Faculty Collaboration Database

Polymorphisms of the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with obesity phenotypes in a large family-based association study. J Med Genet 2006 Oct;43(10):798-803

Date

05/26/2006

Pubmed ID

16723389

Pubmed Central ID

PMC1829485

DOI

10.1136/jmg.2006.041715

Scopus ID

2-s2.0-33750458964 (requires institutional sign-in at Scopus site)   104 Citations

Abstract

BACKGROUND: The low-density lipoprotein receptor-related protein 5 (LRP5) gene, essential for glucose and cholesterol metabolism, may have a role in the aetiology of obesity, an important risk factor for diabetes.

PARTICIPANTS AND METHODS: To investigate the association between LRP5 polymorphisms and obesity, 27 single-nucleotide polymorphisms (SNPs), spacing about 5 kb apart on average and covering the full transcript length of the LRP5 gene, were genotyped in 1873 Caucasian people from 405 nuclear families. Obesity (defined as body mass index (BMI) >30 kg/m(2)) and three obesity-related phenotypes (BMI, fat mass and percentage of fat mass (PFM)) were investigated.

RESULTS: Single markers (12 tagging SNPs and 4 untaggable SNPs) and haplotypes (5 blocks) were tested for associations, using family-based designs. SNP4 (rs4988300) and SNP6 (rs634008) located in block 2 (intron 1) showed significant associations with obesity and BMI after Bonferroni correction (SNP4: p<0.001 and p = 0.001, respectively; SNP6: p = 0.002 and 0.003, respectively). The common allele A for SNP4 and minor allele G for SNP6 were associated with an increased risk of obesity. Significant associations were also observed between common haplotype A-G-G-G of block 2 with obesity, BMI, fat mass and PFM with global empirical values p<0.001, p<0.001, p = 0.003 and p = 0.074, respectively. Subsequent sex-stratified analyses showed that the association in the total sample between block 2 and obesity may be mainly driven by female subjects.

CONCLUSION: Intronic variants of the LRP5 gene are markedly associated with obesity. We hypothesise that such an association may be due to the role of LRP5 in the WNT signalling pathway or lipid metabolism. Further functional studies are needed to elucidate the exact molecular mechanism underlying our finding.

Author List

Guo YF, Xiong DH, Shen H, Zhao LJ, Xiao P, Guo Y, Wang W, Yang TL, Recker RR, Deng HW

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Body Composition
Body Mass Index
Child
Female
Genetic Linkage
Haplotypes
Humans
LDL-Receptor Related Proteins
Linkage Disequilibrium
Low Density Lipoprotein Receptor-Related Protein-5
Male
Middle Aged
Nuclear Family
Obesity
Phenotype
Polymorphism, Genetic
Polymorphism, Single Nucleotide
Sex Characteristics