Bone Mineral Density in Prader Willi Syndrome: A Search for Genetic Markers

Abstract

Introduction: Prader-Willi syndrome (PWS (is caused by lack of paternally expressed imprinted genes at chromosome 15q11.2-q13. Diminished (BMD) and osteoporosis are common in PWS. The purpose of this study was to determine whether polymorphisms in genes previously shown to correlate with bone mineral density (BMD), might explain the variable expression of abnormal BMD in PWS. Material and methods: Blood samples were collected from 96 PWS individuals aged 3.5-47.9 (median 14.4) years. DNA samples were tested for 12 polymorphisms in 8 candidate genes: interleukin-1 (IL1-alfa, IL1-beta and IL1RN), CYP1A1, Low Density Lipoprotein Receptor-Related Protein 5 (LRP5), vitamin D receptor (VDR), RANK and RANKL. All patients underwent BMD measurements at the femoral neck and lumbar spine using a hologic dual energy x-ray absorptiometry (DXA) machine. Results: Abnormal BMD was defined as Z-score <-1.5. Severe reduced BMD as Z-score <-2.5. 67 subjects (70%) had abnormal BMD (youngest 3.7 years old), 25 (26%) had severely reduced BMD (youngest 6.8 years old). BMD correlated negatively with age (p<0.001) and BMI (p=0.006). BMD showed significant correlations with genotypes IL1 alpha C889T (p=0.031), Cyp1A1 C4887A (p=0.04) and VDR FOK I (ff /Ff/FF) (p=0.002); FF genotype has a protective effect. Conclusion: Individuals with PWS have low BMD/osteoporosis at a markedly younger age than the general population. The significant correlation between VDR genotypes and BMD is not specific for PWS. Recommendations including vitamin D, calcium, exercise and specific drugs which slow bone loss or build new bone and hormone replacement should be considered in PWS individuals, particularly patients with the high-risk genetic polymorphisms.