High‐resolution analysis of the HLA‐A, ‐B, ‐C and ‐DRB1 alleles and national and regional haplotype frequencies based on 120 926 volunteers from the Italian Bone Marrow Donor Registry

Abstract

HLA genes are highly polymorphic and structurally complex. They are located in the major histocompatibility complex (MHC) on chromosome 6, and the frequency of alleles and haplotypes varies widely among human populations. In this paper, we calculated the allele and haplotype frequencies using the HLA data of more than 120 000 Italian unrelated bone marrow donors enrolled in the national registry (IBMDR) and typed them with a high‐resolution (HR) method for the HLA‐A, ‐B, ‐C and ‐DRB1 alleles. The allele frequency data were obtained by manual counting; haplotype frequencies were calculated using the expectation maximisation (EM) algorithm. The total numbers of observed alleles were 226 for HLA‐A, 343 for HLA‐B, 201 for HLA‐C and 210 for HLA‐DRB1, which account for 5.4%, 6.7%, 5.2% and 8.5%, respectively, of each locus allele (IPD‐IMGT/HLA Database Release 3.32, April 2018). The three most frequent Italian haplotypes were HLA‐A*01:01~B*08:01~C*07:01~DRB1*03:01 (2.5%), A*02:01~B*18:01~C*07:01~DRB1*11:04 (1.1%) and A*30:01~B*13:02~C*06:02~DRB1*07:01 (1.1%). Moreover, for a relevant subset of the examined population (>100 000 individuals), the birthplace was available, and thus, we grouped the frequency data based on the corresponding Italian geographic areas, describing the HLA specificity of the Italian regional populations. The haplotype frequencies were also compared between national and regional data, and we observed remarkable differences in the regional haplotype frequencies, particularly in Sardinia. This study represents a valid tool to identify a more efficient haematopoietic stem cell unrelated donor recruitment and selection strategy, as well as for population genetic and HLA‐disease association fields.

Correlation of the two most frequent HLA haplotypes in the Italian population to the differential regional incidence of Covid-19

“…The registry contains complete information about the region of provenience and ethnic origin for a sample of 104,135 subjects. 16 The estimated national frequencies for these haplotypes, calculated using the Arlequin programme by the EM algorithm, sum up to 6.9%: HLA-A*:01:01g-B*08:01g-C*07:01g-DRB1*03:01g (2.54%); HLA-A*02.01g-B*18.01g-C*07.01g-DRB1*11.04g (1.14%); HLA-A*30.01g-B*13.02g-C*06.02g-DRB1*07.01g (1.09%); HLA-A*29.02g-B*44.03g-C*16.01g-DRB1*07.01g (1.08%); HLA-A*03.01g-B*07.02g-C*07.02g-DRB1*15.01g (1.02%). The regional frequencies estimated from the data set sample are depicted in Table 2.…”

“…Although the primary scope of a bone marrow registry is to increase the possibilities to nd allogenic compatible donors for transplants, it is also a unique source of precious HLA data from the widest and most representative sample available at the national level, which makes it possible to estimate haplotypes frequencies in a given population and carry out association studies in many disease contexts. We conducted our study on a large sample of 104,135 subjects typed at high resolution fourdigit level, subdivided in the 20 Italian regions, with a regional sample size adequately statistically representative of the resident population for each region [16].…”

“…Association of HLA with viral infections has been observed for human immunode ciency virus (HIV), human hepatitis B virus (HBV), human hepatitis C virus (HCV) and human papilloma virus (HPV) [12][13][14][15]. Noteworthy, studies conducted on a meaningful data set of high-resolution HLA-typed individuals, revealed signi cant differences in single allele and haplotypes frequencies among the Italian regions [16]. Understanding how genetic variation in HLA may affect both susceptibility as well as course and severity of Covid-19 infection could help to identify and stratify individuals at higher risk from the disease.…”

“…For our analyses we used the large dataset from the Italian Bone Marrow Donors Registry (IBMDR) maintained at E.O. Ospedali Galliera di Genova https://www.ibmdr.galliera.it/ibmdr/ [16]. In the study, we used the dataset 2, which is constituted by a sample of 104135 donors with available data about the city of birth, typed for HLA-A, -B, -C and -DRB1 at a high-resolution (HR) level by ASHI or EFI-accredited tissue typing laboratories using HR molecular biology techniques (SBT, SSO, SSP, NGS) as described [16].…”

“…Ospedali Galliera di Genova https://www.ibmdr.galliera.it/ibmdr/ [16]. In the study, we used the dataset 2, which is constituted by a sample of 104135 donors with available data about the city of birth, typed for HLA-A, -B, -C and -DRB1 at a high-resolution (HR) level by ASHI or EFI-accredited tissue typing laboratories using HR molecular biology techniques (SBT, SSO, SSP, NGS) as described [16]. The data, based on the donor's birth region, were divided into the 20 geographical regions of Italy that are in alphabetical order: Abruzzo, Basilicata, Calabria, Campania, Emilia Romagna, Friuli Venezia Giulia, Lazio, Liguria, Lombardia, Marche, Molise, Piemonte, Puglia, Sardegna, Sicilia, Toscana, Trentino Alto Adige, Umbria, Valle d'Aosta and Veneto.…”