, Jersild & Jensenius, 2000). The A allele can be distinguished from R52C, G54D, and G57E polymorphisms described as D, B and C alleles (Garred, Larsen, Seyfarth, Fujita & Madsen, 2006). These polymorphisms in exon 1 together with those in the promoter region profoundly affect circulating levels of MBL (Madsen et al., 1995). Importantly, MBL polymorphisms have been associated with fatal outcome in patients with sepsis, SIRS (Garred, J, Quist, Taaning & Madsen, 2003; Hellemann et al., 2007) and ARDS (Gong, Zhou, Williams, Thompson, Pothier & Christiani, 2007). Also, some (Ip et al., 2005; Tu et al., 2015; Zhang et al., 2005) but not all (Yuan et al., 2005) studies found a significant association between MBL codon variant in exon 1 and the risk of severe SARS-CoV infection. Thus, polymorphisms in exon 1 and/or the promoter region of MBL may define the extent of complement activation in COVID-19 patients (Figure 3). In support of this view, strong differences have been observed between haplotype frequencies in Asians, Caucasians, Hispanic and African Americans(Garred, Larsen, Seyfarth, Fujita & Madsen, 2006). Intriguingly, the G54D polymorphism is extremely rare in West Africa but can be found at higher frequencies in Caucasian, Asians and indigenous South Americans, respectively. In contrast, the C allele is more frequent in sub-Saharan Africa but rare among Caucasians. The D allele is largely restricted to North Africans and Caucasians. It has been speculated that environmental pressures such as a tuberculosis infections could account for the fact that almost 60% of the sub-Saharan population contains the C allele (Bernig, Taylor, Foster, Staats, Yeager & Chanock, 2004). In support, a protective association was found between the C allele and a tuberculosis infection withM. africanum (Thye et al., 2011). Thus, racial differences in MBL-mediated complement activation may account for different complement activation in COVID-19.
In addition to MBL, complement genetics studies in hematopoietic stem cell transplantation (HSCT) recipients provide evidence of racial disparities in predisposition to develop TMA and risk of mortality under intense stress like the transplantation process and may serve as a hypothesis for higher mortality seen in African Americans with COVID-19 infection. A previous large HSCT registry report described inferior survival in African Americans after unrelated donor HSCT, but it was unable to attribute reduced outcomes to risk factors such as HLA-matching and socioeconomic status (Baker et al., 2009). A prospective study examining genetic predisposition for transplant associated thrombotic microangiopathy (TA-TMA) in HSCT recipients demonstrated that 65% of patients with TA-TMA had genetic variants in at least one complement gene as compared with 9% of patients without TA-TMA (P < .0001) using a hypothesis driven 17 gene panel including the complement factors C3, Factor B (FB), C5, FP, FD, FI, FH, FHR1, FHR3, FHR4, FHR5, CD55, CD59, CD46, C4BPA. (Jodele et al., 2016c). Importantly, many of the complement genes belong to complement regulators that either control the amplification of the cascade at the level of C3, i.e. FH, CD55, CD46, FI or fuel the amplification loop (FB, FP, FD).
Complement gene variants were increased in patients of all races with TA-TMA, but African Americans had more variants than Caucasians. While the FD variant (c.357116C.A) was detected only in African American patients with TMA, it was mainly the number of variants occurring in individuals with TA-TMA and not a particular gene variant that was significantly associated with TMA and disease severity. Variants in ≥3 genes were identified only in African Americans with TA-TMA and were associated with very high mortality after HSCT (71%) associated with strong complement activation (Jodele et al., 2014). The finding of multiple variants occurring at high frequency in persons of African descent associated with strong complement activation suggests a selective benefit of strong complement activation in Africans as a defense mechanism to combat infectious pathogens like Neisseria meningitides , a prevalent cause of mortality in endemic areas of Africa (African meningitis belt). Clearly, SNPs in C3 (Adriani et al., 2013) and FH have been associated with susceptibility (Davila et al., 2010) to this pathogen. The homeostasis of complement is controlled by an equilibrium between activation and control. Dysregulation of complement activation at the level of C3 through loss- or gain-of function mutations of regulators or gain of function mutations in activator proteins results in uncontrolled complement activation and inflammation as seen in many inflammatory conditions including HSCT-TMA (Figure 3). The combination of several complement gene polymorphisms, in particular in C3 , FH and FB has been found to determine systemic complement activity and the susceptibility to AP-driven diseases (Heurich et al., 2011; Paun et al., 2016). Thus, the available data from HSCT-TMA suggest that African American with multiple variations in complement genes react with stronger complement activation in response to infection with highly pathogenic coronaviruses including SARS-COV-2 resulting in uncontrolled pulmonary tissue inflammation and complement deposition in several organs.
In support of this view we found at least one complement gene variant in 32% of well children when we investigated 50 African Americans and 50 Caucasians. The frequency of gene variants differed markedly by race with 50% of African American children having at least one gene variant, compared to only 14% of Caucasian children although the overall variant frequencies were lower than those we have reported in HSCT recipients(Jodele, Zhang, Dandoy, Myers, Lane & Davies, 2017).
Taken together, it will be important to examine genetic variants of complement proteins in patients infected with SARS-CoV-2 and to correlate such variants with disease severity. Such data might aid prediction of the risk to develop virus-associated TMA.