ORIGINAL ARTICLE

Polymorphisms of the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with obesity phenotypes in a large family-based association study

Yan-fang Guo^2,*, Dong-hai Xiong^3,*, Hui Shen⁴, Lan-juan Zhao³, Peng Xiao³, Yan Guo³, Wei Wang², Tie-lin Yang², Robert R Recker³, Hong-wen Deng¹

¹ Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, Hunan, P R China
² Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, P R China
³ Osteoporosis Research Center, Department of Biomedical Sciences, Creighton University, Omaha, Nebrasksa, USA
⁴ Departments of Orthopedic Surgery and Basic Medical Sciences, University of Missouri–Kansas City, Kansas City, Missouri, USA

Correspondence to:
H-W Deng
Departments of Orthopedic Surgery and Basic Medical Sciences, University of Missouri–Kansas City, 2411 Holmes Street, Room M3-C03, Kansas City, MO 64108-2792, USA;dengh{at}umkc.edu

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.

Abbreviations: 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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