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From SNPedia

Geno Mag Summary
(C;C) 0 normal
(C;T) 1.3 increased risk for osteoporosis
(T;T) 1.7 increased risk for osteoporosis
ReferenceGRCh38 38.1/141
is asnp
is mentioned by
dbSNP (classic)rs3736228
1000 genomesrs3736228
GWAS Ctlgrs3736228
Max Magnitude1.7
CPMC Logo.png

This SNP has been recognized by the Coriell Personalized Medicine Collaborative ICOB.
Additional information is available here

? (C;C) (C;T) (T;T) 28

rs3736228 is a SNP in the LRP5 gene that is also known as Ala1330Val or A1330V; the more common (C) allele encodes the Ala (alanine), while the rarer (T) allele encodes the Val (valine), which is the risk allele.

rs3736228(T) is associated with vertebral fractures and reduced bone mineral density (BMD), with an overall odds ratio for fractures of 1.06 per allele (CI: 1.01-1.12; 7802 fractures among 31,199 individuals studied). More specifically, the rs3736228(T) allele was associated with reduced lumbar spine BMD (p = 2.6 x 10-9), and femoral neck BMD (p = 5.0 x 10-6).[PMID 18349089OA-icon.png]

Note that rs4988321, another LRP5 SNP (also known as Val667Met), was independently associated with BMD in this same study.[PMID 18349089OA-icon.png]

news rs3736228 was associated with a 30% increase in the risk of both osteoporosis and osteoporotic fractures. Both increases were significant, at P=0.002 and P=0.008, respectively.

[PMID 18455228OA-icon.png] rs3736228 associated with decreased bone mineral density (p=6.3x10(-12) for lumbar spine and p=1.9x10(-4) for femoral neck) and an increased risk of both osteoporotic fractures (odds ratio [OR] 1.3, 95% CI 1.09-1.52, p=0.002) and osteoporosis (OR 1.3, 1.08-1.63, p=0.008).

rs4355801 associated with decreased bone mineral density (p=7.6x10(-10) for lumbar spine and p=3.3x10(-8) for femoral neck) and increased risk of osteoporosis (OR 1.2, 95% CI 1.01-1.42, p=0.038).

The presence of both risk alleles increased the risk of osteoporotic fractures (OR 1.3, 1.08-1.63, p=0.006) and this effect was independent of bone mineral density.

A later study (2009) also found an association between rs3736228 and hip BMD; subjects with rs3736228(T;T) genotypes had 8.4% higher total-hip BMD compared to other genotypes (p = 0.009) at baseline in a study of 249 osteoporotic Caucasian men.[PMID 19148563]

SNP rs3736228
PubMedID [PMID 18455228OA-icon.png]
Condition Bone mineral density
Gene LRP5
Risk Allele T
pValue 6.00E-012
OR 0.13
95% CI NR) SD decreas

[PMID 20146170] Association of LPR5 Polymorphism with Bone Mass Density and Cholesterol Level in Population of Chinese Han

[PMID 20960157] A polymorphism near osteoprotegerin gene confer risk of obesity in Uyghurs

[PMID 21876774OA-icon.png] Association analysis of canonical Wnt signalling genes in diabetic nephropathy

[PMID 16723389OA-icon.png] Polymorphisms of the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with obesity phenotypes in a large family-based association study.

[PMID 17137849OA-icon.png] Genetic variation at the low-density lipoprotein receptor-related protein 5 (LRP5) locus modulates Wnt signaling and the relationship of physical activity with bone mineral density in men.

[PMID 17903296OA-icon.png] Genome-wide association with bone mass and geometry in the Framingham Heart Study.

[PMID 18058054OA-icon.png] Polymorphisms in the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with peak bone mass in non-sedentary men: results from the Odense androgen study.

[PMID 18588671OA-icon.png] Association between LRP5 polymorphism and bone mineral density: a Bayesian meta-analysis.

[PMID 19181680OA-icon.png] Common variants in the region around Osterix are associated with bone mineral density and growth in childhood.

[PMID 19629617OA-icon.png] Replication study of candidate genes/loci associated with osteoporosis based on genome-wide screening.

[PMID 20072603OA-icon.png] Genome-wide association study identifies ALDH7A1 as a novel susceptibility gene for osteoporosis.

[PMID 20534768OA-icon.png] OPG and RANK polymorphisms are both associated with cortical bone mineral density: findings from a metaanalysis of the Avon longitudinal study of parents and children and gothenburg osteoporosis and obesity determinants cohorts.

[PMID 20554715] Analysis of recently identified osteoporosis susceptibility genes in Han Chinese women.

[PMID 21432225OA-icon.png] A1330V polymorphism of the low-density lipoprotein receptor-related protein 5 gene and bone mineral density in Japanese male workers.

GWAS snp
PMID [PMID 22504420OA-icon.png]
Title Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
Risk Allele T
P-val 2E-26
Odds Ratio 0.0800 None

[PMID 23054017] The joint effect of cigarette smoking and polymorphisms on LRP5, LEPR, near MC4R and SH2B1 genes on metabolic syndrome susceptibility in Taiwan

[PMID 24130145] Polymorphism of LRP5, but not of TNFRSF11B, is associated with a decrease in bone mineral density in postmenopausal maya-mestizo women

[PMID 24482712OA-icon.png] Association of LRP5 gene polymorphism with type 2 diabetes mellitus and osteoporosis in postmenopausal women

[PMID 23242660] Association of LRP5 haplotypes with osteoporosis in Mexican women.

[PMID 25232223OA-icon.png] LRP5 polymorphism-A potential predictor of the clinical outcome in advanced gastric cancer patients treated with EOF regimen

[PMID 27582019OA-icon.png] Low density lipoprotein receptor-related protein 5 gene polymorphisms and osteoporosis in Thai menopausal women.

Risk Rs3736228(T;T)
Alt Rs3736228(T;T)
Reference Rs3736228(C;C)
Significance Non-pathogenic
Disease not specified
Variation info
Gene LRP5
CLNDBN not specified
Reversed 0
HGVS NC_000011.9:g.68201295C>T
CLNACC RCV000242123.2,