Osteoporosis and obesity are two complex diseases that are prevalent in the United States. Obesity is a condition of excess body fat that exacerbates several major public health problems. Osteoporosis is a skeletal disease characterized by a reduction in bone mass. The relationship between obesity and osteoporosis has long been investigated. It is a widely held dogma that interventions lowering the risk of obesity may generally result in higher risk for osteoporosis. It is also believed that increasing body weight is related to higher bone mass and thus lower risk for osteoporosis. However, previous analyses generally confounded total body weight, of which the majority is skeletal muscle, with fat mass measurement for obesity. Also, the prior analyses did not duly control for increased mechanical loading due to larger total body weight in increasing bone mass. In this project I analyzed data collected from both China and USA. Whole body fat mass, lean mass, body mass index (BMI), and bone mass were measured in two samples: 1,988 unrelated Chinese subjects and 4,489 subjects from 512 Caucasian pedigrees. I first evaluated the Pearson correlation, then dissected the phenotypic correlations into genetic and environmental components with bone mass unadjusted or adjusted for body weight (to control for its mechanical loading effects on bone mass). I discovered that in both Chinese and Caucasians fat mass and BMI were, phenotypically, positively correlated with weight-unadjusted bone mass, in agreement with the dogma. However, when bone mass was adjusted for body weight, the phenotypic correlation (including its genetic and environmental components) between fat mass and bone mass turned out to be negative. These results indicate that when the mechanical loading effect of body weight on bone mass is adjusted for, increased fat mass is actually associated with decreased bone mass, both genetically and environmentally. Thus, in contrast to the dogma, my results show that both genetic and environmental factors that tend to decrease risk for obesity may also decrease risk for osteoporosis. In light of the above findings and previous reports that RANK (receptor activator of nuclear factor-KB) is expressed in skeletal muscles which are important for energy metabolism, I hypothesized that RANK, a gene essential for osteoclastogenesis, is a pleiotropic gene for both osteoporosis and obesity. I first performed a linkage analysis in a genomic region of ~80 cM around the RANK gene in 4,087 Caucasian subjects from 482 pedigrees using 9 microsatellite markers. I then genotyped 19 SNPs in or around the RANK gene in 405 nuclear families with 1,873 individuals. A family-based association test (FBAT) was performed with both quantitative measures of obesity (fat mass, lean mass and BMI and a dichotomously defined obesity phenotype - OB (OB if BMI >30 kg/m2). Empirical'global P values were derived from 10,000 permutations and reported as follows. In the linkage analysis, an empirical P=0.004 was achieved at the location of the RANK gene for BMI. Family based association analysis revealed significant associations of six SNPs (SNP1 (rs4941125), SNP2 (rs7235803), SNP4 (rs8086340), SNP7 (rsl 1664594), SNP10 (rs4303637) and SNP16 (rs884205)) with at least one obesity-related phenotype (P<0.01). Evidence of association was obtained at SNP10 (P=0.002) and SNP16 (P=0.001) with OB; SNP1 with fat mass (P=0.003), SNP1 (P=0.003) and SNP7 (P=0.003) with lean mass, SNP1 (/M).002) and SNP7 (P-0.002) with BMI. SNP1, SNP2, and SNP16 showed consistent associations across all obesity-related phenotypes (P<0.05). In addition, significant results were observed for markers SNP4 and SNP7 with all the quantitative traits (P<0.05). The analyses of the common haplotypes containing the six SNPs provide further association evidence. In conclusion, for the first time, my results suggest that RANK is a novel candidate gene for obesity.
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