Association of Genetics and B Vitamin Status With the Magnitude of Optic Disc Edema During 30-Day Strict Head-Down Tilt Bed Rest

Abstract

Importance: Optic disc edema among astronauts after long-duration spaceflight is associated with 1-carbon pathway single-nucleotide polymorphisms and B vitamin status. A recent strict 6° head-down tilt bed rest (HDTBR) study documented development of optic disc edema and increased total retinal thickness in participants exposed to carbon dioxide, 0.5%, for 30 days, but genetic risk factors have not been explored in the cohort.

Objective: To examine whether peripapillary retinal thickness measures obtained from optical coherence tomography images during HDTBR and carbon dioxide, 0.5%, exposure are associated with B vitamin status and single-nucleotide polymorphisms involved in folate-dependent and vitamin B12-dependent 1-carbon metabolism pathways.

Design, setting, and participants: This study was conducted with a cohort of healthy volunteers at the Institute of Aerospace Medicine at the German Aerospace Center in Cologne, Germany. Data collection occurred from October 2017 to November 2017. After a 14-day ambulatory phase without carbon dioxide, participants maintained strict HDTBR with carbon dioxide, 0.5%, for 30 days, followed by a 13-day ambulatory phase without carbon dioxide.

Main outcomes and measures: Blood samples were collected before HDTBR to assess vitamin levels and single-nucleotide polymorphism status. Optical coherence tomographic images were collected before HDTBR; at days 1, 15, and 30 of the resting period; and 6 and 13 days after the period ended. Total retinal thickness was measured from a radial-24 B-scan centered over the optic disc, and global retinal nerve fiber layer thickness was measured from a circle scan. The changes in total retinal thickness and retinal nerve fiber layer thickness were evaluated against the number of risk alleles (defined as 5-methyltetrahydrofolate-homocysteine methyltransferase reductase [MTRR] 66 G and serine hydroxymethyltransferase 1 [SHMT1] 1420C alleles), along with folate, vitamin B6 (pyridoxine), and vitamin B12 (cobalamin) status.

Results: Eleven heathy volunteers (6 men and 5 women) had a mean (SD) age of 33.4 (8.0) years and a mean (SD) body mass index of 23.4 (2.2). After statistical adjustment for B vitamin status, total retinal thickness at the end of HDTBR in participants with 3 or 4 risk alleles was 40 um (SE, 19 μm) greater than in participants with 0 to 2 risk alleles. In addition, the baseline retinal nerve fiber layer thickness was 14 um (SE, 2 μm) greater in those with 3 or 4 risk alleles compared with those with 0 to 2 risk alleles.

Conclusions and relevance: The magnitude of optic disc edema in individuals experiencing HDTBR and exposed to a chronic headward fluid shift in a mild hypercapnic environment was higher in participants with more MTRR 66 G and SHMT1 1420C alleles, even when this finding was statistically adjusted for B vitamin status. These findings may help explain the variability in magnitude of optic disc edema observed during bed rest and spaceflight and thereby improve efforts to counteract this phenomenon.

Conflict of interest statement

Conflict of Interest Disclosures: None reported.

