| Osteoporosis is a serious healthy disease, which is characterized by low bone mineral density (BMD) and deterioration of skeletal microarchitecture, leading to increased risk of fragility fracture. Low BMD is recognized as a major risk factor for osteoporotic fracture (OF). A large number of studies used BMD as the major surrogate phenotype for osteoporotic fracture. BMD is a quantitative trait determined by genetic and environmental factors, with heritability estimates ranging from 50% to 90%. Bone size (BS) is also another risk factor for OF independent of BMD, and also is under strong genetic determination. Using traditional association analysis, transmission disequilibrium test (TDT) and also by genotyping RFLP and microsatellite marker, the present study was performed to test the complex relationship of nine bone candidate genes with osteoporosis related phenotypes. Then microarray was performed to test the differential expression RNA between two groups with high BMD and low BMD. Our results showed as follows: 1)Using program QTDT, significant within-family association (via TDT) between the - 1997 G/T polymorphism of COL1A1 gene with BMD variation at all the hip sites were found (p < 0.05) in 1,263 subjects from 402 Chinese nuclear families, consisted of bothparents and at least one healthy female offspring aged from 20 to 45 years. The amount of BMD variation explained by the - 1997G/T polymorphism was 1.6%, 2.0%, 1.2% and 1.3% at the total hip, femoral neck, trochanter and intertrochanter, respectively. 2^Population stratification, total-family association, andrwithin-family association were performed between BMDs at the spine and hip and the (GT)n marker in the intron 1 of the COL1A& gene and the (AAAG)n marker in the P3 promoter of PTHR1 gene in 388 nuclear families composed of both parents and at least one healthy daughter with a total of 1, 220 individuals. Significant within-family association was found between the M(G1) i2 haplotype and trochanter BMD (p < 0. 001) . Individuals with this haplotype have, on average, 9. 53% lower trochanter BMD than the non-carriers. Suggestive evidence of the within-family association was detected between the (GT)i7 allele and BMD at the spine (p = 0.012), hip (p = 0.011), femoral neck (p = 0.032), trochanter (p = 0.023), and intertrochanter {p = 0. 034).3 )A total of 258 unrelated healthy Chinese men aged 50-80 years were genotyped the Msp I, Hind III, BsrB I, Sac I and BstB I markers in C0L1A2, BGP, IL-6, AHSG and PTH genes, respectively. Significant association of the AHSG gene with the spine BMD (p - 0. 006), even after adjusting for multiple testing in our study.Carriers of 1*1 and 2*2 genotypes of AHSG gene had, â– respectively, ~5. 1% and ~~8. 1% higher spine BMD than those of 1*2 genotype. For the other four genes, no evidence of association was found (p > 0.10). No significant evidence of gene-by-gene interaction was found by two-way factorial ANOVA on the BMD variation.4 population stratification, total-family association, andwithin-family association were used to test the relationship of BS (at the spine and hip) and height with Pvull and Xbal polymorphisms in the intron 1 of the gene and the Mspl and (GT)n markers in the intron 47 and intron 1 of the C0L1A2 gene in 400 Chinese nuclear families with a total of 1,256 individuals. Weak within-family association was found between the C0LlA2-ifepI {p = 0. 05) and the femoral neck BS, between the ER-a-PJ (p = 0. 04) and the intertrochanter BS, and between the COL1A2-(GT) n (p= 0. 02), COL1A2-/?(GT) n (/?= 0.009) and height. Subsequent permutation tests generally confirmed the suggestive within-family association. For the weak within-family association, the proportions of phenotypic variance accounted by the C0LlA2-ifepI, ER-a~PX, CQLlk2-(GT)n, C0L1A2-JZ?(ï¿¡#i7markers were 1.50%, 1.51%, 2.15%, and 2.43% for the corresponding phenotypes.5 population stratification, total-family association, andwithin-family association were used to test the relationship of the Apal, Eco31I, BstBl and (AAAG)n polymorphisms in the vitamin D receptor (VDR), collagen type I a 1 (C0L1A1), parathyroid hormone (PTH), and parathyroid hormone (PTH)/PTH~related peptide receptor (PTHR1) genes with the variation of bone size (BS) and â– height in 400 Chinese nuclear families with a total of 1,256 individuals. We did not detect any significant within-family association and total-family association between the VDR, COL1A1,â– ?PTH and PTHR1 gene polymorphisms, and the variations of BS and height in our sample.6)0n RNA level, we used microarray of affymetrix to analysis thedifferential expression of nine bone candidate genes between two?groups with extremely high and low peak bone mass (PBM). Theresults from t^test detected no significant differentialexpressions of these genes were found in the present sample.Based on the complex determination for osteoporosis relatedphenotypes, the present study represented the first effort onidentify the complex relationship of nine bone candidate genes andosteoporosis related phenotypes from two gene expression levels inChinese.
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