rs3736228 — LRP5 A1330V

The LRP5 A1330V Variant — Your Genetic Blueprint for Bone Strength

Your bones are living tissue, constantly remodeling themselves in response to stress, hormones, and nutrition. At the heart of this process is the Wnt signaling pathway¹¹ Wnt signaling pathway
a critical cellular communication system that tells bone-forming cells (osteoblasts) when to build new bone. LRP5 (low-density lipoprotein receptor-related protein 5) acts as a co-receptor in this pathway, working alongside Frizzled proteins to transmit Wnt signals into bone cells. The A1330V variant changes a single amino acid at position 1330 from alanine (the common version) to valine (the variant), subtly altering how effectively LRP5 can do its job.

This isn't a defect — it's a natural variation that exists in populations worldwide. About 68% of people have two copies of the alanine version (CC), 24% carry one copy of each (CT), and 3% have two copies of the valine version (TT)²² 68% of people have two copies of the alanine version (CC), 24% carry one copy of each (CT), and 3% have two copies of the valine version (TT). The variant is notably more common in East Asian populations (~26% T allele frequency) than in European populations (~11%).

The Mechanism

The A1330V substitution occurs in exon 18 of the LRP5 gene, within one of the protein's four β-propeller motifs³³ β-propeller motifs
repeating structural elements where most LRP5 ligands bind. Laboratory studies have shown that when cells express the valine version of LRP5, Wnt signaling activity is significantly reduced compared to the alanine version⁴⁴ Wnt signaling activity is significantly reduced compared to the alanine version. Specifically, when researchers transfected cells with LRP5-1330V and activated Wnt signaling, the downstream TCF-Lef transcription activity — the endpoint that turns on bone-building genes — was measurably lower than in cells with normal LRP5.

This dampened signaling means osteoblasts receive a weaker "build bone" message throughout your life. The effect is modest but cumulative: each copy of the T allele is associated with approximately 0.02 g/cm² lower bone mineral density at the lumbar spine⁵⁵ approximately 0.02 g/cm² lower bone mineral density at the lumbar spine, translating to roughly 2-3% lower peak bone mass in TT individuals compared to CC.

The Evidence

The link between rs3736228 and bone health has been replicated extensively. A 2008 Bayesian meta-analysis pooling 16,705 individuals from 10 studies⁶⁶ 2008 Bayesian meta-analysis pooling 16,705 individuals from 10 studies
Tran et al. Association between LRP5 polymorphism and bone mineral density: a Bayesian meta-analysis. BMC Med Genet, 2008 found that people with the CC genotype had significantly higher lumbar spine BMD (mean difference 0.018 g/cm², 95% CI: 0.008-0.028) and femoral neck BMD than those with CT or TT genotypes. The association was consistent across ethnic groups, though effect sizes varied slightly.

More critically, the T allele increases fracture risk. A 2014 meta-analysis of seven case-control studies⁷⁷ 2014 meta-analysis of seven case-control studies
Xu et al. Common polymorphism in the LRP5 gene may increase the risk of bone fracture and osteoporosis. Biomed Res Int, 2014 found T allele carriers had a 30% increased risk of osteoporosis and fractures under most genetic models (OR ~1.3, p<0.01). The effect was seen in both Asian and Caucasian populations.

A landmark 2008 GWAS of over 30,000 individuals⁸⁸ landmark 2008 GWAS of over 30,000 individuals
Richards et al. Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet, 2008 identified rs3736228 as one of the strongest genetic associations with BMD genome-wide, with the T allele reducing lumbar spine BMD (p = 2.6×10⁻⁹) and femoral neck BMD (p = 5.0×10⁻⁶). This wasn't a subtle effect buried in the data — it was one of the most significant signals in the entire genome.

Practical Implications

If you carry one or two copies of the T allele, you're starting with a slightly lower genetic ceiling for bone density. This doesn't doom you to fractures — peak bone mass is only about 60-80% heritable, with lifestyle factors accounting for the rest⁹⁹ peak bone mass is only about 60-80% heritable, with lifestyle factors accounting for the rest. But it does mean you have less margin for error and should prioritize bone health throughout your life, not just after menopause or in old age.

The most modifiable factors are calcium and vitamin D intake, weight-bearing exercise, and avoiding smoking and excessive alcohol¹⁰¹⁰ weight-bearing exercise, and avoiding smoking and excessive alcohol. Calcium provides the raw material for bone, vitamin D enables its absorption, and mechanical stress from exercise stimulates osteoblasts to build bone. The A1330V variant doesn't change how your body responds to these interventions — it just means you need to be more diligent about them.

Interestingly, the effect of this variant may depend on your activity level. The Odense Androgen Study of 783 young men¹¹¹¹ Odense Androgen Study of 783 young men
Saarinen et al. Polymorphisms in the LRP5 gene are associated with peak bone mass in non-sedentary men. Calcif Tissue Int, 2007 found that the A1330V polymorphism was only associated with lower BMD in physically active men, not sedentary men. This suggests the variant may alter how bones respond to mechanical loading¹²¹² the variant may alter how bones respond to mechanical loading, making exercise even more critical if you carry the T allele. A study in Japanese male workers¹³¹³ study in Japanese male workers
Nakamura et al. A1330V polymorphism and bone mineral density in Japanese male workers. Environ Health Prev Med, 2011 found that VV individuals had significantly lower BMD than AA, but exercise (past or current) was independently protective even in those with genetic susceptibility.

For postmenopausal women with the T allele, consider discussing bone density screening (DEXA scan) earlier than standard guidelines suggest¹⁴¹⁴ bone density screening (DEXA scan) earlier than standard guidelines suggest, perhaps starting in your 50s rather than 65. Early identification of low bone mass allows intervention before fractures occur.

Interactions

LRP5 doesn't act alone in determining bone health. Another common variant in the same gene, rs4988321 (V667M), also affects BMD and fracture risk¹⁵¹⁵ rs4988321 (V667M), also affects BMD and fracture risk and is often inherited together with A1330V in certain populations. The two variants may have additive effects on bone density.

Beyond LRP5, genetic variants in genes like SOST (which produces sclerostin, an inhibitor of Wnt signaling), VDR (the vitamin D receptor), and COL1A1 (type I collagen, the main structural protein in bone) also influence bone health. The cumulative effect of multiple genetic variants likely explains why some people develop severe osteoporosis while others maintain strong bones into old age.