(including the within-family association and 1000-permuta- tion tests) between any SNPs and the BMD at the lumbar spine and hip, although rs2073438 was associated with the femoral neck BMD in the total-population analysis (P ¼ 0.029) (Table 6). Table 6 P-values of tests for population stratification, total association and within-family association using the QTDT. rs2073438 rs2292350 rs312470 rs434473 rs312462 Tests of population stratification Lumbar spine BMD 0.409 Femoral neck BMD 0.335 Total hip BMD 0.535 BMI 0.110 TFM 0.408 PFM 0.377 TLM 0.989 Test of total association Lumbar spine BMD Femoral neck BMD Total hip BMD BMI TFM PFM TLM 0.683 0.029 0.420 0.146 0.002 0.007 0.331 Test of within-family association Lumbar spine BMD 0.359 Femoral neck BMD 0.826 Total hip BMD 0.892 BMI 0.038 TFM 0.007 PFM 0.012 TLM 0.492 0.170 0.190 0.303 0.569 0.456 0.351 0.206 0.738 0.172 0.851 0.669 0.434 0.668 0.405 0.293 0.585 0.411 0.489 0.283 0.323 0.669 0.558 0.783 0.957 0.828 0.438 0.457 0.817 0.554 0.279 0.405 0.289 0.942 0.758 0.853 0.845 0.479 0.700 0.781 0.608 0.755 0.766 P-value of 1000 permutations of the within-family association Lumbar spine BMD 0.344 0.267 0.812 Femoral neck BMD 0.830 0.628 0.457 Total hip BMD 0.887 0.446 0.705 BMI 0.122 0.599 0.838 TFM 0.033 0.385 0.673 PFM 0.015 0.312 0.754 TLM 0.153 0.696 0.793 Abbreviations: BMD, bone mineral density; BMI, body mass index; PFM, percentage fat mass; QTDT, quantitative transmission disequilibrium test; TFM, total fat mass; TLM, total lean mass. The BMD values are adjusted for age, height and weight. The BMI, TFM and TLM values are adjusted for age. Bold indicates significant P-values (Po0.05). 0.531 0.760 0.828 0.894 0.268 0.135 0.349 0.542 0.081 0.915 0.369 0.472 0.744 0.977 0.399 0.585 0.809 0.624 0.192 0.184 0.474 0.365 0.610 0.832 0.692 0.294 0.163 0.531 0.957 0.923 0.712 0.870 0.751 0.421 0.471 0.501 0.655 0.276 0.929 0.0012 0.001 0.284 0.814 0.909 0.844 0.907 0.049 0.117 0.846 0.770 0.925 0.801 0.927 0.126 0.125 0.854 Test of total association 0.853 0.019 0.353 0.431 0.0001 0.003 0.632 ALOX12 polymorphisms are associated with fat mass in men W-J Xiao et al Relationship of haplotypes and phenotypes We conducted haplotype analyses using genotype data from all five SNPs, and four common haplotypes accounted for 91.8% of the unrelated parents. We further evaluated the association of haplotypes and the peak BMD with the obesity phenotypes using the QTDT. There were 252, 246, 164 and 146 informative families for the TDT analysis at haplotype 1 (AGAGG), haplotype 2 (GAAAG), haplotype 3 (GGGAG) and haplotype 4 (GGAGA), respectively. We failed to find any evidence of population stratification for all haplotypes (P40.05). For the total and within-family associations, a significant association was found between the most common haplotype (haplotype 1) and the TFM and PFM (both Po0.05). Furthermore, haplotype 1 was still significantly associated with the PFM after 1000 permutations (corrected Pc ¼ 0.033), but not with the TFM (corrected Pc ¼ 0.092). The results of the haplotype 1-association analysis are presented in Table 7. In addition, we also investigated the association between haplotype 1 and the BMD and obesity phenotypes in 400 unrelated sons using GLM-ANOVA. The subjects carrying at least one copy of haplotype 1 had a higher TFM and PFM than non-carriers (P ¼ 0.006 and 0.004, respectively). This haplotype accounted for 2.5 and 2.7% of the variation in the TFM and PFM, respectively, in this sample of younger males. However, no significant association was found between any haplotype and the BMI, TLM or peak BMD at any site (data not shown). Discussion To the best of our knowledge, this is the first study to investigate the possible influence of SNPs and haplotypes in the ALOX12 gene on variations in obesity-related pheno- types. Our results showed that the polymorphism rs2073438 of the ALOX12 gene is significantly associated with the TFM and PFM, but not with the BMI or TLM in young men. Furthermore, haplotype-based analyses supported this signi- ficant association from the single-locus analyses. The SNP rs2073438, with a polymorphism of G4T, is located in the Test of within-family association P-value of 1000 permutations of the within-family association 383 Table 7 The QTDT results for the associations between haplotype 1 and phenotypic variations Haplotype 1 (AGAGG) Lumbar spine BMD Femoral neck BMD Total hip BMD BMI TFM PFM TLM Test of population stratification 0.508 0.347 0.630 0.848 0.892 0.721 0.284 0.502 0.835 0.909 0.856 0.021 0.034 0.256 Abbreviations: BMD, bone mineral density; BMI, body mass index; PFM, percentage fat mass; QTDT, quantitative transmission disequilibrium test; TFM, total fat mass; TLM, total lean mass. The BMD values are adjusted for age, height and weight. The BMI, TFM and TLM values are adjusted for age. Bold indicates significant P-values (Po0.05). 0.456 0.840 0.912 0.853 0.092 0.033 0.275 International Journal of Obesity