P-194: A Germline Variant of BNIP1 Gene (rs28199) is Associated with Familial Multiple Myeloma

Introduction: BNIP1 gene plays a pivotal role in cellular degradation processes, notably apoptosis and autophagy. A variant in BNIP1 gene (NM_001205.3/c.*1208A >G; rs28199) has been reported to be associated with multiple myeloma (MM) risk (OR = 1.18, (95% CI:1.11–1.23), p = 3.18 × 10⁻¹⁰) (Macauda et al. Leukemia 2023, Interlymph-Heidelberg Consortium). It is predicted to affect the binding site of IRF1, STAT2_STAT1and FOXP1 transcription factors, have a strongest effect for IRF1 (interferon regulatory factor 1) and be associated with an increased blood level of Interleukin-6. We have recently reported in our targeted and whole exome sequencing study on familial cases (BJH, 2024) that this variant is present in 13 of 18 familial MM cases (72.2%). In this study, we expanded our familial cases to analyze rs28199 variant and aimed to compare it to non-familial MM patients and healthy population.

Methods: A total of 32 familial MM and 30 non-familial MM cases were included to the study from hematology centers in Turkey and defined as having one or more first, second or third-degree relatives who have plasma cell diseases. Non-familial MM cases were randomly selected from the samples of the reference hematology center in Ankara University, Faculty of Medicine. Targeted NGS sequencing was utilized to investigate the germline variant from patients’ peripheral blood samples. Allele frequencies of the study group was also compared to the Turkiye Genome Project data of the Turkiye National Genome Center.

Results: 65.6% (n=21) of the familial and 40% (n=12) of the non-familial MM cases were positive for the BNIP1 variant, revealing a significant association between the variant and familial MM (OR: 2.86 (95% CI: 1.02-8.04), p=0.04). Among the variant positive patients, the rates of homozygosity were 47.6% (n=12) in the familial and 8.3% (n=1) in the non-familial MM cases (OR: 10, (95% CI: 1.08-91.98), p=0.02). The variant allele frequencies were 0.48 and 0.22 in familial and non-familial MM cases, respectively (p=0.00). Likewise, rs28199 allele frequency among familial MM cases was also more frequent than the frequency observed within germline whole genome data of healthy population (Turkiye Genome Project) (0.48 vs 0.32, p=0.02).

Conclusions: This study shows that germline BNIP1 variant (rs28199), when in homozygous state is particularly associated with familial MM. Our data on BNIP1 rs28199 variant among familial cases contributes the findings of the Interlymph-Heidelberg Consortium which suggests this variant to be associated with MM as one of the genetic risk factors.