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Genetic advances in osteoporosis: What's next?

Elvira Manzano
16 Oct 2017
Prof Peter Ebeling

Osteoporosis is an age-related complex disease with a strong genetic component. However, the genes responsible for the disease remain poorly defined, says an expert at AFOS 2017.

“The 95 genes/loci identified in the largest genome-wide association study (GWAS) to date can only explain 5.8 percent of the genetic contribution to bone mineral density [BMD] variability,” said Professor Peter Ebling from the Department of Medicine at the School of Clinical Sciences, Monash University, Australia. As for the majority of the candidate genes identified from GWAS, additional biological evidence of their involvement in bone fragility still lacks, opening up an opportunity for more research.

In one study, EN1, a low frequency non-coding genetic variant near a novel locus, was identified and found to have an effect size that is fourfold larger than the mean of previously reported common variants for lumbar spine BMD. EN1 was also associated with a decreased fracture risk (odds ratio [OR], 0.85). In an EN1 mouse model, conditional loss of EN1 resulted in low bone mass, likely due to high bone turnover. [Nature 2015;526:112-117]

Other genes have been identified through studies of rare monogenic disorders affecting the bone, namely COL1A1/COL1A2 and 13 other genes in osteogenesis imperfecta; SEC24D and P4HB in Cole-Carpenter syndrome; FKBP10, PLOD2 in Bruck syndrome; CLCN7, TNFSF11, and 5 other genes in osteopetrosis; CTSK in pycnodysostosis; SOST in sclerosteosis and van Buchem disease, LRP5 in high bones mass syndrome and osteoporosis-pseudoglioma syndrome, and NOTCH2 in Hadju-Cheney syndrome, said Ebeling.

Search for candidate genes continues

The search for the genetic basis of extreme cases of nonsyndromic idiopathic osteoporosis has also led to the identification of several genes LRP5, DKK 1, WNT3A linked to juvenile osteoporosis, LRP5, MTHFR to pregnancy and lactation-associated osteoporosis, PLS3 to X-linked osteoporosis, and WNT1 to early-onset autosomal dominant osteoporosis. [Arch Endocrinol Metab 2016;60:391-401] 

“As for atypical femur fractures [AFF], genetic factors may also play an important role in the pathogenesis of the disease,” said Ebeling. “The association of AFF with seven rare monogenic bone diseases, including that linked with the COL1A1/COL1A2, CTSK, PLS3 and LRP5 genes, supports this concept.”

A pilot study using an exome array in 13 patients with AFF and 268 controls identified a greater number of rare gene variants in AFF cases vs controls. “However, analyses were restricted to the variants with minor allele frequencies less than 3 percent, which limited the ability to make meaningful inferences about individual variants,” he added.

A recent whole exome sequencing (WES) study in 3 sisters who developed AFF while taking bisphosphonates and 3 unrelated AFF cases showed a p.Asp188Tyr mutation in the GGPS1 gene, which is critical to osteoclast function, in the mevalonate pathway.

“In two targeted ALPL gene sequencing studies, an ALPL heterozygous mutation was found in one case, but not in the other,” Ebeling reported. “Targeted sequencing of ALPL, COL1A1, COL1A2, and SOX9 genes in five AFF cases has identified a variant in COL1A2 in one out of five cases.”

Future directions

Ongoing studies that can leverage well-phenotyped cases and controls in sufficient numbers are needed to detect rare variants associated with AFFs, while not overlooking the possibility that common variants in multiple genes may also come into play, said Ebeling.

“We certainly need new drug development to circumvent AFF. To add to that, the Biomarkers Consortium Bone Quality Project is also attempting to qualify a surrogate marker for fracture prediction for use in clinical trials, obviating the need for multiple large RCTs with fracture as an endpoint.”

If a surrogate marker is approved for osteoporosis drug development, that will push new therapies into the market, Ebeling concluded.

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Most Read Articles
Dr. Joseph Delano Fule Robles, 5 days ago

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