Figures

Figure 1.. Changes in Peripapillary Total Retinal Thickness

A, Change in peripapillary total retinal thickness in participants with 3 or 4 risk alleles (n = 4) or 0 to 2 risk alleles (n = 7), after 1, 15, and 30 days of head-down tilt bed rest and 6 and 13 days of recovery. B, Change in peripapillary total retinal thickness with marginal means adjusted for B vitamin status. In A and B, means are indicated by dots and 95% CIs by bars. All total retinal thickness values for participants with 3 or 4 risk alleles differed significantly from the baseline values for this group, except for on bed rest day 1 (marginal means, bed rest day 1: 2.0 μm [95% CI, −22.9 to 26.8 μm]; day 15, 52.4 μm [95% CI, 23.5-81.3 μm]; P < .001; day 30, 76.5 μm [95% CI, 39.2-113.9 μm]; P < .001; day 6 after bed rest, 66.4 μm [95% CI, 33.3-99.5 μm]; P < .001; day 13 after bed rest, 57.3 μm [95% CI, 28.3-86.3 μm]; P < .001). All total retinal thickness values for those with 0 to 2 risk alleles also differed significantly from the baseline for this group (marginal means: bed rest day 1, 11.6 μm [95% CI, 2.3-20.9 μm]; P = .02; day 15, 26.8 μm [95% CI, 13.5-40.1 μm]; P < .001; day 30, 40.9 μm [95% CI, 17.3-64.6 μm]; P < .001; day 6 after bed rest, 26.8 μm [95% CI, 13.9-39.7 μm]; P < .001; day 13 after bed rest, 19.7 μm [95% CI, 9.6-29.9 μm]; P < .001). Some values for participants with 3 or 4 risk alleles (marginal means, day 6 after bed rest, 66.4 μm [95% CI, 33.3-99.5 μm]; day 13 after bed rest, 57.3 μm [95% CI, 28.3-86.3 μm]) differed significantly from those of participants with 0 to 2 risk alleles (marginal means: day 6 after bed rest, 26.8 μm [95% CI, 13.9-39.7 μm]; P = .04; day 13 after bed rest, 19.7 μm [95% CI, 9.6-29.9 μm]; P = .03). C, Peripapillary retinal nerve fiber layer (RNFL) thickness from 6 days before bed rest began through 13 days after bed rest ended. D, Change in peripapillary retinal nerve fiber layer thickness in the same time range, with marginal means adjusted for B vitamin status. Values for participants with 0 to 2 risk alleles (marginal means: 6 days before bed rest began, 97.7 μm [95% CI, 95.1-100.4 μm]; bed rest day 1, 97.7 μm [95% CI, 95.7-99.8 μm]; day 15, 98.2 μm [95% CI, 95.7-100.6 μm]; day 30, 99.2 μm [95% CI, 96.1-102.4 μm]; 6 days after bed rest, 99.7 μm [95% CI, 96.7-102.7 μm]; 13 days after bed rest, 99.0 μm [95% CI, 96.1-101.9 μm]) were significantly different from those of participants with 3 or 4 risk alleles (6 days before bed rest began, 111.3 μm [95% CI, 106.8-115.9 μm]; bed rest day 1, 111.2 μm [95% CI, 106.8-115.6 μm]; day 15, 116.6 μm [95% CI, 112.8-120.4 μm]; day 30, 121.7 μm [95% CI, 117.0-126.4 μm]; 6 days after bed rest, 121.5 μm [95% CI, 116.6-126.3 μm]; 13 days after bed rest, 120.3 μm [95% CI, 116.9-123.7 μm]; all comparisons, P < .001). All values for the group with 3 to 4 risk alleles also differed significantly from the baseline value for this group (marginal mean, 111.3 μm [95% CI, 106.8-115.9 μm]; all comparisons, P < .001, except at day 15 of bed rest [P = .001]). D shows a difference between the 2 genetic categories at all points as anticipated marginal means adjusted for covariates folate, vitamin B6, and vitamin B12 status (dots), and 95% CIs (bars).

Figure 2.. Depiction of Hypothesized Multihit Mechanism Associating 1-Carbon Pathway Genetics With Ocular Pathologic Conditions

Genetics and B vitamin status could lead to endothelial dysfunction and leaking microvasculature; the resulting edema could block cerebrospinal fluid (CSF) drainage, increasing subarachnoid space (SAS) CSF pressure impinging on the optic nerve and eye., Similarly, uncoupled endothelial nitric oxide synthase (eNOS) yields increased oxidative stressors, including peroxynitrite (ONOO−). Peroxynitrite may affect the elasticity of the lamina cribrosa or sclera, affecting the optic cup shape and rendering some individuals vulnerable to pressure from a headward fluid shift during head-down tilted bed rest or spaceflight. Matrix metalloproteinases (MMPs) are zinc-dependent proteolytic enzymes that degrade extracellular matrix components, including structural components such as collagen and elastin. Most vascular and scleral MMPs are constitutively latent because of the presence of inhibitors, including nitric oxide. Cells in the optic nerve head and sclera have mechanosensory capabilities and respond to hydrostatic pressure by activating MMPs. Additionally, low folate status and higher homocysteine can directly activate MMPs, affect nitric oxide bioavailability and production, cause constrictive vascular remodeling, and reduce arterial compliance. Connective tissue remodeling could lead to changes in elasticity, fluid leakage, and ultimately ophthalmic changes. 5-MTHF indicates 5-methyltetrahydrofolate; 5, 10-MTHF, 5,10-methylenetetrahydrofolate; AGE, advanced glycation end product; BH2, boron dihydride; BH4, tetrahydrobiopterin; CO2, carbon dioxide; DHFR, dihydrofolate reductase; H2O2, hydrogen peroxide; HCY, homocysteine; MTHFR, methylenetetrahydrofolate reductase; MTRR, 5-methyltetrahydrofolate-homocysteine methyltransferase reductase; O2−, superoxide; SAH, S-adenosyl-L-homocysteine; SAM, S-adenosyl methionine; SHMT1, serine hydroxymethyltransferase 1; THF, tetrahydrofolate.