Mitochondrial DNA variation associated with gait speed decline among older HIVinfected non-hispanic white males October 2 nd, 2017 Jing Sun, Todd T. Brown, David C. Samuels, Todd Hulgan, Gypsyamber D Souza, Beth D. Jamieson, Kristine Erlandson, Jeremy Martinson, Steven Wolinsky, Joseph Margolick, Gregory D. Kirk, Jennifer A. Schrack
Background Some studies suggested physical function decline may be accelerated in HIV+ Gait speed is a component of frailty and predictor of functional decline, hospitalization, disability & deaths among older adults Among men who have sex with men in the Multicenter AIDS Cohort Study (MACS), HIV+ has a faster decline in gait speed compared to HIV- Mitochondrial function may be important to changes in physical function among people aging with HIV Schrack, JAIDS, 2015; Piggott, J Gerontol, 2015; Erlandson, Current HIV/AIDS, 2014, Studenski, JAMA, 2011
Mitochondrial Genetic Variation and Haplogroups Mitochondrial genetic variation has been associated with frailty and mortality in general population Mitochondrial DNA haplogroups represent major branch points on the mitochondrial phylogenetic tree (maternal ancestry) mtdna haplogroups are race-specific. Haplogroup has been associated with aging & disease risk in HIV population AIDS progression (haplogroup J & U5a) Metabolic disorders Neurocognitive Impairment Moore, PlosONE, 2010; Hendrickson, AIDS, 2008; Holzinger, J Nerovirol, 2012; Micheloud, JAIDS, 2011; Hulgan, CID, 2015
Objective Evaluate the effect of common European mtdna haplogroups on functional (gait speed) decline among aging HIV+ white men.
Methods Study population: Multicenter AIDS Cohort Study(Baltimore/Washington DC, Chicago, Pittsburgh, and Los Angeles) has recruited MSM with and without HIV since 1984 Participants are seen at semi-annual visits. Sample Selection: 455 white HIV+ males aged over 50 (included due to GWAS and gait speed data availability) Study visit between October 1 st, 2007 and September 30 th, 2016
Methods Measurements Gait Speed: time to walk 4 meters at usual pace measured semi-annually; Gait speed calculated as meters/second (m/s). Slow gait: <1 m/s mtdna haplogroups: extracted from GWAS data through multiple genotyping panels in MACS, haplogroup determined by HaploGrep. Four primary groups were defined: H, J, T, Uk, and others. HIV disease state: diagnosis with AIDS, log10 of HIV viremia copy-year Other: sociodemographic, cigarette smoking, detectable HCV RNA, peripheral neuropathy Cesari, J Am Geriatr Soc, 2005; Schrack, JAIDS, 2015; Cole, Am J Epidemiol, 2010
Statistical Methods Descriptive: Fisher s Exact test & ANOVA Longitudinal: Rate of gait speed decline: random effects mixed linear models Probability of slow gait (<1.0 m/s): mixed effects logistic regression models Covariates: HCV infection, AIDS diagnosis, viremia copy year, college education, smoking, peripheral neuropathy.
