Mendelian randomization study on vitamin D levels and osteoarthritis risk: a concise report.

OBJECTIVE: The role of vitamin D in OA is unclear and previous epidemiological studies have provided inconsistent results. We conducted a two-sample Mendelian randomization (MR) study to investigate the causal relationship between genetically determined serum vitamin D levels and hip/knee OA. METHODS: Six single-nucleotide polymorphisms (SNPs) associated with vitamin D levels in the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits Consortium were selected as instrumental variables. Summary statistics of the SNPs effects on OA were derived from the Iceland and UK Biobank, comprising 23 877 knee OA cases, 17 151 hip OA cases and >562 000 controls. The control samples match the OA cases in age, sex and county of origin. RESULTS: The MR analyses showed no causal association between genetically determined vitamin D levels and knee OA [odds ratio (OR) 1.03 (95% CI 0.84, 1.26)] or hip OA [OR 1.06 (95% CI 0.83, 1.35)]. CONCLUSION: Genetic variations associated with low vitamin D serum levels are not associated with increased risk of hip or knee OA in community-dwelling older adults, suggesting that vitamin D levels are not causally linked to OA. It is therefore unlikely that vitamin D supplementation protects against hip or knee OA.

Are Bone Mineral Density and Fractures Related to the Incidence and Progression of Radiographic Osteoarthritis of the Knee, Hip, and Hand in Elderly Men and Women? The Rotterdam Study.

OBJECTIVE: To examine the longitudinal relationship between bone mineral density (BMD) and the incidence and progression of knee, hip, and hand osteoarthritis (OA), and to examine the relationship between prevalent vertebral and nonvertebral fractures and the incidence and progression of OA in elderly men and women in the Rotterdam Study. METHODS: Age- and sex-specific quartiles of baseline femoral neck BMD data were constructed for 4,154 subjects. Radiographs were scored for incidence and progression of knee and hip OA, and for incidence of hand OA. Prevalent vertebral fractures were scored using the McCloskey/Kanis method, and prevalent nonvertebral fractures were reported by baseline interview. RESULTS: Subjects in the highest quartile of femoral neck BMD had an increased risk of incident radiographic knee OA (ROA) (odds ratio [OR] 1.58 [95% confidence interval (95% CI) 1.14-2.18]), and an increased risk of incident hip ROA (OR 1.57 [95% CI 1.06-2.32]), compared to the lowest quartile. No significant relationship was found between high femoral neck BMD and progression of knee or hip ROA or the incidence of hand ROA. Prevalent vertebral and nonvertebral fractures were not related to an increase in the incidence or progression of knee or hip ROA. However, vertebral fractures were associated with incident hand ROA (OR 1.74 [95% CI 1.02-2.98]). CONCLUSION: Results from the present study confirm earlier findings and thus provide strong evidence that high femoral neck BMD is a prognostic risk factor for the development of knee and hip ROA. Vertebral fractures were found to be a risk factor for incident hand ROA.

25-Hydroxyvitamin D and osteoarthritis: A meta-analysis including new data.

OBJECTIVES: To study the relationship between 25-hydroxy (OH) vitamin D serum levels and osteoarthritis (OA) of the knee, hip, and hand in a meta-analysis, with updated and expanded results of our previous study. METHODS: Pubmed was searched from February 1975 to December 2014 for articles assessing the relationship between vitamin D levels and OA. In our meta-analysis, 6 cross-sectional and 6 longitudinal studies were included. The number of subjects in these studies ranged from 99 to 1248 subjects. The latter 1248 subjects (58% women) were drawn from the Rotterdam Study, a prospective population-based cohort study of the elderly. At baseline, 25(OH) vitamin D serum levels were measured and prevalent OA of knees, hips and hands was scored by the Kellgren-Lawrence grading system. After a mean follow-up time was 8.4 years, incidence and progression of OA were assessed. RESULTS: No clear association between vitamin serum levels and prevalent, incident or progressive knee, hip or hand OA was observed. The quality of most studies was low, and the results were conflicting. Meta-analysis of 3 cross-sectional studies on vitamin D levels and knee joint space narrowing (JSN) showed an increased risk of prevalent JSN with decreasing vitamin D levels (OR = 1.52, 95% CI: 1.15-2.01). The association observed in the meta-analysis of 3 studies on low vitamin D levels and incident and progressive knee OA was not significant (OR = 1.37, 95% CI: 0.97-1.92); however, when considering solely progressive knee OA, the risk was significantly increased (OR = 2.40, 95% CI: 1.22-4.72). CONCLUSIONS: Epidemiological studies do not provide evidence of an independent association between 25(OH) vitamin D serum levels with hip or hand OA. When analyzing subgroups of knee OA, significant associations of low vitamin D levels with prevalent knee JSN and with progressive knee OA were observed. Overall, the results of this study do not support the advice to supplement vitamin D to prevent the onset or worsening of osteoarthritis, except perhaps for progressive knee OA.

