Morbidity and mortality of COVID-19 negatively associated with the frequency of consanguineous marriages, an ecologic study

Background Union between second cousins and closer relatives is called consanguineous marriage. Consanguineous marriage is associated with increased risk of autosomal recessive diseases and several multifactorial traits. In order to evaluate the association between prevalence/mortality of COVID-19 and the frequency of consanguineous marriage, the present ecologic study was carried out. For the present study, data of prevalence (per 106 people) and mortality (per 106 people) and number of performed laboratory diagnostic test (per 106 people) of COVID-19 disease at four time points (December 2020; March, August and October 2021) of 65 countries were used. Results Univariable correlation and generalized estimating equation analysis were used. In analysis, prevalence and mortality of COVID-19 were used as dependent variables and human development index, number of performed diagnosis test and the mean of inbreeding coefficient (α-value) were introduced into model as covariates, and time point was used as a factor in analysis. The square root (SR) of prevalence (P = 0.008) and SR-mortality (P < 0.001) of COVID-19 negatively associated with the log-transformed of α-value. Conclusions The present finding means that in countries with high levels of consanguineous marriages, the prevalence of COVID-19 and mortality due to COVID-19 were lower than countries having low level of marriage with relatives.


Background
In genetics, union between second cousins and closer relatives is called consanguineous marriage [1]. Previously it has been shown that consanguineous marriage is a long-standing social custom which depends with numerous factors, such as religious, socio-economic and demographic variables [2][3][4]. The frequency of consanguineous marriage has geographical distribution; it has high prevalence in several Asia and Africa countries. Iranian populations showed high levels of consanguineous marriages [5][6][7].
Numerous studies have shown that this type of marriage is associated with increased risk of autosomal recessive diseases and several multifactorial traits [1,[8][9][10][11][12][13][14][15]. It is well established that primary immunodeficiency diseases are genetically heterogeneous group and are associated with parental consanguinity [16]. There is significant association between parental consanguineous marriage and the risk of some infections [17,18]. There is about one-fifth of the world's population living in countries where marriage with biological relatives is prevalent. Therefore, for countries with high prevalence of consanguineous marriage, the association between frequency of consanguineous marriage and the Coronavirus Disease 2019 (COVID-19) is highly important. To the best of our knowledge, there is no study regarding the Normality of variables was investigated using Kolmogrov-Smirnov test. If a variable was not distributed normally, its log-transformed or square root-transformed (SR-transformed) was used in statistical analysis. Univariable correlation analysis was used. To overcome the effects of confounders on prevalence/mortality, generalized estimating equation analysis was used. Prevalence/ mortality of COVID-19 was considered as outcome variables, and the α-values as well as the potential confounders (number of performed test and HDI) were introduced into model as covariates. It should be noted that time point was used as a factor in analysis. Data were analyzed using SPSS software (version 25; SPSS Inc., Chicago, IL). Statistical analysis was performed using P < 0.05 as the cutoff point for significant association.

Results
Normality test showed that HDI has normal distribution. Other variables were not distributed normally. For statistical analysis, the log-transformed of α-value, and the SR-prevalence and SR-mortality of COVID-19 and SRnumber of performed test were used. Table 2 summarizes the correlations between the study variables. It should be noted that almost all of the studies variables had significant correlation with each other. The SR-prevalence (P < 0.001) and SR-mortality of COVID-19 (P < 0.001) were negatively associated with the log-transformed of α-value.
On the other hand, there was significant negative relationship between log-transformed of α-value and HDI (r = −0.618, df = 63, P < 0.001). In all of the study time points, the SR-prevalence (P < 0.001) and SR-mortality of COVID-19 (P < 0.001) were significantly associated with HDI.
In order to neutralized the potential confounding effects of the HDI and number of performed tests on the correlation between α-values and epidemiologic parameters, generalized estimating equations were used ( Table 3). The construction final models showed that SR-prevalence (P = 0.008) and SR-mortality (P < 0.001) parameters of COVID-19 negatively associated with the log-transformed of α-value.

Discussion
The current study revealed that in countries with high levels of consanguineous marriages, the prevalence of COVID-19 and mortality due to COVID-19 were lower than countries having low frequency of marriage with relatives. The α-value can explain 36% of the differences observed in the mortality due to COVID-19 between different countries. Although the main finding of the current study is not consistent with previous reports which reported that primary immunodeficiency diseases [16] and risk of infection of tuberculosis and hepatitis [17] positively correlated with consanguineous marriages, it is consistent with the negative association between parental consanguinity and risk of HIV-1 infection [18].
The present finding that countries with high frequency of consanguineous marriages have low prevalence/mortality of COVID-19 might be interpreted by increased number of resistant individuals against infection SARS-CoV-2 or outcome of COVID-19 due to parental consanguinity. Consanguineous marriage results in elevation of homozygosity of mutant alleles with low frequency. Let's assume the frequency of a given mutant allele which is resistance to COVID-19 be equal to q in a given population. The probability of homozygosity for this allele when marriage with biologic relatives is present and absent at population level becomes equal to q 2 + apq and q 2 , respectively (α is the mean of inbreeding coefficient). Therefore, parental consanguinity increases the frequency of mutant homozygotes which they are resistance to COVID-19. Taken together, it is concluded that the present negative association between α-value and prevalence/mortality of COVID-19 might be a reflection of elevation of the homozygosity of several mutant alleles involved in resistance against infection of SARS-CoV-2 and/or severe form of COVID-19. The present study is an ecologic study, and other ecologic studies have some considerations and limitations. It should be noted that frequency of consanguineous marriages and the epidemiologic parameters COVID-19 are not uniformly distributed on different parts of countries. Here average levels of consanguinity and COVID-19 epidemiologic parameters for countries were used for analysis. Hence, the present finding does not mean a causal relationship between parental consanguinity and susceptibility/mortality due to COVID-19. Several case-control and/or cohort studies are needed to confirm the present findings. Finding mutations that induced the resistance to the COVID-19 is also needed.

Conclusions
The findings of present ecologic study revealed that countries with high frequency of consanguineous marriages, the prevalence of COVID-19 and mortality due to COVID-19 were lower than countries having low level of marriage with relatives. Considering that here the average levels of consanguinity and COVID-19 epidemiologic parameters for countries were used for analysis, the present finding does not mean a causal relationship between parental consanguinity and susceptibility/mortality due to COVID-19.