Yanamandra, Uday

Introduction: Considerable variation has been observed in the prevalence of monoclonal gammopathies across the globe. Although the prevalence of monoclonal gammopathy of undetermined significance (MGUS) has been evaluated in two hospital-based studies in India, no data exists on its prevalence in community-based settings amongst the rural Indian population. Objectives: To determine the prevalence of MGUS in a rural Indian population in a community-based setting. Methods: A cross-sectional study was conducted across 58 agrarian villages/hamlets of a tribal (aboriginals) district and 8 agrarian villages of a Non-Tribal district of Western India spreading over 2299 square miles (sq-mi), as part of SIMPLe (Screening Intervention for Myeloma and Prevention of Lifestyle diseases) study. For the complete study population, demographic details, medical history, and blood samples were collected after a thorough medical examination. Hemograms and serum protein electrophoresis (SPEP) were performed in all individuals. SPEP was performed using on-site capillary zone electrophoresis. Serum immunofixation electrophoresis (SIFE), and biochemistry (liver and renal function tests) were performed for those with abnormal SPEP graphs (those with M spike and those with abnormal bulges in beta-2 or gamma region suspicious of MGUS). Patients with monoclonal protein on SPEP or SIFE were further assessed for any smoldering/ multiple myeloma features. The data was analyzed using JMP ver. 17.2.0. Results: A total of 10,024 individuals were screened and data was analyzed for 9283 (8527 Tribal + 756 Non-tribal) individuals. The prevalence of MGUS in the study population was 62 (0.66%) and was 1.79% above the age of 55y (62 of 3447w). The median age of individuals with MGUS was 65y (IQR 59-72) with male preponderance. None of the patients satisfied the criteria for smoldering or multiple myeloma using IMWG criteria. The median Hb of the study population was 12g/dL (IQR 11.4-13). Among those with MGUS, the distribution of heavy and light chains was IgG - 83.33%, IgA - 16.67%, with none having IgM/ IgD paraprotein, Kappa - 50%, and Lambda - 50%. Two individuals only had light chain MGUS. There was no statistically significant difference between the tribal and non-tribal populations (aged >45y) in the incidence of MGUS (1.798% Vs. 1.745%, p=0.78), total protein levels (7.71 vs. 7.19 g/dL, p=0.87) and albumin-globulin ratio (1.54 vs 1.62, p=0.77) with numerically more patients having polyclonal gammaglobulinemia in the tribal population. The low Hb reflected the statistically lower Hb levels in the tribal population (9.1±4.2 Vs. 12.39±1.8g/dL, p-0.021) owing to concurrent hemoglobinopathies (sickle cell/ thalassemia traits). Conclusion: The prevalence of MGUS in the rural population of Western India is low at 0.66%, rising to 1.79% in individuals over 55 years, predominantly affecting older males, with IgG MGUS being the most common type. There are no significant differences in MGUS prevalence, total protein levels, or Albumin-globulin ratios between tribal and non-tribal populations over 45 years. Our study comprehensively describes the prevalence of MGUS in rural community settings in India. The background prevalence appears to be lower compared to the Western (both USA ~3% and European~5%) population.

Erythrocytosis is characterized by an increase in red cells in peripheral blood. Polycythemia vera, the commonest primary erythrocytosis, results from pathogenic variants in JAK2 in ∼98% of cases. Although some variants have been reported in JAK2 -negative polycythemia, the causal genetic variants remain unidentified in ∼80% of cases. To discover genetic variants in unexplained erythrocytosis, we performed whole exome sequencing in 27 patients with JAK2 -negative polycythemia after excluding the presence of any mutations in genes previously associated with erythrocytosis ( EPOR , VHL , PHD2 , EPAS1 , HBA , and HBB ). We found that the majority of patients (25/27) had variants in genes involved in epigenetic processes, including TET2 and ASXL1 or in genes related to hematopoietic signaling such as MPL and GFIB . Based on computational analysis, we believe that variants identified in 11 patients in this study could be pathogenic although functional studies will be required for confirmation. To our knowledge, this is the largest study reporting novel variants in individuals with unexplained erythrocytosis. Our results suggest that genes involved in epigenetic processes and hematopoietic signaling pathways are likely associated with unexplained erythrocytosis in individuals lacking JAK2 mutations. With very few previous studies targeting JAK2 -negative polycythemia patients to identify underlying variants, this study opens a new avenue in evaluating and managing JAK2 -negative polycythemia.