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Neuropathic pain-like joint symptoms (NP) are seen in a proportion of individuals diagnosed with osteoarthritis (OA) and post total joint replacement (TJR). In this study, we performed a genome-wide association study (GWAS) using NP as defined by the painDETECT questionnaire (score >12 indicating possible NP) in 613 post-TJR participants recruited from Nottinghamshire (UK). The prevalence of possible NP was 17.8%. The top four hits from the GWAS and two other biologically relevant single-nucleotide polymorphisms (SNPs) were replicated in individuals with OA and post TJR from an independent study in the same area (N=908) and in individuals from the Rotterdam Study (N=212). Three of these SNPs showed effect sizes in the same direction as in the GWAS results in both replication cohorts. The strongest association upon meta-analysis of a recessive model was for the variant allele in rs887797 mapping to the protein kinase C alpha (PRKCA) gene odds ratio (OR)possNP=2.41 (95% CI 1.74–3.34, P=1.29 × 10−7). This SNP has been found to be associated with multiple sclerosis and encodes a functional variant affecting splicing and expression of the PRKCA gene. The PRKCA gene has been associated with long-term potentiation, synaptic plasticity, chronic pain and memory in the literature, making this a biologically relevant finding.

In this large population‐based cohort study, variants in ESR2were associated with increased risk of vertebral and incident fragility fracture in postmenopausal women. Interaction of ESR2with ESR1and IGF1was determined and revealed a deleterious genetic combination that enhances the risk of osteoporotic fracture.Introduction:Osteoporosis is a complex disease with strong genetic influence, but the genes involved are ill‐defined. We examined estrogen receptor β (ESR2)polymorphisms in interaction with estrogen receptor α (ESR1)and insulin‐like growth factor I (IGF1)variants in relation to the risk of osteoporotic fracture, BMD, and bone geometry.Materials and Methods:In the Rotterdam study, a prospective population‐based cohort of elderly white individuals, we studied six single nucleotide polymorphisms (SNPs) in ESR2(n= 6343, 60% women). We analyzed the genetic variants in the form of haplotypes reconstructed by a statistical method. Results refer to the most frequent ESR2 haplotype 1estimated from two SNPs in intron 2 and the 3′‐untranslated region (UTR). Outcomes included vertebral and incident nonvertebral fractures, BMD, and hip structural analysis (HSA). We also studied the interaction with (the most frequent) ESR1 haplotype 1estimated from the PvuII and XbaI polymorphisms and an IGF1promoter CA‐repeat.Results:Compared with ESR2 haplotype 1noncarriers, female homozygous carriers had a 1.8‐ and 1.4‐fold increased risk of vertebral and fragility fractures. HSA showed that ESR2 haplotype 1homozygote women had 2.6% thinner cortices, 1.0% increased neck width, and 4.3% higher bone instability (buckling ratios). For testing the gene interaction, we assumed a recessive model of ESR2 haplotype 1. Female homozygous carriers of ESR2 haplotype 1and noncarriers of ESR1 haplotype 1had a 3.5‐ and 1.8‐fold increased risk of vertebral and fragility fractures (pinteraction= 0.10). Such effects and interactions were stronger in women homozygous for the IGF1 192‐bpallele, with 9.3‐fold increased risk (pinteraction= 0.002) for vertebral and 4.0‐fold increased risk (pinteraction= 0.01) for fragility fractures. Multilocus interaction analyses of fracture endured correction for multiple testing using Monte‐Carlo simulations (pinteraction= 0.02 for vertebral and pinteraction= 0.03 for fragility fractures). Similar patterns of interaction were observed for BMD, cortical thickness, bone strength (section modulus), and instability (buckling ratio). In men, no such effects were observed.Conclusions:Variants of ESR2alone and in interaction with ESR1and IGF1influence the risk of fracture in postmenopausal women. These findings reinforce the polygenic and complex character of osteoporosis.

In this large population‐based cohort study, variants in ESR2were associated with increased risk of vertebral and incident fragility fracture in postmenopausal women. Interaction of ESR2with ESR1and IGF1was determined and revealed a deleterious genetic combination that enhances the risk of osteoporotic fracture.

After reported associations of variations in the BMP‐2gene with osteoporosis in small populations, we studied the association of the BMP‐2gene polymorphisms Ser37Ala and Arg190Ser with osteoporosis in 6353 men and women from the Rotterdam Study. We did not observe an association of these variants with BMD, bone loss, hip structural analysis parameters, and fracture risk.

