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.