Follicular lymphoma (FL) is an indolent, sometimes fatal disease characterized by recurrence at progressively shorter intervals and is frequently refractive to therapy. Genome-wide association studies have identified SNPs in the human leukocyte antigen (HLA) region on chromosome 6p21.32–33 that are statistically significantly associated with FL risk. Low to medium resolution typing of single or multiple HLA genes has provided an incomplete picture of the total genetic risk imparted by this highly variable region. To gain further insight into the role of HLA alleles in lymphomagenesis and to investigate the independence of validated SNPs and HLA alleles with FL risk, high-resolution HLA typing was conducted using next-generation sequencing in 222 non-Hispanic white FL cases and 220 matched controls from a larger San Francisco Bay Area population-based case-control study of lymphoma. A novel protective association was found between the DPB1*03:01 allele and FL risk (OR=0.39, 95% CI 0.21–0.68). Extended haplotypes DRB1*01:01-DQA1*01:01-DQB1*05:01 (OR=2.01, 95% CI 1.22–3.38) and DRB1*15-DQA1*01-DQB1*06 (OR=0.55, 95% CI 0.36–0.82) also influenced FL risk. Moreover, DRB1*15-DQA1*01-DQB1*06 was highly correlated with an established FL risk locus, rs2647012. These results provide further insight into the critical roles of HLA alleles and SNPs in FL pathogenesis that involve multi-locus effects across the HLA region.

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Major histocompatibility complex class I chain-related gene A (MICA) was identified within the human leukocyte antigen (HLA) class I region and was located 46 kb centromeric from HLA-B locus. It functions as a ligand for human gammadelta T, CD8 T and natural killer (NK) cells by binding the NKG2D receptor. The aims of the present study were to determine the distribution of MICA alleles and MICA-HLA-B haplotypes in a sample of Euro-Brazilians. Through the combination of three typing methods, polymerase chain reaction (PCR)-sequence-specific oligonucleotide probe, PCR-sequence-specific primer and PCR-restriction fragment length polymorphism, 19 alleles were detected besides a MICA gene deletion in a sample composed by 204 unrelated Euro-Brazilians. The most commonly observed alleles were: MICA*00801 (25.3%), MICA*00201 (17.7%) and MICA*00901 (13.7%). The GCT repeat polymorphism variant A6 was the most commonly found. The most frequent haplotype found in this study was MICA*00901-B*51 (8.1%), followed by haplotypes MICA*00201-B*35 (6.1%) and MICA*00801-B*07 (6.1%). MICA*00801 truncated product, and its low affinity for NKG2D receptor may work as an inhibitor in its putative soluble form. It may also be that selective forces may favor MICA*00801 heterozygosity with NKG2D high affinity MICA alleles enabling activation and inhibition of cytotoxic activity of cells expressing the NKG2D receptor. The possibility of selective neutrality or of balancing selection still provides no explanation for MICA gene polymorphisms. Is it maintained by genetic drift or by the influence of migratory waves? Are there favored alleles while others present the same adaptive value?

MICA is a nonclassical polymorphic MHC molecule. We investigated MICA allelic frequencies and MICA-HLA-B-HLA-C haplotypes in Brazilian Amerindians to describe the polymorphism and to extract information about the evolution of MICA gene. Kaingang is the first population described to have a high frequency of MICA*020, found associated with HLA-B*3505-HLACw*0401. Allele MICA*020 probably originated de novo in South America. The Guarani population had high frequencies of MICA*027. Allele MICA*00801 is common worldwide but rare among Amerindians, occurring only because of gene flow. The analysis of the 64 described MICA alleles revealed that in exons 2 and 4, synonymous substitutions are in excess, a result compatible with purifying selection. The opposite was observed for exons 3 and 6 and the excess of nonsynonymous substitutions was significant for exon 3, indicating positive selection. Few of the alleles described so far had exon 6 sequenced, impeding conclusions for the corresponding portion of the molecule. The analysis of the entire gene is required for a better understanding of the evolution of MICA's polymorphism and its functional consequences. This knowledge is of prime importance in view of the increasing awareness of the functional and medical implications of MICA gene variability.

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