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

• Published in: Journal of medical genetics Vol. 43; no. 10; pp. 798 - 803
• Main Authors: Guo, Yan-fang, Xiong, Dong-hai, Shen, Hui, Zhao, Lan-juan, Xiao, Peng, Guo, Yan, Wang, Wei, Yang, Tie-lin, Recker, Robert R, Deng, Hong-wen
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.10.2006; BMJ; BMJ Publishing Group LTD; BMJ Group
• Subjects: Adult; Aged; Biological and medical sciences; BMI; Body Composition; Body Mass Index; Bone density; Child; Confidence intervals; Diabetes; family-based association analysis; FBAT; Female; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; generalised linear model; Genes; Genetic Linkage; Genetics of eukaryotes. Biological and molecular evolution; GLM; haplotype version of FBAT; Haplotypes; HBAT; Humans; LDL-Receptor Related Proteins - genetics; Linkage Disequilibrium; Lipoproteins; Low Density Lipoprotein Receptor-Related Protein-5; low-density lipoprotein receptor-related protein 5 gene; LRP5 gene; MAF; Male; Medical genetics; Medical sciences; Metabolic diseases; Middle Aged; minor allele frequencies; Molecular and cellular biology; Nuclear Family; Obesity; Obesity - genetics; Original; Osteoporosis; percentage of fat mass; PFM; Phenotype; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Sex Characteristics; single-nucleotide polymorphism; SNP; Studies; California; Human; Obesity; Family study; Nutrition disorder; Protein; Lipoprotein LDL; Phenotype; Association; Gene; Genetics; Nutritional status; Polymorphism; Biological receptor
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.2006.041715

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.