Cohort Baseline Characteristics Overall H J T UK Others Overall (%) 455 188 (41.3) 44 (9.7) 53 (11.7) 108 (23.7) 62 (13.6) Age, mean, year (SD) College degree (%) Ever Smoking (%) HCV infection (%) CD4+ count, cells/mm3, (SD) HIV virally suppressed (%) Peripheral Neuropathy (%) Gait speed, m/s, (SD) 52.9 (4.6) 52.4 (4.4) 52.8 (3.6) 52.8 (4.6) 53.0 (5.5) 53.7 (3.7) 267 (58.7) 100 (53.2) 26 (59.1) 34 (64.2) 69 (63.9) 38 (61.3) 307 (70.7) 119 (68.0) 34 (79.1) 42 (79.3) 72 (68.6) 40 (69.0) 75 (16.5) 29 (15.4) 6 (13.6) 16 (30.2) 16 (14.8) 8 (12.9) 561.4 552.5 558.7 601.4 577.5 530.6 (27.9) (29.2) (27.9) (29.7) (28.4) (21.7) 316 (69.5) 129 (68.6) 28 (63.6) 39 (73.6) 72 (66.7) 48 (77.4) 170 (37.4) 70 (37.2) 16 (36.4) 19 (35.8) 44 (40.7) 16 (35.6) 1.15 (0.19) 1.13 (0.17) 1.07 (0.21) 1.20 (0.21) 1.20 (0.23) 1.19 (0.19) Baseline gait speed: J: 1.07 m/s vs. non-j: 1.18 m/s (p=0.003)
Scatter Plots and Predicted Gait Speed over Age of 50 by Haplogroup J
Walk Speed over Time by Common European Haplogroups Adjusted estimation* Slope (m/s/year) SE P J*age -0.006 0.003 0.017 gait speed -0.011 0.001 <0.001 (Non-J) gait speed -0.017 0.003 <0.001 (group J) H*age 0.002 0.002 0.27 gait speed -0.012 0.001 <0.001 (Non-H) Gait speed -0.010 0.001 <0.001 (group H) T*age 0.0002 0.002 0.92 Gait speed -0.012 0.001 <0.001 (Non-T) Gait speed -0.011 0.002 <0.001 (group T) Uk*age 4.97e-06 0.002 0.997 Gait speed (Non-Uk) Gait speed (group Uk) -0.012 0.001 <0.001-0.012 0.002 <0.001 All slopes of gait speed decline over time were significant across all groups. The interaction between haplogroup and age was only significant in the model with haplogroup J *Models adjusted for HCV infection, AIDS diagnosis, viremia copy year, college education, smoking, peripheral neuropathy.
Adjusted Predictions of Gait Speed Decline by Haplogroup J with 95% CIs
Effect of Haplogroup J on Odds of Slow Gait Speed over Time after Age of 50 in MACS Crude estimation Adjusted estimation * OR 95% CIs P OR 95% CIs P Haplogroup J 3.35 2.37-8.86 0.015 2.73 1.08-6.91 0.034 Age 1.15 1.11-1.21 <0.001 1.14 1.09-1.19 <0.001 HCV 1.39 0.58-3.35 0.456 History with AIDS 1.90 1.01-3.57 0.046 Viremia copy year 1.29 1.05-1.58 0.015 College degree 0.33 0.18-0.59 <0.001 Ever smoke 1.09 0.88-1.35 0.42 Peripheral neuropathy 1.31 0.99-1.73 0.058 *Models adjusted for HCV infection, AIDS diagnosis, viremia copy year, college education, smoking, peripheral neuropathy.
Limitations and Strengths Limitations Unclear if findings are generalizable to women The haplogroups are specific to Caucasians Small sample size for haplogroup J Limited information about visits after age of 67 among haplogroup J Strengths First study to evaluate mtdna genetic & physical function in HIV population Used validated repeated measurement of gait speed Controlled for HIV disease state through various methods
Conclusions mtdna haplogroup J was associated with more rapid decline of gait speed and higher risk of having slow gait speed compared to other groups over age 50. These findings suggest the difference in mtdna haplogroup may be predictive of mitochondrial function and present a potential pathway to understand the pathophysiology of physical function decline in an HIV population. Investigation into the relationship between mt genetic variation and changes in physical function could bring insights toward development of novel medications or management strategies to promote healthy aging among PLWHIV.
