International Journal of Obesity (2011) 35, 378–386 & 2011 Macmillan Publishers Limited All rights reserved 0307-0565/11 www.nature.com/ijo ORIGINAL ARTICLE ALOX12 polymorphisms are associated with fat mass but not peak bone mineral density in Chinese nuclear families W-J Xiao, J-W He, H Zhang, W-W Hu, J-M Gu, H Yue, G Gao, J-B Yu, C Wang, Y-H Ke, W-Z Fu and Z-L Zhang Department of Osteoporosis, Metabolic Bone Disease and Genetic Research Unit, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China Objective: Arachidonate 12-lipoxygenase (ALOX12) is a member of the lipoxygenase superfamily, which catalyzes the incorporation of molecular oxygen into polyunsaturated fatty acids. The products of ALOX12 reactions serve as endogenous ligands for peroxisome proliferator-activated receptor g (PPARG). The activation of the PPARG pathway in marrow-derived mesenchymal progenitors stimulates adipogenesis and inhibits osteoblastogenesis. Our objective was to determine whether polymorphisms in the ALOX12 gene were associated with variations in peak bone mineral density (BMD) and obesity phenotypes in young Chinese men. Methods: All six tagging single-nucleotide polymorphisms (SNPs) in the ALOX12 gene were genotyped in a total of 1215 subjects from 400 Chinese nuclear families by allele-specific polymerase chain reaction. The BMD at the lumbar spine and hip, total fat mass (TFM) and total lean mass (TLM) were measured using dual-energy X-ray absorptiometry. The pairwise linkage disequilibrium among SNPs was measured, and the haplotype blocks were inferred. Both the individual SNP markers and the haplotypes were tested for an association with the peak BMD, body mass index, TFM, TLM and percentage fat mass (PFM) using the quantitative transmission disequilibrium test (QTDT). Results: Using the QTDT, significant within-family association was found between the rs2073438 polymorphism in the ALOX12 gene and the TFM and PFM (P ¼ 0.007 and 0.012, respectively). Haplotype analyses were combined with our individual SNP results and remained significant even after correction for multiple testing. However, we failed to find significant within-family associations between ALOX12 SNPs and the BMD at any bone site in young Chinese men. Conclusions: Our present results suggest that the rs2073438 polymorphism of ALOX12 contributes to the variation of obesity phenotypes in young Chinese men, although we failed to replicate the association with the peak BMD variation in this sample. Further independent studies are needed to confirm our findings. International Journal of Obesity (2011) 35, 378–386; doi:10.1038/ijo.2010.157; published online 10 August 2010 Keywords: ALOX12; fat mass; lean mass; peak bone mineral density; quantitative transmission disequilibrium test Introduction It was once thought that osteoporosis and obesity were unrelated,1 but there is accumulating evidence confirming their association in recent decades. Weight is a major determinant of bone mineral density (BMD); subjects who are overweight or obese have a relatively higher BMD, and Correspondence: Professor Z-L Zhang, Department of Osteoporosis, Meta- bolic Bone Disease and Genetic Research Unit, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600 Yi-Shan Road, Shanghai 200233, People’s Republic of China. E-mail: ZZL2002@medmail.com.cn Received 16 March 2010; revised 8 June 2010; accepted 24 June 2010; published online 10 August 2010 weight loss is associated with an increased risk of osteo- porotic fracture.2,3 With aging, bone mass is reduced, whereas adipocyte volume in bone marrow is increased.4 Both osteoporosis and obesity have strong genetic components, as the heritability of obesity is estimated at 40–60%,5 and 60–80% of the variance in BMD is genetically determined.6 In addition, both osteoblasts and adipocytes are derived from mesenchymal stem cells. Extensive data have shown that both adipogenesis and osteogenesis share multiple common genetic factors and signaling pathways, such as vitamin D receptor, peroxisome proliferator-activated receptor g (PPARG), transforming growth factor-b and Wnt pathways.1,7,8. Mean- while, adipocytes can secrete estrogen, leptin and inflamma- tory cytokines to influence bone metabolism.9 Therefore,