Vitamin D status, bone mineral density, and the development of radiographic osteoarthritis of the knee: The Rotterdam Study.

OBJECTIVE: To study the association between baseline vitamin D status, bone mineral density (BMD), and the development of radiographic osteoarthritis (ROA) of the knee in a large population-based cohort of men and women. METHODS: A sample of 1248 subjects (728 women and 520 men) was drawn from the Rotterdam Study, a prospective population-based cohort study of the elderly. At baseline, vitamin D dietary intake was determined, and BMD and 25-hydroxy vitamin D (25(OH)D) serum levels were measured. After a mean follow-up time of 6.5 years incidence and progression of knee ROA of was assessed. RESULTS: The mean vitamin D intake in our study population was 64 IU/d and the mean 25(OH)D level 66 nmol/L. Vitamin D levels were associated with baseline BMD, particularly in subjects with baseline knee ROA. Progressive ROA occurred in 5.1% of the participants in the highest tertile of vitamin D intake against 12.6% in the lowest tertile, resulting in an adjusted odds ratio of 7.7 (95% CI: 1.3-43.5). Both intake and levels of 25(OH)D were not significantly related to incident ROA. However, we found a significant interaction between vitamin D intake and BMD in the association with incident knee ROA (P = 0.03): in subjects with low lumbar spine BMD at baseline we observe an increasing incidence of knee ROA with decreasing vitamin D intake and serum levels. CONCLUSIONS: Low dietary vitamin D intake increases the risk of progression of knee ROA. Particularly in subjects with low baseline BMD, vitamin D status seems to influence the incidence and progression of knee ROA. Thus, improving the vitamin D status in the elderly could protect against the development and worsening of knee OA, especially in those with low BMD.

Height in pre- and postmenopausal women is influenced by estrogen receptor alpha gene polymorphisms.

The estrogen receptor alpha gene (ESR1) is known to be involved in metabolic pathways influencing growth. We have performed two population-based association studies using three common polymorphisms within this candidate gene to determine whether these are associated with variation in adult stature. In 607 women, aged 55-80 yr, from the Rotterdam Study, the ESR1 PvuII-XbaI haplotype 1 (px) and the L allele of the TA repeat polymorphism (<18 TA repeats) were significantly associated with an allele dose-dependent decrease in height. The per allele copy of ESR1 PvuII-XbaI haplotype 1 height was 0.9 cm shorter (P trend = 0.02) and 1.0 cm/allele copy of the TA repeat L allele (P trend = 0.003). These results were independent of age, age at menarche and menopause, and lumbar spine bone mineral density and remained significant after participants with vertebral fractures were excluded. In 483 men from the Rotterdam Study we found no association with height. In 1500 pre- and perimenopausal women from the Eindhoven Study a similar association was observed; women were 0.5 cm shorter per allele copy of the ESR1 haplotype 1 (P for trend = 0.03). In conclusion, we demonstrate a role for genetic variations in the estrogen receptor alpha gene in determining adult stature in women.

Osteoarthritis of the knee is associated with vertebral and nonvertebral fractures in the elderly: the Rotterdam Study.

