Background: HLA associations for the risk of developing MM have been described in various non-Caucasian ethnic groups but have not revealed consistent results. Racial and genetic differences in cytokine polymorphisms linked to extended haplotypes; association of autoimmune disorders with HLA types; the proximity of the HLA Class I and II genes to TNF and other Class III genes responsible for complement and cytokines suggest that HLA polymorphisms may be associated with the risk of developing MM.

Aim: We compared HLA-A,-B and -DRB1 2-digit allele and haplotype frequencies in patients with MM to the normal population in order to define HLA specificities associated with the risk of developing MM.

Methods: A cohort of 1803 US Caucasian patients with MM were identified based on availability of HLA-A, B, DRB1 DNA-based typing or serologic typing converted to 2-digit alleles. These patients had either received a matched sibling allogeneic transplant for MM reported to the CIBMTR (N=174) or had HLA typing performed for an unrelated donor search conducted through the US National Marrow Donor Program (NMDP) (N=1629). HLA-A, B and DRB1 allele frequencies among patients were compared to A-B-DRB1 frequencies in HLA typed healthy US Caucasian controls (N= 433838) from the NMDP database. The most frequent alleles among patients and controls as well as HLA haplotype frequencies generated using the EM (expectation-maximization) algorithm were compared using Chi-Square analysis with Bonferroni correction for the number of comparisons.

Results:  Patients with MM had a median age of 49 (range 3-78) years and M/F ratio of 1.86 (1172/631).  The controls had a median age of 44 (range 18-60) years and M/F ratio of 0.735 (183785 / 250053).

Comparison of HLA-A, -B and –DRB1 single-locus allele frequencies   between the myeloma patients and controls (those in the top 10 in either group) revealed similarity except for HLA-B*07 and B*44. B*44 was observed less frequently among the patients (a protective effect) frequency (f): 0.126 vs 0.145 (p= 0.005, Odds Ratio (OR): 0.848). On the contrary, HLA-B*07 was more common (a predisposing effect) among patients (OR: 1.135, p=0.047).  Among the top 20 two locus (HLA-A-B and HLA-B-DRB1) haplotype frequencies in either group, B*44-DRB1*13 and B*07-DRB1*13 were significant: OR: 0.506 and 1.714 (p=0.003 and 0.007) respectively. A-B-DRB1 haplotype comparisons showed significance for: A*02-B*44-DRB1*04 (OR: 0.686, p=0.021), A*02-B*44-DRB1*13 (OR: 0.445, p=0.065) and A*02-B*07-DRB1*04 (OR: 1.968, p=0.029) confirming the single and B-DRB1 combination comparison results.

Significantly different HLA-A, -B and -DRB1 single-locus allele or haplotype frequencies between patients and controls are shown in table 1.

Conclusion: This is the largest epidemiologic study of HLA allele frequencies and the first study on HLA haplotype frequencies in MM. We observed a protective effect on the risk of developing MM with B*44 and a predisposing effect with B*07.  Similar predisposing and protective haplotype associations were observed with A*02-B*07-DRB1*04 and A*02-B*44-DRB1*04 respectively. A revised analysis using a gender-matched control group is in progress. Further study including major histocompatibility region SNP mapping and candidate gene testing will help elucidate the genetic basis underlying this observation.

Table 1.