Association of oestrogen receptor alpha gene polymorphisms with postmenopausal bone loss, bone mass, and quantitative ultrasound properties of bone.

BACKGROUND: The gene encoding oestrogen receptor alpha (ESR1) appears to regulate bone mineral density (BMD) and other determinants of osteoporotic fracture risk. OBJECTIVE: To investigate the relation between common polymorphisms and haplotypes of the ESR1 gene and osteoporosis related phenotypes in a population based cohort of 3054 Scottish women. RESULTS: There was a significant association between a common haplotype "px", defined by the PvuII and XbaI restriction fragment length polymorphisms within intron 1 of the ESR1 gene, and femoral neck bone loss in postmenopausal women who had not received hormone replacement therapy (n = 945; p = 0.009). Annual rates of femoral neck bone loss were approximately 14% higher in subjects who carried one copy of px and 22% higher in those who carried two copies, compared with those who did not carry the px haplotype. The px haplotype was associated with lower femoral neck BMD in the postmenopausal women (p = 0.02), and with reduced calcaneal broadband ultrasound attenuation (BUA) values in the whole study population (p = 0.005). There was no association between a TA repeat polymorphism in the ESR1 promoter and any phenotype studied, though on long range haplotype analysis subjects with a smaller number of TA repeats who also carried the px haplotype had reduced BUA values. CONCLUSIONS: The ESR1px haplotype is associated with reduced hip BMD values and increased rates of femoral neck bone loss in postmenopausal women. An association with BUA may explain the fact that ESR1 intron 1 alleles predict osteoporotic fractures by a mechanism partly independent of differences in BMD.

Association of PLOD1 polymorphisms with bone mineral density in a population-based study of women from the UK.

The PLOD1 gene is situated within a quantitative trait locus for regulation of bone mineral density (BMD) on chromosome 1p36 and is a strong functional candidate for the regulation of BMD and bone quality. PLOD1 encodes the enzyme procollagen-lysine, 2-oxoglutarate 5-dioxegenase (lysyl hydroxylase; EC 1.14.11.4), which catalyses the hydroxylation of lysine residues during the posttranslational modification of type I collagen, the major protein of bone. We investigated the role of PLOD1 as a genetic determinant of osteoporosis by studying two coding polymorphisms located in exon 3 of the PLOD1 gene in relation to BMD and bone loss in a population-based cohort of 678 Scottish women. We observed a significant association between lumbar spine (LS) BMD and a polymorphism at nucleotide 386 (G386A) of PLOD1, which results in an alanine-threonine amino acid change at codon 99 (A99T). Heterozygotes for G386A had significantly reduced LS-BMD when compared with the other genotype groups, and the difference remained significant after correcting for confounding factors. A similar association was observed between LS-BMD and a conservative polymorphism at position 385 (C385T), but this was in strong linkage disequilibrium (LD) with G386A. There was no evidence for an allele dose effect for either polymorphism, and the strongest association was observed in heterozygotes. No association was found between PLOD1 alleles and femoral-neck BMD or bone loss, but the hydroxylysylpyridinoline to lysylpyridinoline ratio was significantly increased in G386A heterozygotes compared with other genotype groups, suggesting a functional effect of this polymorphism on enzyme activity. Our findings show that heterozygosity for the A99T variant of PLOD1 is associated with reduced LS-BMD and an altered ratio of hydroxylysylpyridinoline to lysylpyridinoline. Whilst further studies will be required to confirm and extend these observations, our studies raise the possibility that A99T heterozygosity might affect lysyl hydroxylase function and regulate bone mass.

Type II benign osteopetrosis (Albers-Schönberg disease) caused by a novel mutation in CLCN7 presenting with unusual clinical manifestations.

A 16-year-old male patient with type II autosomal dominant benign osteopetrosis (ADO) was genotyped and found to harbor a novel mutation in exon 25 of the gene encoding for the osteoclast-specific chloride channel, CLCN7, inherited from the father, who was asymptomatic. The patient had normal biochemical findings and acid-base balance, except for increased serum levels of creatine kinase, lactic dehydrogenase, and the bone formation markers bone alkaline phosphatase isoenzyme, osteocalcin and N-terminal type I collagen telopeptide/creatinine ratio. Unusual generalized osteosclerosis was observed together with a canonical increase in vertebral and pelvis bone mass. An affected first grade cousin presented with normal biochemical findings and a milder osteosclerotic pattern of the pelvis. At the cellular level, cultured osteoclasts from the patient showed increased motility, with lamellipodia, membrane ruffling and motile pattern of podosome distribution, all of which could have contributed to functional impairment of bone resorption. The present report documents a novel mutation of the CLCN7 gene causing osteopetrosis in a radiologically uncertain form of the diseases, with apparent incomplete penetrance.