Genetic Variation in Sex Hormone Genes Influences Heel Ultrasound Parameters in Middle-Aged and Elderly Men: Results From the European Male Aging Study (EMAS)

Abstract

Genes involved in sex hormone pathways are candidates for influencing bone strength. Polymorphisms in these genes were tested for association with heel quantitative ultrasound (QUS) parameters in middle-aged and elderly European men. Men 40-79 yr of age were recruited from population registers in eight European centers for the European Male Aging Study (EMAS). Polymorphisms were genotyped in AR, ESR1, ESR2, CYP19A1, CYP17A1, SHBG, SRD5A2, LHB, and LHCGR. QUS parameters broadband ultrasound attenuation (BUA) and speed of sound (SOS) were measured in the heel and used to derive BMD. The relationships between QUS parameters and polymorphisms were assessed using linear regression adjusting for age and center. A total of 2693 men, with a mean age of 60.1 ± 11.1 (SD) yr were included in the analysis. Their mean BUA was 80.0 ± 18.9 dB/Mhz, SOS was 1550.2 ± 34.1 m/s, and BMD was 0.542 ± 0.141 g/cm 2 . Significant associations were observed between multiple SNPs in a linkage disequilibrium (LD) block within CYP19A1, peaking at the TCT indel with the deletion allele associating with reduced ultrasound BMD in heterozygotes (b =20.016, p = 20.005) and homozygotes (b = 20.029, p = 0.001). The results for BUA and SOS were similar. Significant associations with QUS parameters were also observed for the CAG repeat in AR and SNPs in CYP17A1, LHCGR, and ESR1. Our data confirm evidence of association between bone QUS parameters and polymorphisms in CYP19A1, as well as modest associations with polymorphisms in CYP17A1, ESR1, LHCGR, and AR in a population sample of European men; this supports a role for genetically determined sex hormone actions in influencing male bone health.

Effect of Polymorphisms in Selected Genes Involved in Pituitary-Testicular Function on Reproductive Hormones and Phenotype in Aging Men

“…Only minor effects of this polymorphism on circulating T and E 2 levels are apparent, reaching statistical significance with large sample sizes. We have reported previously from the EMAS cohort associations of the AR exon 1 CAG repeat polymorphism with endocrine and metabolic parameters (23), and of AR exon 1 CAG repeat and other polymorphisms with heel ultrasound parameters (8). Other genes with polymorphisms associated with androgen and/or estrogen levels in men include SHBG (28), CYP17 (29), CYP19A1 (30), 17␤HSD5 (31), and uridine diphosphate glucuronyltransferase 2B7 (UGT2B7) (32), but many potentially important polymorphic influences have apparently not yet been identified.…”

“…Genotyping of the SHBG repeat, SRD5A2 repeat, and the CYP19A1 indel was described previously (8). Genotyping of V-LHB was based on differential immunoreactivity of wild-type (WT) and V forms of LH in serum samples, as described before (9).…”

“…All SNPs were in HardyWeinberg equilibrium (P Ͼ 0.01). Subject characteristics have been partly published before (7,8,23) and are presented in Supplemental Table 1, published on The Endocrine Society's Journals Online web site at http:// jcem.endojournals.org.…”

Genetics of osteoporosis: accelerating pace in gene identification and validation

“…In vitro functional analyses suggested that rs1062033, which is located »12 kb upstream of the translation initiation site, represents a true regulatory polymorphism (Riancho et al 2009). Finally, signiWcant associations were observed between multiple SNPs in a LD block within CYP19A1 with reduced ultrasound BMD and bone strength in middleaged and elderly men (Limer et al 2009). …”

“…The hypothesis that this SNP may aVect gene expression by creating a Sp1 binding site (Carey et al 1994) was not supported by in vitro studies (Nedelcheva Kristensen et al 1999). Several studies have analyzed whether this SNP is associated with osteoporosis, but they have yielded inconsistent results Limer et al 2009;Somner et al 2004;Tofteng et al 2004a;Valero et al 2005;Yamada et al 2005b;Zarrabeitia et al 2007;Zmuda et al 2001). Here, we focus on the three studies that analyzed >1,000 subjects.…”