Acknowledgements Collaborators & mentors: Todd Brown Gregory Kirk Jennifer Schrack David Samuels Todd Hulgan Technique & data supports: MACS data center Johns Hopkins Institute for Clinical & Translational Research Funding: Data in this manuscript were collected by the Multicenter AIDS Cohort Study (MACS) with centers at Baltimore (U01-AI35042); Chicago (U01-AI35039); Los Angeles (U01-AI35040); Pittsburgh (U01-AI35041); and the Data Coordinating Center (UM1-AI35043). The MACS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), with additional co-funding from the National Cancer Institute (NCI), National Institute for Drug Abuse (NIDA), and the National Institute for Mental Health (NIMH). Targeted supplemental funding for specific projects was also provided by the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute on Deafness and Communication Disorders (NIDCD). MACS data collection is also supported by UL1-TR000424 (JHU CTSA). This work was also supported by the JHU CFAR (1P30AI094189). K24 AI120834 to TB, R21 DK101342 to TH/TB, K01AG048765 to JAS
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Backup slides
Illumina Human Hap 550 171 SNPs 498 individuals Illumina 1MDuo 121 SNPs 263 individuals Illumina 1M 158 SNPs 806 individuals TaqMan 32 SNPs 1536 individuals Preliminary QC in Plink: Heterozygous mitochondrial SNPs were set to missing SNPs strands were checked and flipped to match mitochondrial reference Reformatting: Check whether platform used Yoruba mitochondrial reference sequence Translated position numbers to rcrs as necessary Identified reference and alternate allele alleles in each SNP Reformatted data for HaploGrep Identified SNP genotyping list for each individual Identified variants from rcrs present in each individual Identify haplogroups using HaploGrep Checked haplogroup concordance on duplicated samples 1,865 individuals 18 Failed haplogroup 17 Discordant haplogroup
Walk Speed over Time by Common European Haplogroups Crude estimation Adjusted estimation* Coef. SE P Coef. SE P J*age -0.006 0.003 0.026-0.006 0.003 0.017 gait speed -0.012 0.001 <0.001-0.011 0.001 <0.001 (Non-J) gait speed -0.017 0.003 <0.001-0.017 0.003 <0.001 (group J) H*age 0.001 0.002 0.48 0.002 0.002 0.27 gait speed -0.013 0.001 <0.001-0.012 0.001 <0.001 (Non-H) Gait speed -0.011 0.001 <0.001-0.010 0.001 <0.001 (group H) T*age 0.00001 0.002 0.996 0.0002 0.002 0.92 Gait speed -0.012 0.001 <0.001-0.012 0.001 <0.001 (Non-T) Gait speed -0.012 0.002 <0.001-0.011 0.002 <0.001 (group T) Uk*age -0.0005 0.002 0.78 4.97e-06 0.002 0.997 Gait speed (Non-Uk) Gait speed (group Uk) -0.012 0.001 <0.001-0.012 0.001 <0.001-0.013 0.001 <0.001-0.012 0.002 <0.001
Effect of haplogroup J on gait speed over time after age of 50 Rate of gait decline by independent variables Crude estimation Adjusted estimation * Coef. SE P Coef. SE P Intercept 1.21 0.012 <0.001 1.28 0.034 <0.001 J*age (per year after age of 50) -0.006 0.003 0.026-0.006 0.003 0.017 Age (Non-J) -0.012 0.001 <0.001-0.011 0.001 <0.001 Age (group J) -0.017 0.003 <0.001-0.017 0.003 <0.001 HCV - - - -0.016 0.023 0.48 Ever diagnosed with AIDS - - - -0.049 0.017 0.004 Viremia copy - - - -0.013 0.006 0.024 year education - - - 0.072 0.017 <0.001 Ever smoke - - - -0.008 0.006 0.167 Peripheral neuropathy - - - -0.017 0.006 0.008
Rate of gait speed decline by HIV+ and HIV- in MACS N = 2,205 HIV+ HIV- 973 1,052 21,187 person visits
Kaplan Meier Survival Curve for slow gait speed by HIV status in MACS Censor = gait speed <1.0 m/s Log Rank Test: p < 0.001 Adjusted HR: 1.57 (1.29 1.92)