OBJECTIVE: To study the association between prevalent radiographic osteoarthritis (ROA) of the knee and incident vertebral and nonvertebral fractures. METHODS: A sample of 2,773 subjects was drawn from the Rotterdam Study, a prospective population-based cohort study of the elderly. Status on knee ROA was assessed at baseline using the Kellgren score. Incident nonvertebral fractures were scored for all subjects, and for 1,466 subjects additional data on incident vertebral fractures were available. RESULTS: Although people with ROA had a higher bone mineral density (BMD), their incident fracture risk was increased as compared with those without ROA. After adjustment for potential confounding factors, including parameters of postural stability, the relative risks for incident vertebral and nonvertebral fractures in the presence of knee ROA were 2.0 (95% confidence interval [95% CI] 1.1-3.4) and 1.5 (95% CI 1.1-2.0), respectively. CONCLUSIONS: Knee ROA is associated with an increased risk of incident vertebral and nonvertebral fractures, independent of BMD and parameters of postural stability.

Cdx-2 polymorphism in the promoter region of the human vitamin D receptor gene determines susceptibility to fracture in the elderly.

UNLABELLED: A Cdx-2 binding site polymorphism (G to A) in the promoter region of the human vitamin D receptor gene was reported. In an ecological study in eight ethnic groups and an association study in 2848 elderly whites, we found the A-allele to be associated with decreased fracture risk. Our findings expand previous similar findings in a Japanese study to whites and show a relationship with fracture risk of this functional polymorphism. INTRODUCTION: A single nucleotide polymorphism (SNP) within a binding site of the intestinal-specific transcription factor Cdx-2 in the promoter region of the human vitamin D receptor (VDR) gene was previously reported. It was found to modulate the transcription of the hVDR gene and to be associated with decreased bone mineral density in a small group of postmenopausal Japanese women. In this study, we investigated the relationship between the VDR Cdx-2 genotype and risk of fracture. METHODS: We first determined the location of this SNP in the VDR gene by sequencing analysis, and we developed an allele-specific multiplex polymerase chain reaction test to determine the Cdx-2 genotype. We then performed an ecological study in eight ethnic groups and an association analysis in a large epidemiological cohort of 2848 Dutch white men and women, > or = 55 years old. RESULTS AND CONCLUSIONS: The location of the G to A substitution was found in the promoter region of exon le (le-G-1739A) of the VDR gene. By comparing the frequency of the A-allele in eight different ethnic groups, we observed a negative correlation between prevalence of the A-allele and published hip fracture incidence rates in these ethnic groups (p = 0.006 for men and p = 0.02 for women), suggesting a protective effect of this allele on fracture risk. Subsequently, in the association study, the A-allele (population frequency 19%) was observed to have a protective effect on occurrence of osteoporotic fractures, especially for nonvertebral fracture in women (relative risk of AA versus GG genotype is 0.2; 95% CI, 0.05-0.8). This effect remained after adjustment for age, weight, and bone mineral density. We conclude that the A-allele of the VDR Cdx-2 polymorphism is present in whites, albeit at low frequency, and show a protective effect of this allele on risk of fracture.

Estrogen receptor alpha gene haplotype is associated with radiographic osteoarthritis of the knee in elderly men and women.

OBJECTIVE: Genetic influences have been shown to play an important role in the etiology of osteoarthritis (OA), but the genes involved are ill-defined. We studied the association between polymorphisms in the estrogen receptor alpha (ERalpha) gene and the prevalence of radiographic OA of the knee. METHODS: The study group comprised 1,483 men and women from the Rotterdam Study. Direct molecular haplotyping was used to determine the relationship between 2 polymorphisms in the ERalpha gene (the Pvu II and Xba I restriction fragment-length polymorphisms). Radiographs of the knee were evaluated according to the Kellgren/Lawrence (K/L) score, along with separate scores for osteophytosis and joint space narrowing. RESULTS: Three different haplotype alleles were identified: px (54%), PX (34%), and Px (12%). Allele PX was associated with an increased prevalence of radiographic knee OA (K/L score >/=2). The prevalence of radiographic OA was 22% among subjects without allele PX, 24% among those carrying 1 copy, and 35% among subjects carrying 2 copies. The corresponding odds ratios, after adjustment for confounding factors, were 1.3 (95% confidence interval [95% CI] 0.9-1.7) for heterozygotes and 2.2 (95% CI 1.5-3.4) for homozygotes. Separate analyses for men and women showed similar risk estimates. The association appeared to be driven by osteophytosis and is somewhat consistent with the association observed in previous studies of these polymorphisms in relation to OA. CONCLUSION: This study shows that polymorphisms in the ERalpha gene are associated with radiographic OA of the knee, and in particular with osteophytosis, in both elderly men and elderly women.

