rs3900940 — MYH15 T1105A

MYH15 and Coronary Risk — An Emerging but Uncertain Link

Myosin heavy chains are the molecular motors that drive muscle contraction. The MYH gene family encodes 15 isoforms, each specialized for different muscle types: cardiac myosins power the heart, skeletal myosins drive limb movement, and a handful of unconventional isoforms serve more specialized roles. MYH15 falls into this last group. Expressed primarily in extraocular muscles (which control eye movement) and muscle spindles¹¹ muscle spindles
proprioceptive sensory organs embedded in skeletal muscle, it is not a classic cardiac or smooth muscle myosin. Yet genetic studies from the mid-to-late 2000s flagged rs3900940 in MYH15 as a possible contributor to coronary heart disease risk — a finding that remains intriguing but incompletely explained.

The Mechanism

rs3900940 lies on chromosome 3 at position 108,428,881 (GRCh38). Because MYH15 is transcribed from the minus strand, the plus-strand reference allele T corresponds to a coding-strand A at position 3313 of the transcript (NM_014981.3). The alternate C allele on the plus strand produces a coding-strand G, changing codon 1105 from Thr (ACT) to Ala (GCT) — the p.Thr1105Ala substitution. Threonine at position 1105 sits in the C-terminal tail domain²² C-terminal tail domain
the region of myosin heavy chain responsible for filament assembly and interaction with other structural proteins. Replacing a polar, phosphorylatable threonine with a nonpolar alanine could in principle alter filament packing or post-translational regulation, but the functional consequence of this specific substitution has not been directly characterized.

How a variant in an extraocular/spindle myosin might influence coronary disease risk is mechanistically unclear. One hypothesis: MYH15 may have low-level expression in vascular smooth muscle or coronary endothelium that has been missed by bulk transcriptomic surveys but contributes to vessel wall mechanics. A 2014 study found that intronic MYH15 variants associate with abnormal coronary flow reserve in men³³ intronic MYH15 variants associate with abnormal coronary flow reserve in men
Yoshino et al., Coronary Artery Disease 2014 with odds ratios of 2.27–2.60, the authors noting that "further studies are needed to clarify how MYH15 might be involved in vascular biology." Another possibility is that rs3900940 is in linkage disequilibrium with a nearby causal variant in a different gene. Given the limited mechanistic work, the association currently rests on epidemiological evidence without a confirmed molecular pathway.

The Evidence

The original genetic risk signal emerged from prospective cohort work. Bare et al. (2007)⁴⁴ Bare et al. (2007) examined five genetic variants in the Atherosclerosis Risk in Communities (ARIC) cohort of 9,129 white adults. Participants carrying the highest-risk combination of all five variants (including rs3900940) had a 57% increased hazard for incident coronary heart disease (HR 1.57, 95% CI 1.21–2.04, P = 0.001). However, individual effect estimates for rs3900940 were not reported separately in the published paper — the variant was evaluated only as part of a combined polygenic score, limiting interpretation of its independent contribution.

The stroke connection came from the Vienna Stroke Registry. Luke et al. (2009)⁵⁵ Luke et al. (2009) tested CHD-linked SNPs in 562 stroke cases and 815 controls, finding that rs3900940 in MYH15 was among those associated with noncardioembolic stroke: OR 1.31 (90% CI 1.07–1.60). Noncardioembolic stroke includes large-artery atherosclerotic stroke and small-vessel disease — phenotypes that share pathophysiological features with coronary atherosclerosis. The same group extended this analysis to the Cardiovascular Health Study, finding that rs3900940's prespecified risk allele showed nominal association with ischemic stroke in white participants (one-sided P < 0.05), though this study specifically flagged seven SNPs including MYH15 without providing individual ORs for each.

The coronary microvascular angle comes from a 2014 candidate-gene study of 643 patients evaluated for coronary flow reserve (CFR). Yoshino et al.⁶⁶ Yoshino et al. found that two intronic MYH15 variants (rs4855559 and rs7630352, distinct from rs3900940) showed striking male-specific associations with impaired CFR (OR ≈ 2.3–2.6, SNP-sex interaction P < 0.001) with no significant signal in women. This sex-specific pattern suggests MYH15 may interact with androgen-driven vascular biology, but rs3900940 was not among the variants tested in that study.

Taken together, the evidence is consistent but not strong. Multiple small-to-medium studies point in the same direction, but the variant has never been a standalone genome-wide significant hit, effect sizes are modest, and the biological mechanism connecting an extraocular myosin to coronary risk is unresolved. The evidence level is therefore emerging rather than moderate or strong.

Practical Actions

The modest, replicated association between rs3900940 and coronary/stroke risk means that CC homozygotes have a somewhat elevated probability of atherosclerotic cardiovascular disease. The effect size (OR ~1.3 for one copy of the risk allele) is comparable to many common cardiovascular risk variants — meaningful at a population level, modest at an individual level. The most actionable implication is that CC carriers should prioritize surveillance of established cardiovascular risk factors (LDL, blood pressure, glucose) rather than treating this variant as a high-penetrance finding.

TC heterozygotes carry an intermediate risk. The variant appears to act additively, with each copy of the C allele contributing approximately proportionally to risk.

Interactions

rs3900940 was originally evaluated alongside four other variants — rs20455 in KIF6, rs7439293 in PALLD, rs2298566 in SNX19, and rs1010 in VAMP8 — in a combined genetic risk score for coronary heart disease. When all five risk alleles are present, the combined effect (HR 1.57) exceeds what any single variant contributes. This multi-variant interaction context suggests that rs3900940 may be most informative when interpreted in conjunction with these co-validated CHD risk markers.