Emerging new alleles suggest high diversity of HLA‐C locus

Abstract

Human leukocyte antigen (HLA)-C has only recently emerged as an important transplantation antigen and as a receptor for natural killer cells. Over the last few years, sequence-based typing (SBT) revealed the true diversity of HLA-C locus; however, the frequency at which new alleles are detected still remains high. During routine SBT of 3500 samples for the National Marrow Donor Program, we have identified 20 new HLA-C alleles reported in this article in 26 individuals. New variants have been characterized by direct sequencing of polymerase chain reaction product obtained by allele-specific amplification of potential new alleles. Most of the new alleles carry coding substitutions of residues located within the antigen-binding groove. The substitutions are predominantly located in the alpha2-helix which is consistent with the unique to HLA-C conservation of alpha1-helix. Seven new alleles, or 35%, have been identified in African Americans, two of them in three and four individuals each, suggesting that these alleles may not be rare. This observation reflects the fact that the minority groups, previously under-represented in the HLA research pools subjected to SBT, now begin to emerge as a main source of new HLA-C alleles. This study further confirms that HLA-C locus is at least as polymorphic as HLA-A and HLA-B.

HLA-C polymorphisms and PCR dropout in exons 2 and 3 of the Cw*0706 allele in sequence-based typing for unrelated Chinese marrow donors

“…3500 NMDP donors. The frequency of emerging new alleles still remains high, and some new alleles Cw*030304, 0413 detected four and three times in African Americans, respectively, suggesting that HLA-C common to African Americans and probably other minorities is still not adequately characterized [11]. In this study, we examined 1795 Chinese Han donors by SBT and identified nine novel HLA-C alleles with a new allele emerging rate of 0.5% (9/1795), which is comparable to that reported by Lebedeva et al (0.57%, 20/3500).…”

“…In previous studies, HLA-C typing by SBT was restricted to analyze polymorphisms at exons 2 and 3 [10,11,19,20]. The HLA-C diversity and novel polymorphisms had been reported for NMDP samples of which the majority are of Caucasian origin, but the allelic diversity of HLA-C in non-Caucasians is still underestimated [10].…”

“…Of 19 new alleles, 13 were found in Caucasian individuals. Six years later, Lebedeva et al [11] identified 20 novel alleles in Note: Alleles cannot be distinguished within exons 2, 3, and 4 were assigned with an abbreviation for each allele group according to Waller et al [15]. Cw*0303g is the abbreviation for Cw*030301/0320N, Cw*0401g for Cw*04010101/04010102/0409N, Cw*0704g for Cw*070401/0711.…”

“…More recent studies showed that HLA-C interacts with killer-cell immunoglobulinlike receptors (KIR) and play an important role in regulating inhibition and activation of natural killer (NK) cells [3]. In recent years, HLA-C has attracted revived research interests on its biologic functions, influence on marrow transplantation [4 -9], and allelic diversity in human populations [10,11].…”

Genome-Wide Oligonucleotide Microarray Analysis of Gene-Expression Profiles of Taiwanese Patients with Anaplastic Astrocytoma and Glioblastoma Multiforme

“…HLA-C emerges as an important transplantation antigen and as a receptor for natural killer cells. 28 HLA-C is up-regulated in GBM; therefore its presence could promote tumorigenesis.…”