Test of linkage and/or association of genes and bone mineral density in Chinese

Abstract

Bone mineral density (BMD), one of the major determinants of osteoporosis and fracture risk, is a complex trait with a heritability estimate that ranges from 50% to 90%. Linkage and/or association of 14 loci of 8 candidate genes were evaluated in 177 southern Chinese pedigrees with 674 subjects (each pedigree was identified through a proband having BMD Z score <-1.28 at the hip or spine) by the quantitative trait locus transmission disequilibrium test (QTDT). The candidate genes studied include estrogen receptor alpha (ERα) and beta (ERβ), calcium sensing receptor (CASR), vitamin D receptor (VDR), collagen type Iα1 (COLIA1), LDL receptor-related protein 5 (LRP5), transforming growth factor β1 (TGFβ1) and parathyroid hormone receptor (PTHR). Nucleotide (nt) Ivs1-397T/ C (Pvu II genotype) and Ivs1-351G/A (Xba I genotype) of ERα; 1082A/G (Rsa I genotype), 1730G/A (Alu I genotype) and CA repeat polymorphism (D14s1026) of ERβ; CA repeat polymorphism of CASR; 2T/C (Fok I genotype) of VDR; -1363 C/G and -1997 T/G of COLIA1; 266 A/G, 2220 C/T and 3989 C/T of LRP5; 29 T/C of TGFβ1 and D3S1289 (which is closely related to the PTHR gene) were analyzed. BMD values were adjusted for sex, age, height and weight. For the total association, D14s1026 genotypes of ERβ were associated with femoral neck and total hip BMD (both p<0.05); D3S1289 (which is closely related to the PTHR gene) was associated with trochanter BMD (p<0.02) and total hip BMD (p<0.03). For within-family association, D14s1026 genotypes of ERβ were associated with femoral neck and total hip BMD (both p<0.05); D3S1289 was associated with trochanter BMD (p<0.02) and total hip BMD (p<0.03). For linkage analysis of all pedigree, Ivs1-351G/A genotype of ERα was in linkage with L1-4 BMD (p<0.05); 1082A/G, 1730G/A and D14s1026 genotypes of ERβ were linkage with L1-4 (p<0.05) and femoral neck BMD (p<0.03); ERβ 1082A/G and D14s1026 genotypes of ERβ were linkage with total hip BMD (p<0.05). These data suggested that ERα and ER beta gene might play a modulatory role in determining bone mineral density in our population. Further mapping studies are required to determine the genetic association of D3S1289 with BMD.