Is a gene important for bone resorption a candidate for obesity? An association and linkage study on the RANK (receptor activator of nuclear factor-κB) gene in a large Caucasian sample

Abstract

In light of findings that osteoporosis and obesity may share some common genetic determination and previous reports that RANK (receptor activator of nuclear factor-κB) is expressed in skeletal muscles which are important for energy metabolism, we hypothesize that RANK, a gene essential for osteoclastogenesis, is also important for obesity. In order to test the hypothesis with solid data we first performed a linkage analysis around the RANK gene in 4,102 Caucasian subjects from 434 pedigrees, then we genotyped 19 SNPs in or around the RANK gene. A family-based association test (FBAT) was performed with both a quantitative measure of obesity [fat mass, lean mass, body mass index (BMI), and percentage fat mass (PFM)] and a dichotomously defined obesity phenotype-OB (OB if BMI ≥ 30 kg/m 2 ). 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 eight SNPs with at least one obesity-related phenotype (P < 0.05). 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 (P = 0.002) and SNP7 (P = 0.002) with BMI; SNP1 (P = 0.003), SNP4 (P = 0.007), and SNP7 (P = 0.002) with PFM. In order to deal with the complex multiple testing issues, we performed FBAT multi-marker test (FBAT-MM) to evaluate the association between all the 18 SNPs and each obesity phenotype. The P value is 0.126 for OB, 0.033 for fat mass, 0.021 for lean mass, 0.016 for BMI, and 0.006 for PFM. The haplotype data analyses provide further association evidence. In conclusion, for the first time, our results suggest that RANK is a novel candidate for determination of obesity.

Human Cardiovascular Disease IBC Chip-Wide Association with Weight Loss and Weight Regain in the Look AHEAD Trial

“…Links between change in weight and bone mass density are well described and further highlight reciprocal pathways of influence in adipose and bone [46]. RANK has been associated with percentage fat mass in animal linkage studies [49] and body mass index in humans [50]. Our results provide support for a novel role for the RANK - RANK ligand-OPG pathway in adipose tissue response to a lifestyle intervention in addition to their well-established role in bone.…”

Polymorphisms in the interleukin-6 receptor gene are associated with bone mineral density and body mass index in Spanish postmenopausal women

“…This is not the first time that polymorphisms in a gene are related simultaneously to osteoporosis and obesity. For example, genes such as IL6 and RANK, both participating in bone resorption, were associated with BMD and with BMI (41)(42)(43). Although it is generally considered that obese women are at lower risk of osteoporosis, there are some controversial results that question this assumption (44).…”

TNFRSF11A and TNFSF11 are associated with age at menarche and natural menopause in white women

“…The study participants were recruited from the metropolitan area of Omaha, NE as described previously 40. The study protocol was approved by the institutional review board of Creighton University.…”