African Mitochondrial DNA Haplogroup L2 is Associated with Slower Decline of β-Cell Function and Lower Incidence of Diabetes Mellitus in non-Hispanic Black Women with HIV

BACKGROUND: Susceptibility to metabolic diseases may be influenced by mitochondrial genetic variability among people living with HIV (PLWH), but remains unexplored in African-ancestry populations. We investigated the association between mitochondrial DNA (mtDNA) haplogroups and beta-cell function (HOMA-B), insulin resistance (HOMA-IR), and incident diabetes mellitus (DM) among black women with or at risk for HIV. METHODS: Women without DM who had fasting glucose (FG) and insulin (FI) data for >/=2 visits were included. Haplogroups were inferred from genotyping data using HaploGrep. HOMA-B and HOMA-IR were calculated using FG and FI. Incident DM was defined by a combination of FG >/=126 mg/dL, use of DM medication, DM diagnosis, or HbA1c >/=6.5%. We compared HOMA-B, HOMA-IR, and incident DM by haplogroups and assessed the association between HOMA-B and HOMA-IR and DM by haplogroup. RESULTS: Of 1288 women (933 HIV+, 355 HIV-), PLWH had higher initial HOMA-B and HOMA-IR than people without HIV (PWOH). PLWH with haplogroup L2 had slower decline in HOMA-B per year (Pinteraction=0.02) and lower risk of incident DM (Hazard Ratio [HR]: 0.51, 95% CI: 0.32, 0.82) than PLWH with other haplogroups after adjustment for age, body mass index, cART use, CD4 cell counts, and HIV RNA. The impact of HOMA-IR on incident DM was less significant in those with haplogroup L2 compared to non-L2 (HR 1.28 [95% CI: 0.70, 2.38] vs 4.13 [95% CI: 3.28, 5.22], pinteraction<0.01) among PLWH. CONCLUSIONS: Mitochondrial genetic variation is associated with beta-cell function, and incident DM in non-Hispanic Black women with HIV and alters the relationship between insulin resistance and DM.