Assessment of linkage and association of 13 genetic loci with bone mineral density

Abstract

Bone mineral density (BMD), an important risk factor for osteoporosis, is a complex trait likely affected by multiple genes. The linkage and/or association of 13 polymorphic loci of seven candidate genes (estrogen receptor alpha [ERalpha] and beta [ERbeta], calcium-sensing receptor, vitamin D receptor, collagen type 1alpha1, low-density lipoprotein [LDL] receptor-related protein 5 [LRPS], and transforming growth factor beta1) were evaluated in 177 southern Chinese pedigrees of 674 subjects, with each pedigree identified through a proband having a BMD Z score of -1.28 or less at the hip or spine. A suggestive linkage was detected between the IVS1-351A/G polymorphism of ERalpha and spine BMD, and between the 1082G/A, 1730G/A, and D14S1026 polymorphisms of ERbeta and BMD at both spine and hip. The quantitative transmission disequilibrium test (QTDT) detected total family association between 1730G/A of ERbeta and BMD at spine and hip; between D14S1026 of ERbeta and hip BMD; and between the 266A/G and 2220C/T polymorphisms of LRP5 and hip BMD. Similar total family associations were detected when only the females were analyzed. In addition, the IVS1-397T/C polymorphism of ERalpha was associated with spine BMD, and the 266A/G and 2220C/T polymorphisms of LRP5 were associated with femoral neck BMD in the females. A within-family association was detected with the IVS1-397T/C polymorphism of ERalpha, and the 266A/G and 2220C/T polymorphisms of LRP5 in the females. The effect of each polymorphism on BMD variance ranged from 1% to 4%. In conclusion, ERalpha, ERbeta and LRP5 are important candidate genes determining BMD variation, especially in females.

Polymorphisms in the human ALOX12 and ALOX15 genes are associated with peak bone mineral density in Chinese nuclear families

“…This method was also successful in identifying genetic variation associated with BMD [17,18,22]. The within-family test can eliminate the effect of an admixed and stratified population [24,26,27], and 1,000 permutations can be employed to generate the empirical p values required to avoid falsepositive results [10,30]. In addition, our haplotype analyses further support for this association.…”

“…Raw BMD values were adjusted by age, height, and weight as covariates. Permutations (1,000 simulations) were performed to generate the necessary empirical p values and avoid false-positive results from multiple tests [26,27]. Permutation p<0.05 was considered significant in all analyses.…”

Association between VDR and ESR1 gene polymorphisms with bone and obesity phenotypes in Chinese male nuclear families

“…The BMI, fat mass and lean mass were adjusted by age as a covariate. Because false-positive results can be generated in multiple tests (as in the present study) permutations (1000 simulations) were performed to generate the empirical p values to assess the reliability of the results [28][29][30][31] . The QTDT program generates P values for various tests via asymptotic χ 2 distribution.…”

A1330V Variant of the Low-density Lipoprotein Receptorrelated Protein 5 (LRP5) Gene Decreases Wnt Signaling and Affects the Total Body Bone Mineral Density in Japanese Women

“…Q89R was associated with femoral neck BMD in young korean men [23] and pre-and postmenopausal Chinese women [24][25][26]. Q89R was also associated with osteophyte formation in Japanese postmenopausal women [27].…”

“…We also examined the association between the LRP5-A1330V polymorphism and total body BMD osteophyte formation [16][17][18][19][21][22][23][24][25][26][27]. These SnPs included 3 nonsynonymous variations: Q89R, V667M, and A1330V.…”