Homocysteine and small vessel stroke: A mendelian randomization analysis

Area of Science:

• Genetics and Neurology
• Cardiovascular Disease Research
• Nutritional Science

Background:

• B vitamin therapy trials to reduce total homocysteine (tHcy) for stroke prevention have yielded inconclusive results.
• Epidemiological studies and secondary trial analyses suggest a potential association between tHcy levels and small vessel stroke (SVS).

Purpose of the Study:

• To investigate the selective association of circulating tHcy and B vitamin levels with SVS, distinct from other stroke subtypes.
• To utilize Mendelian randomization to assess genetic predispositions for tHcy and B vitamin levels in relation to stroke subtypes.

Main Methods:

• Employed summary statistics from genome-wide association studies for tHcy, folate, vitamin B6, and vitamin B12.
• Utilized data from the MEGASTROKE consortium, including 16,952 subtyped ischemic stroke cases and 404,630 noncases.

Main Results:

• Genetically predicted tHcy was significantly associated with SVS (OR 1.34 per SD increase), but not large artery or cardioembolic stroke.
• Genetically predicted folate and vitamin B6 levels showed a protective association with SVS (ORs 0.49 and 0.70, respectively).
• No significant association was found between genetically predicted vitamin B12 levels and any stroke subtype.

Conclusions:

• The findings suggest that any stroke-preventive effect of homocysteine-lowering treatments may be specific to the SVS subtype.
• Further research is warranted to explore if genetic variants near MTHFR and MUT genes influence SVS risk through mechanisms beyond homocysteine levels.