After reported associations of variations in the BMP‐2gene with osteoporosis in small populations, we studied the association of the BMP‐2gene polymorphisms Ser37Ala and Arg190Ser with osteoporosis in 6353 men and women from the Rotterdam Study. We did not observe an association of these variants with BMD, bone loss, hip structural analysis parameters, and fracture risk.Introduction:Bone morphogenetic protein 2 (BMP‐2) plays a role in osteoblast differentiation. BMP‐2gene variation has previously been associated with osteoporosis in various small populations, but current evidence remains inconclusive about the exact association with osteoporosis. Therefore, we studied the association of two polymorphisms located in the BMP‐2gene (Ser37Ala and Arg190Ser) and haplotypes defined by these polymorphisms with BMD, rates of bone loss, parameters of hip structural analysis (HSA), and fractures in the Rotterdam Study, a large prospective cohort study of diseases in the elderly.Materials and Methods:Databases were searched for polymorphisms and haplotype blocks in the BMP‐2gene region. Allele frequencies for Ser37Ala and Arg190Ser were determined in 60 blacks and 110 Chinese from Coriell panels. Genotype data on Ser37Ala and Arg190Ser were available for 6353 individuals from the Rotterdam Study population. Haplotype alleles defined by Ser37Ala and Arg190Ser were inferred using PHASE software. Genotype and haplotype analyses for BMD (measured at the lumbar spine and femoral neck), bone loss per year (measured at the femoral neck), and HSA were performed using AN(C)OVA. Fractures were analyzed using a Cox proportional‐hazards model and logistic regression. All outcomes were adjusted for age, height, and weight.Results:Allele frequencies were 2.5% for Ala37and 40.2% for Ser190, whereas haplotype allele frequencies were 57.28% (Ser37Arg190), 40.19% (Ser37Ser190), 2.50% (Ala37Arg190), and 0.02% (Ala37Ser190). For BMD, bone loss, HSA outcomes, and (incident) fractures, no differences could be seen between genotype and haplotype groups.Conclusions:In this large population‐based cohort of Dutch whites, we conclude that the BMP‐2 Ser37Ala and Arg190Ser polymorphisms or haplotypes thereof are not associated with parameters of osteoporosis.

Both LRP5and LRP6genes have been implicated to play a role in bone metabolism. In a large population‐based study, we related common variation in both genes to bone parameters and fractures. LRP5variation was associated to both BMD and frame size, whereas both LRP5and 6variations were associated with an increased fracture risk in males.

Both LRP5and LRP6genes have been implicated to play a role in bone metabolism. In a large population‐based study, we related common variation in both genes to bone parameters and fractures. LRP5variation was associated to both BMD and frame size, whereas both LRP5and 6variations were associated with an increased fracture risk in males.Introduction: The low‐density lipoprotein receptor‐related protein 5(LRP5) gene has a clear role in rare BMD traits and also in normal variation in peak BMD. We examined whether common variation in LRP5and its close homolog, LRP6, plays a role in BMD in old age and fractures, the main clinical endpoint of osteoporosis.Materials and Methods: We analyzed four variants of LRP5and one amino acid variant of the LRP6gene in a large prospective population‐based cohort study of elderly subjects.Results and Conclusions: In men, the LRP5 1330‐valinevariant was associated with decreased BMD at the lumbar spine and the femoral neck with evidence for an allele‐dose effect (p= 0.001 and 0.01, respectively). The Valallele was also associated with decreased vertebral body size and femoral neck width. Haplotype analysis of studied polymorphisms did not improve the association found and suggested that the 1330 variant was driving the association. We observed a borderline significant association of the LRP6Ile1062Valpolymorphism with height and vertebral body size in males. Male carriers of the LRP5 1330‐valinevariant had a 60% increased risk for fragility fractures, and the LRP61062‐valineallele also conferred a 60% higher risk. Carriers of both the risk alleles of LRP5and 6had a 140% (p= 0.004) higher risk compared with noncarriers of both risk alleles and accounted for 10% of the fractures in males. The fracture risks were independent of age, height, weight, and BMD. In women, all of these associations were weaker and less consistent compared with men. The polymorphisms that were found associated were both situated in potentially important domains of the receptor and show considerable evolutionary conservation, which is evidence for functional importance of these residues.

A Cdx‐2 binding site polymorphism (G to A) in the promoter region of the human vitamin D receptorgene 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.

A Cdx‐2 binding site polymorphism (G to A) in the promoter region of the human vitamin D receptorgene 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 hVDRgene 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 VDRCdx‐2 genotype and risk of fracture.Methods:We first determined the location of this SNP in the VDRgene 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, ≥55 years old.Results and Conclusions:The location of the G to A substitution was found in the promoter region of exon 1e (1e‐G−1739A) of the VDRgene. 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 VDRCdx‐2 polymorphism is present in whites, albeit at low frequency, and show a protective effect of this allele on risk of fracture.