Association of 5' estrogen receptor alpha gene polymorphisms with bone mineral density, vertebral bone area and fracture risk.

This study investigates the influence of genetic variation of the estrogen receptor alpha (ESR1) gene locus on several bone parameters in 2042 individuals of The Rotterdam Study, a prospective population-based cohort study of elderly subjects. We analysed three polymorphic sites in the 5' region of the ESR1 gene; a (TA)(n)-repeat in the promoter region, and molecular haplotypes of the PvuII and XbaI RFLPs in intron 1, and inferred long-range haplotypes (LRH) thereof. We observed only three of the possible four PvuII-XbaI haplotypes in our population. A comparison with other Caucasian populations showed similar haplotype frequencies, while in Asian and African populations these were different. Linkage disequilibrium (LD) analysis between the PvuII-XbaI haplotype and the (TA)(n) repeat showed strong LD between the two sites. Reconstruction of long range haplotypes over the entire 5' region, revealed six frequent LRH. In men, we did not observe an association between the ESR1 polymorphisms studied and bone parameters. In women, we demonstrated an allele dose effect of haplotype "px" (P=0.003) and a low number of (TA)(n) repeats (P=0.008) with decreased lumbar spine bone mineral density (BMD) (4.8% lower BMD in women homozygous for haplotype "px", representing 28% of the population, compared with homozygous non-carriers) and decreased vertebral bone area (2.3% difference between extreme genotypes; P=0.016). Most importantly, we found an increased vertebral fracture risk with evidence for an allele dose effect with an odds ratio of 2.2 (95%CI 1.3-3.5) for haplotype "px", and 2.0 (1.5-3.2) for a low number of (TA)(n) repeats. The ESR1 genotype dependent fracture risk is largely independent of BMD and bone area. Combination of risk alleles at both loci by long-range haplotyping improved the associations slightly, but because of the strong LD between the two polymorphic sites, we were unable to determine if any particular polymorphic site is driving the associations found. We conclude that ESR1 polymorphism in the 5' (promoter) region is associated with vertebral fracture risk, lumbar spine BMD and vertebral bone area in postmenopausal women, but not in men. The molecular mechanism underlying this association needs further study.

The role of vitamin D receptor gene polymorphisms in bone biology.

The role of vitamin D and its receptor (VDR) in skeletal metabolism is well known but the vitamin D endocrine system seems to play an important role in other metabolic pathways as well, such as those involved in osteoarthritis, the immune response and cancer. One approach to understand the vitamin D endocrine system is to study the influence of variations in the DNA sequence of important proteins of this system. For example, deleterious mutations in the VDR gene cause 1,25-dihydroxyvitamin D-resistant rickets, a rare monogenetic disease. More subtle sequence variations (polymorphisms) in the VDR gene occur much more frequently but their effects are poorly understood. Their influence on the vitamin D endocrine system is currently under scrutiny in relation to a number of so-called complex diseases and traits such as osteoporosis. The interpretation of polymorphic variations in the VDR gene is severely hindered by the fact that several of the polymorphisms used have unknown effects. However, current data indicate that dozens of additional polymorphic variations exist in the VDR gene that could each have different types of consequences. Therefore, efforts are focussed on finding novel sequence variations and to study their interaction in molecular- and cell-biological experiments as well as in genomic epidemiological studies. The ultimate goal of this approach is to identify the combinations of functional sequence variants that modulate the vitamin D endocrine system and confer risk of disease.