rs4855559 — MYH15

MYH15 and Coronary Microvascular Function — A Sex-Specific Risk Variant

The small arteries and capillaries that feed heart muscle — the coronary microcirculation¹¹ coronary microcirculation
vessels less than 500 µm in diameter, responsible for ~70% of total coronary resistance — are increasingly recognized as a distinct site of cardiovascular disease. Unlike the large coronary arteries that atherosclerosis typically affects, microvascular dysfunction operates through impaired vasodilation, excessive vasoconstriction, and structural rarefaction of small vessels. The rs4855559 variant in MYH15 emerged from a systematic genetic screen of 643 patients as a male-specific determinant of this underdiagnosed condition.

The Mechanism

MYH15 encodes myosin heavy chain 15²² myosin heavy chain 15
one of the unconventional class II myosin heavy chains, expressed primarily in extraocular muscles, muscle spindles, and at lower levels in vascular and cardiac tissue. The rs4855559 variant sits within intron 36 of MYH15³³ intron 36 of MYH15
a non-coding region on chromosome 3q13.13, plus-strand position 108,396,189 in GRCh38. As an intronic variant, it does not alter the amino acid sequence of the myosin protein. The likely mechanism is regulatory — altered splicing efficiency, intronic enhancer disruption, or expression-level effects⁴⁴ regulatory — altered splicing efficiency, intronic enhancer disruption, or expression-level effects
the T allele is in linkage disequilibrium with other MYH15 variants previously associated with myocardial infarction and maladaptive cardiac remodeling.

Why myosin heavy chain biology would influence coronary microvascular tone is not yet fully characterized. Candidate mechanisms include altered contractile properties of vascular smooth muscle cells lining small coronary arteries⁵⁵ vascular smooth muscle cells lining small coronary arteries
smooth muscle myosin isoform composition affects vasoconstrictor tone and myogenic reactivity, and indirect effects on cardiomyocyte contractility that alter microvascular perfusion pressure. The pronounced sex-specificity of the association — present in men, absent in women — suggests interaction with androgen-dependent cardiovascular regulatory pathways, though this remains speculative.

The Evidence

Yoshino et al. (2014)⁶⁶ Yoshino et al. (2014)
Single nucleotide polymorphisms associated with abnormal coronary microvascular function. Coron Artery Dis 2014;25(4):281-9 conducted the largest candidate-gene study of coronary microvascular dysfunction to date: 643 patients referred for cardiac catheterization without significant obstructive coronary disease. Coronary flow reserve (CFR) was measured by intracoronary adenosine injection⁷⁷ Coronary flow reserve (CFR) was measured by intracoronary adenosine injection
CFR below 2.5 defined abnormal microvascular function, a widely used clinical threshold. Of 184 patients with abnormal CFR (36 men, 148 women), rs4855559-T was associated with OR 2.27 for abnormal CFR in men (p=0.0029), with a highly significant sex interaction (p=0.0008). In women, the association was null (OR 1.22, p=0.22).

A companion MYH15 variant, rs7630352⁸⁸ rs7630352
a second intronic variant in moderate linkage disequilibrium with rs4855559, showed an even larger effect in men (OR 2.60, p=0.0006). The convergence of two independent MYH15 variants on the same male-specific phenotype strengthens the biological signal.

A 2024 systematic review of genetic determinants of coronary microvascular dysfunction⁹⁹ 2024 systematic review of genetic determinants of coronary microvascular dysfunction
Stein et al., J Am Heart Assoc 2024; surveying 30 SNPs across 22 genes from the available literature confirmed that MYH15 variants are among the most consistently replicated loci and noted their prior association with myocardial infarction and maladaptive remodeling. Separately, a large genome-wide association study (n>28,000 European-ancestry participants) by Purves et al. (2019)¹⁰¹⁰ Purves et al. (2019)
A major role for common genetic variation in anxiety disorders. Mol Psychiatry 2020 found rs4855559-T genome-wide significantly associated with lifetime anxiety disorder (beta=0.12 decrease on a continuous anxiety scale, p=4×10⁻⁸). Whether this reflects shared autonomic regulation between cardiac and anxiety pathways, or independent pleiotropic effects, is unknown.

Evidence is classified as emerging: the CFR association derives from a single candidate-gene study with a modest sample of men (n=36 with CMD), and has not yet been replicated in an independent cohort with similar methodology. The anxiety GWAS is genome-wide significant but identifies correlation, not causation.

Practical Actions

Men carrying one or two T alleles at rs4855559 have approximately double the odds of measurable coronary microvascular dysfunction. Because CMD frequently presents as angina with no obstructive coronary disease — a pattern more common in women but underdiagnosed in men — awareness of this genetic predisposition should lower the threshold for physiological testing if symptoms arise. Coronary flow reserve can be assessed non-invasively using cardiac PET or echocardiography with pharmacological stress¹¹¹¹ Coronary flow reserve can be assessed non-invasively using cardiac PET or echocardiography with pharmacological stress
these tests quantify microvascular vasodilatory capacity without catheterization.

Microvascular dysfunction responds to interventions targeting endothelial health. Nitrate-rich vegetables (beetroot, arugula, spinach) raise plasma nitrite and support NO-mediated vasodilation¹²¹² Nitrate-rich vegetables (beetroot, arugula, spinach) raise plasma nitrite and support NO-mediated vasodilation
particularly relevant when endothelial NOS function is impaired in CMD. Phosphodiesterase inhibitors and ACE inhibitors have shown benefit in small CMD trials. Given the overlap between CMD and anxiety neurobiology implicated by the GWAS data, autonomic modulation strategies may also be relevant.

Interactions

The rs4855559 association concentrates in men and interacts multiplicatively with sex (interaction p=0.0008). This marks rs4855559 as one of the few cardiovascular risk variants with a robust, formally tested sex-by-genotype interaction. A second MYH15 intronic variant, rs7630352, appears to act in the same direction with a larger effect size (OR 2.60 in men); individuals carrying T alleles at both variants may face compounded microvascular risk, though this has not been formally tested in a compound genotype analysis.