Mitochondrial DNA Haplogroups, Biomarkers of Inflammation and Immune Activation, and Risk of Diabetes in Veterans With and Without Human Immunodeficiency Virus.

Yan A, Kundu S, Samuels DC, Bailin S, Xu K, So-Armah K, Butt AA, Gerschenson M, Goetz MB, Doyle M, Tracy R, Marconi VC, Justice A, Freiberg M, Koethe JR, Hulgan T. Mitochondrial DNA Haplogroups, Biomarkers of Inflammation and Immune Activation, and Risk of Diabetes in Veterans With and Without Human Immunodeficiency Virus. The Journal of Infectious Diseases. 2025 Dec 20; 232(6):e1003-e1011, DOI: 10.1093/infdis/jiaf304.

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Abstract:

BACKGROUND: Type 2 diabetes mellitus (DM) is common among people with human immunodeficiency virus (HIV). We previously reported that DM risk was greater in women of African ancestry with HIV who had mitochondrial DNA (mtDNA) haplogroup L3. We examined haplogroup associations with DM and selected soluble and cellular immune biomarkers among people with HIV (PWH) and those without HIV in the Veterans Aging Cohort Study (VACS) Biomarker Cohort. METHODS: VACS participants had mtDNA haplogroups determined from genome-wide genotyping and adjudicated DM outcomes. Serum interleukin 6, D-dimer, and soluble CD14 were quantified, and cellular phenotyping was performed by flow cytometry, on blood collected during 2005-2007. Analyses included logistic and Cox regression of prevalent and incident DM, stratified by self-reported ancestry and HIV status, and adjusted for selected covariates. RESULTS: mtDNA haplogroups, soluble and/or cellular biomarkers, and DM outcomes were available for 2019 participants (65% with HIV; 68% non-Hispanic Black; 95% male). Among 781 Black PWH, mtDNA haplogroup L3 (40%) was associated with incident DM (hazard ratio, 1.56 [95% confidence interval, 1.01-2.40]) adjusting for covariates including senescent (CD28-) CD4+ T cells, which were lower in Black PWH having haplogroup L3 versus other African haplogroups (P = .05). No other haplogroups were associated with DM. There were no significant associations observed in Veterans without HIV, although the effect size was similar. CONCLUSIONS: mtDNA haplogroup L3 was associated with incident DM in predominantly male non-Hispanic Black PWH, replicating an association reported previously. This haplogroup was associated with fewer senescent CD4+ T cells, but the association with DM was independent of T-cell phenotype.