Chromosome 11q has not only been found to contain mutations responsible for the several Mendelian disorders of the skeleton, but it has also been linked to bone mineral density (BMD) variation in several genome-wide linkage studies. Furthermore, quantitative trait loci (QTL) affecting BMD in inbred mice and baboons have been mapped to a region syntenic to human chromosome 11q. The aim of the present study is to determine whether there is a QTL for BMD variation on chromosome 11q in the Chinese population.
Nineteen microsatellite markers were genotyped for a 75 cM region on 11q13-25 in 306 Chinese families with 1,459 subjects. BMD (g/cm(2)) was measured by DXA. Linkage analyses were performed using the variance component linkage analysis method implemented in Merlin software.
For women, a maximum LOD score of 1.62 was achieved at 90.8 cM on 11q21 near the marker D11S4175 for femoral neck BMD; LOD scores greater than 1.0 were observed on 11q13 for trochanter BMD. For men, a maximum LOD score of 1.57 was achieved at 135.8 cM on 11q24 near the marker D11S4126 for total hip BMD.
We have not only replicated the previous linkage finding on chromosome 11q but also identified two sex-specific QTL that contribute to BMD variation in Chinese women and men.
"Koller et al.  also found linkage of femoral neck BMD and 11q region (LOD 1.15), even so the LOD score had decreased from theirs previous report . This study was also replicated in Chinese women (LOD = 1.62) . These studies suggest chromosome 1q and 11q regions as the regions which can harbor bone maintenance/formation genes. "
[Show abstract][Hide abstract] ABSTRACT: To investigate linkage to chromosome 1q and 11q region for lumbar spine, femoral neck and total body BMD and volumetric BMD in Brazilian sister adolescents aged 10-20-year-old and 57 mothers.
We evaluated 161 sister pairs (n=329) aged 10-20 years old and 57 of their mothers in this study. Physical traits and lifestyle factors were collected as covariates for lumbar spine (LS), femoral neck (FN) and total body (TB) BMD and bone mineral apparent density (BMAD). We selected nine microsatellite markers in chromosome 1q region (spanning nearly 33cM) and eight in chromosome 11q region (spanning nearly 34cM) to perform linkage analysis.
The highest LOD score values obtained from our data were in sister pairs LS BMAD analysis. Their values were: 1.32 (P<0.006), 2.61 (P<0.0002) and 2.44 (P<0.0004) in D1S218, D1S2640 and D1S2623 markers, respectively. No significant LOD score was found with LS and FN BMD/BMAD in chromosome 11q region. Only TB BMD showed significant linkage higher than 1.0 for chromosome 11q region in the markers D11S4191 and D11S937.
Our results provided suggestive linkage for LS BMAD at D1S2640 marker in adolescent sister pairs and suggest a possible candidate gene (LHX4) related to adolescent LS BMAD in this region. These results reinforce chromosome 1q21-23 as a candidate region to harbor one or more bone formation/maintenance gene. In the other hand, it did not repeat for chromosome 11q12-13 in our population.
"There were nonetheless some limitations in this study. Our linkage cohort had sufficient power to detect QTL with large effect size, but not QTL with small effect size (Cheung et al. 2006; Huang et al. 2006). We only have replication data from the European population, despite the fact that the sample size is large. "
[Show abstract][Hide abstract] ABSTRACT: Low bone mineral density (BMD) is a risk factor for osteoporotic fracture with a high heritability. Previous large scale linkage study in Northern Chinese has identified four significant quantitative trait loci (QTL) for BMD variation on chromosome 2q24, 5q21, 7p21 and 13q21. We performed a replication study of these four QTL in 1,459 Southern Chinese from 306 pedigrees. Successful replication was observed on chromosome 5q21 for femoral neck BMD with a LOD score of 1.38 (nominal p value = 0.006). We have previously identified this locus in a genome scan meta-analysis of BMD variation in a white population. Subsequent QTL-wide gene-based association analysis in 800 subjects with extreme BMD identified CAST and ERAP1 as novel BMD candidate genes (empirical p value of 0.032 and 0.014, respectively). The associations were independently replicated in a Northern European population (empirical p value of 0.01 and 0.004 for CAST and ERAP1, respectively). These findings provide further evidence that 5q21 is a BMD QTL, and CAST and ERAP1 may be associated with femoral neck BMD variation.
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Human Genetics 03/2011; 130(4):539-46. DOI:10.1007/s00439-011-0972-2 · 4.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Osteoporosis is a common, complex disease that is influenced by genetic and environmental factors. Although molecular genetic studies have identified several potential regions of linkage, underlying susceptibility gene(s) are largely unknown. Genetic susceptibility to osteoporosis may be both context dependent and developmentally regulated, and epigenetic mechanisms are the likely link between gene and environment. In this paper we will review the status of genetic research into osteoporosis, and present the evidence for gene-environment interaction in its pathogenesis. Finally, the current challenges and future directions of research will be briefly discussed.
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