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/m2) 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.
- BMI, body mass index
- FBAT, family-based association analysis
- GLM, generalised linear model
- HBAT, haplotype version of FBAT
- LRP5 gene, low-density lipoprotein receptor-related protein 5 gene
- MAF, minor allele frequencies
- PFM, percentage of fat mass
- SNP, single-nucleotide polymorphism
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Published Online First 24 May 2006
↵* These two authors contributed equally to this work.
Funding: This work was partially supported by grants from NIH (R01 AR050496, K01 AR02170-01, R01 AR45349-01 and R01 GM60402-01A1) and an LB595 grant from the State of Nebraska. The study also benefited from grants from the National Science Foundation of China, Huo Ying Dong Education Foundation, HuNan Province, Xi’an Jiaotong University and the Ministry of Education of China.
Competing interests: None declared.