Genotype-Phenotype Correlations, Response to Bisphosphonate Treatment and Pharmaco-genetics in 150 Swedish Families with Osteogenesis Imperfecta (Type I, IV and III)
(English)Manuscript (preprint) (Other academic)
Introduction: Osteogenesis imperfecta (OI) is a rare heterogeneous disorder leading to bone fragility, spanning from mild to lethal in severity. Over 1500 mutations have been described in collagen type I, encoded by COL1A1 and COL1A2. Bisphosphonate treatment is standard of care and published studies clearly show beneficial effects on Bone Mineral Density (BMD) and vertebral geometry. However, information on BMD increase in relation to age and BMD at onset is limited and there are few studies on influence of mutation type on treatment response. In this study Swedish patients with OI types I, IV and III were investigated with respect to genotype-phenotype correlations, BMD response on bisphosphonate treatment, and pharmaco-genetics.
Materials and Methods: 150 families (202 individuals) with OI participated: 137 type I, 40 type IV and 25 type III. Data on phenotype and bisphosphonate treatment were collected and sequencing of COL1A1 and COL1A2 performed.
Results: In 119 families a mutation was detected; in COL1A1 52 quantitative and 35 qualitative mutations were found and in COL1A2 32 qualitative mutations were found. Several unrelated individuals were found to harbor mutations with the same positions and substitutions and only 15 qualitative mutations were novel, supporting the idea of mutational hotspots. Genotype-phenotype analysis confirmed that mutations situated in the a1-chain are associated with a more severe phenotype, blue sclerae are strongly associated with COL1A1 null alleles, qualitative mutations are associated with DI, and for qualitative mutations position relative to N- and C-terminal is correlated to phenotype. A few novel mutations with unconventional locations were found.
Bisphosphonate treatment response was inversely correlated with age (p=<0.0001) and lumbar spine BMD at onset (p=0.006). Mutations associated with a more severe phenotype had an improved response to treatment when analyzing 2-year delta lumbar spine Z-score values; mutations in COL1A1 vs. COL1A2 (p=0.03), qualitative mutations in COL1A1 vs. COL1A2 (p=0.006), serine substitutions in COL1A1 vs. COL1A2 (p=0.007) and qualitative vs. qualitative mutations in COL1A1 (p=0.02) all exhibited this pattern. Bisphosphonate response was not correlated to either OI type or gender.
Conclusions: The genotype-phenotype correlations described here confirm previous reports of influence of chain affected, intrachain location, and mutation type on phenotype. BMD response to bisphosphonate treatment is inversely related to age and BMD at onset. Pharmaco-genetic analyses show an increased response to bisphosphonate treatment for more severe mutations types. This effect is attenuated over time.
Osteogenesis imperfecta, OI, Bisphosphonate, Therapy, Genotype, Phenotype, Parmaco-genetics, Mutation
Endocrinology and Diabetes
Research subject Medical Genetics; Genetics; Medicine
IdentifiersURN: urn:nbn:se:uu:diva-208940OAI: oai:DiVA.org:uu-208940DiVA: diva2:655410