Key Immune System Genes Identified to Explain High COVID Deaths and Spread in Northern Italy Versus Fewer Cases and Deaths in the South

Not long after the Coronavirus disease (Covid-19) outbreak in China, Italy was hard-hit by the infection and rapidly became one of the countries with the highest mortality rate. The disease was first detected on February 20 in Lombardy, a region in the Northern area, and rapidly spread throughout the country. The Southern regions and the Islands, however, registered much lower infection rates even though a massive migration from the affected regions to the South was recorded before the national lockdown.

What spared the South of Italy from such a heavy disease burden? Various reasons have been proposed including that milder climate conditions in the South could have helped to prevent viral spreading, but none so far convincingly explained the different incidence rates throughout the country.

To investigate whether a specific genetic asset could have contributed to protect Southern citizens, Antonio Giordano, M.D., Ph.D., Founder and Director of the Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, in Philadelphia and Professor of Pathology at the University of Siena, Italy, and his research team investigated the prevalence of alleles of the Human Leukocyte Antigen (HLA) gene system in the Italian population. The HLA system is a highly polymorphic set of genes, inherited in block by the parents, which encode molecules with a key role in shaping the antiviral immune response. Specific alleles of the HLA system are associated with development of a wide range of diseases including autoimmune diseases and viral infections.

The authors performed a geographical ecological study evaluating the possible association of HLA allele prevalence and Covid-19 incidence across the twenty Italian regions and their provinces. HLA data were retrieved from the published dataset of the Italian Bone Marrow Donor Registry including nearly 500.000 donor volunteers. The authors selected those HLA alleles which showed differences in prevalence across the country to assess whether they could correlate with the new coronavirus infection. Overall the authors identified a set of 7 HLA class I alleles which showed a positive association with Covid-19 incidence data (provided by the Civil Protection) and 3 HLA class I alleles, which showed a negative association.

The authors then performed a multivariable regression analysis to examine HLA alleles independently of each other to rule out mutual confounding and including also the regions in the model as possible confounders. The analysis showed that, among the ten alleles, only HLA-B*44 and C*01 alleles maintained a positive and independent association with Covid-19 incidence, suggesting that these variants might be permissive to viral infection. The authors zoomed into regions such as Emilia Romagna and Marche which showed unexplained intra-regional differences within provinces. Here the prevalence of B*44 could almost exactly predict the incidence of Covid-19.

“It is not surprising that both HLA-B*44 and C*01 were previously associated with inflammatory autoimmune diseases and C*01 was correlated to recurrent sino-pulmonary infections,” says Pierpaolo Correale, Director of the Medical Oncology Unit of the Grand Metropolitan Hospital ‘Bianchi Melacrino Morelli’ of Reggio Calabria, lead author of the study. “This highlights the ability of these HLA alleles to trigger non-proficient and often inappropriate immunological reactions to specific SARS-Cov-2 antigens.”

“The identification of HLA alleles that are permissive or protective towards coronavirus infection could inform priorities in disease management and future vaccination campaigns in an easy, cost-effective manner,” says Prof. Luciano Mutti, MD, from the Sbarro Institute in Philadelphia, co-first author of the study.

“Despite the intrinsic limits of the ecological approaches, such types of studies have the advantage of considering a large number of cases that are readily available through public datasets. Indeed, geographical studies are often the first to identify risk factors for a variety of diseases. Case-control studies will be then necessary to confirm these findings in Covid-19 patient cohorts,” says Giovanni Baglio, coauthor of the study, epidemiologist from the Ministry of Health. 

“We hope that this will be feasible in a reasonable timeframe because the research setting in Italy still presents many hurdles,” concludes Giordano.

The study stems from the collaboration of a multi disciplinary group including Pierpaolo Correale and Rita Emilena Saladino of the Grand Metropolitan Hospital ‘Bianchi Melacrino Morelli’ of Reggio Calabria; Giovanni Baglio and Pierpaolo Sileri of the Italian Ministry of Health; Luciano Mutti of the Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia; Francesca Pentimalli of the National Cancer Institute of Naples, IRCCS, Pascale Foundation; and Antonio Giordano, Director of the Sbarro Institute at Temple University and Professor at the University of Siena.

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