Genome-wide Copy-Number-Variation Study Identified a Susceptibility Gene, UGT2B17, for Osteoporosis

Abstract

Osteoporosis, a highly heritable disease, is characterized mainly by low bone-mineral density (BMD), poor bone geometry, and/or osteoporotic fractures (OF). Copy-number variation (CNV) has been shown to be associated with complex human diseases. The contribution of CNV to osteoporosis has not been determined yet. We conducted case-control genome-wide CNV analyses, using the Affymetrix 500K Array Set, in 700 elderly Chinese individuals comprising 350 cases with homogeneous hip OF and 350 matched controls. We constructed a genomic map containing 727 CNV regions in Chinese individuals. We found that CNV 4q13.2 was strongly associated with OF (p = 2.0 x 10(-4), Bonferroni-corrected p = 0.02, odds ratio = 1.73). Validation experiments using PCR and electrophoresis, as well as real-time PCR, further identified a deletion variant of UGT2B17 in CNV 4q13.2. Importantly, the association between CNV of UGT2B17 and OF was successfully replicated in an independent Chinese sample containing 399 cases with hip OF and 400 controls. We further examined this CNV's relevance to major risk factors for OF (i.e., hip BMD and femoral-neck bone geometry) in both Chinese (689 subjects) and white (1000 subjects) samples and found consistently significant results (p = 5.0 x 10(-4) -0.021). Because UGT2B17 encodes an enzyme catabolizing steroid hormones, we measured the concentrations of serum testosterone and estradiol for 236 young Chinese males and assessed their UGT2B17 copy number. Subjects without UGT2B17 had significantly higher concentrations of testosterone and estradiol. Our findings suggest the important contribution of CNV of UGT2B17 to the pathogenesis of osteoporosis.

A Novel Polymorphism in a Forkhead Box A1 (FOXA1) Binding Site of the Human UDP Glucuronosyltransferase 2B17 Gene Modulates Promoter Activity and Is Associated with Altered Levels of Circulating Androstane-3α,17β-diol Glucuronide

“…This supposition was not supported by our genotyping and analyses of samples from a large Australian population-based case-control study of prostate cancer, and adds to the evidence in other published studies that do not find a link between UGT2B17 expression and prostate cancer risk (Gallagher et al, 2007;Olsson et al, 2008). UGT2B17 has been identified a susceptibility gene for osteoporosis (Yang et al, 2008). The basic findings of this study were that persons with two alleles of UGT2B17 were at higher risk for osteoporosis than those homozygous for the deletion of this gene.…”

“…First described by Murata et al (2003), this deletion, in the homozygous state, leads to substantially reduced levels of urinary testosterone glucuronide (Jakobsson et al, 2006;Juul et al, 2009) and, to a lesser extent, serum androstane-3␣,17␤-diol-17-glucuronide (Swanson et al, 2007). The deletion seems to be a predictor of fat mass and insulin sensitivity in men (Swanson et al, 2007) and is associated with susceptibility for osteoporosis (Yang et al, 2008). The UGT2B17 gene deletion has also been associated with risk of prostate cancer (Park et al, 2006(Park et al, , 2007Karypidis et al, 2008), although studies showing no association have also been reported (Gallagher et al, 2007;Olsson et al, 2008).…”

Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics

“…Between these two extremes may lie those CNVs that are capable of acting as predisposing (or protective) factors in relation to complex disease [Fanciulli et al, 2010]. Thus, for example, a 117 kb deletion encompassing the UDP glucuronosyltransferase 2 family, polypeptide B17 (UGT2B17) gene (MIM] 601903) has been found to be associated with an increased risk of osteoporosis [Yang et al, 2008b]. Intriguingly, some germline CNVs appear to predispose to disease even although no known genes reside within their boundaries Thean et al, 2010].…”

Effect of Dose and 5α‐Reductase Inhibition on the Circulating Testosterone Metabolite Profile of Men Administered Oral Testosterone

“…In particular, UGT2B17 is the major testosterone‐glucuronidation enzyme. UGT2B17 is of interest as it is highly polymorphic and copy number variations in its genes are associated with multiple potentially testosterone related pathologies (e.g., obesity,17 prostate cancer,18 osteoporosis,19 ankylosing spondylitis,20 and endometrial cancer) 21. UGT2B17 is highly expressed in the intestines and the liver 22, 23.…”