Background
Mitochondrial DNA variation is associated with multiple aging-related comorbidities among people with HIV (PWH). Data on the effect of inherited mitochondrial DNA variants on physical function among PWH are limited.
Methods
We included men with ≥2 visits from the Multicenter AIDS Cohort Study. Gait speed and grip strength were evaluated twice annually using standard methods beginning in 2006. Gait speed was defined as the fastest of 2 attempts over a 4-meter distance. Grip strength was the average across three measures with the dominant hand. We categorized all participants into 7 distinct functionally informed mitochondrial DNA (mtDNA) haplotypes, previously validated in the UK Biobank, annotated based on mtDNA SNPs: MT73, MT7028, MT10238, MT12612, MT1317, and MT15257. Less than 5% of the participants were categorized in the other haplotypes and were not included in the analysis. Mixed effect linear regressions evaluated the association of haplotypes with gait speed and grip strength. Models controlled for principal components of ancestry, common mtDNA haplogroups, baseline age, time, BMI, socioeconomic status, risk behavior (smoking, alcohol, injection drug use), and number of comorbidities.
Results
Of 2314 men (1277 PWH) with 38,913 person-years of follow-up, 26% were Black, 59% White; median age at baseline was 47 years [IQR: 40, 54]. Compared to the reference haplotype (2_2_2_2_2_2 based on the listed mtDNA SNPs), haplotype I was associated with slower gait speed (-0.03 m/s [95% CI: -0.05, -0.01]) and haplotype II, III, IV, and V were associated with faster gait speed (all p<0.05). Compared to the reference haplotype, haplotypes I, IV, and VII were associated with greater grip strength (1.22 kg [95% CI: 0.15, 2.29], 1.16 kg (95% CI: 0.11, 2.21), and 1.70 kg [95% CI: 1.13, 2.28]). The association of haplotypes and gait speed differed by HIV serostatus in haplotype III and VII (Figure, panel A). All haplotypes except haplotype I and VII differed by HIV status for grip strength (Figure, Panel B). Results were consistent in the stratified analyses among European ancestry men.
Conclusions
Functionally informed mtDNA haplotypes were associated with gait speed and grip strength in men. But the direction of these associations varied based on HIV status, indicating that each haplotype has distinct functional implications. Further investigation into the underlying mechanisms of mtDNA variation and its impact on physical function in the context of HIV status is warranted.
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