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1.  Large-Scale Analysis of Association Between GDF5 and FRZB Variants and Osteoarthritis of the Hip, Knee, and Hand 
Arthritis and rheumatism  2009;60(6):1710-1721.
GDF5 and FRZB have been proposed as genetic loci conferring susceptibility to osteoarthritis (OA); however, the results of several studies investigating the association of OA with the rs143383 polymorphism of the GDF5 gene or the rs7775 and rs288326 polymorphisms of the FRZB gene have been conflicting or inconclusive. To examine these associations, we performed a large-scale meta-analysis of individual-level data.
Fourteen teams contributed data on polymorphisms and knee, hip, and hand OA. For rs143383, the total number of cases and controls, respectively, was 5,789 and 7,850 for hip OA, 5,085 and 8,135 for knee OA, and 4,040 and 4,792 for hand OA. For rs7775, the respective sample sizes were 4,352 and 10,843 for hip OA, 3,545 and 6,085 for knee OA, and 4,010 and 5,151 for hand OA, and for rs288326, they were 4,346 and 8,034 for hip OA, 3,595 and 6,106 for knee OA, and 3,982 and 5,152 for hand OA. For each individual study, sex-specific odds ratios (ORs) were calculated for each OA phenotype that had been investigated. The ORs for each phenotype were synthesized using both fixed-effects and random-effects models for allele-based effects, and also for haplotype effects for FRZB.
A significant random-effects summary OR for knee OA was demonstrated for rs143383 (1.15 [95% confidence interval 1.09–1.22]) (P = 9.4 × 10−7), with no significant between-study heterogeneity. Estimates of effect sizes for hip and hand OA were similar, but a large between-study heterogeneity was observed, and statistical significance was borderline (for OA of the hip [P = 0.016]) or absent (for OA of the hand [P = 0.19]). Analyses for FRZB polymorphisms and haplotypes did not reveal any statistically significant signals, except for a borderline association of rs288326 with hip OA (P = 0.019).
Evidence of an association between the GDF5 rs143383 polymorphism and OA is substantially strong, but the genetic effects are consistent across different populations only for knee OA. Findings of this collaborative analysis do not support the notion that FRZB rs7775 or rs288326 has any sizable genetic effect on OA phenotypes.
PMCID: PMC4412885  PMID: 19479880
2.  Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region 
Annals of the Rheumatic Diseases  2012;72(3):427-436.
Background and objectives
Chronic widespread pain (CWP) is a common disorder affecting ∼10% of the general population and has an estimated heritability of 48–52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP.
We conducted a GWAS meta-analysis in 1308 female CWP cases and 5791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1480 CWP cases and 7989 controls. Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain.
The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of chaperonin-containing-TCP1-complex-5 gene (CCT5) and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (minor allele frequency=43%; OR=1.30, 95% CI 1.19 to 1.42, p=1.2×10−8). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.7×10−7) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95% CI 1.14 to 1.32, p=3.4×10−8, I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (p>7.7×10−4).
We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain.
PMCID: PMC3691951  PMID: 22956598
Gene Polymorphism; Fibromyalgis/Pain Syndromes; Epidemiology
3.  Genomewide linkage scan of hand osteoarthritis in female twin pairs showing replication of quantitative trait loci on chromosomes 2 and 19 
Annals of the Rheumatic Diseases  2006;66(5):623-627.
Background and objective
Until recently, there has been little agreement between conflicting results of osteoarthritis (OA) linkage. The purpose of this study was to conduct a whole‐genome linkage scan to identify susceptibility loci for idiopathic hand OA in a large, population‐based sample of females.
Two OA‐related radiographic phenotypes DIP (distal interphalangeal joints)‐OA and Tot‐KL (Kellgren‐Lawrence score for both hands) chosen a priori were examined on 538 (269 pairs) monozygous and 1256 (628 pairs) dizygous (DZ) females. A genome‐wide scan using microsatellite markers spaced 10 cM apart was performed on 1028 DZ twins. First, the heritability of the two OA phenotypes was estimated. Next, multipoint linkage analysis was conducted using a modified version of the Haseman–Elston method in a generalised linear model.
Heritability for DIP‐OA and Tot‐KL was found to be 47.6% and 67.4%, respectively. A genome‐wide scan produced reliable evidence of significant linkage of DIP‐OA on chromosome 2 at 90 cM (logarithmic odds ratio (LOD) = 2.90) and for Tot‐KL on chromosome 19 at 65 cM (LOD = 4.26). These results are in agreement with data published previously. Several other significant linkage peaks were observed—for example, on chromosome 1 at 250 cM and on chromosome 3 at 30 cM—but were confirmed less reliably.
This is one of the largest OA linkage studies performed to date and provides clear evidence for linkage at two quantitative trait loci (on chromosome 2 at 90 cM and on chromosome 19 at 65 cM). As the results were robust and replicated in previous smaller studies, the fine mapping of these regions is a logical next step to pinpoint potential susceptibility gene(s) of interest.
PMCID: PMC1954638  PMID: 17127684
4.  The UK Adult Twin Registry (TwinsUK Resource) 
TwinsUK is a nation-wide registry of volunteer twins in the UK, with about 12,000 registered twins (83% female, equal number of monozygotic and dizygotic twins, predominantly middle-aged and older). Over the last 20 years, questionnaire and blood/urine/tissue samples have been collected on over 7,000 subjects, as well as three comprehensive phenotyping assessments in the clinical facilities of the Department of Twin Research and Genetic Epidemiology, King’s College London. The primary focus of study has been the genetic basis of healthy ageing process and complex diseases including cardiovascular, metabolic, musculoskeletal, and ophthalmologic disorders. Alongside the detailed clinical, biochemical, behavioural, and socio-economic characterisation of the study population, the major strength of TwinsUK is availability of several ‘omics’ technologies for the participants. These include genome-wide scans of single nucleotide variants, next-generation sequencing, exome sequencing, epigenetic markers (MeDIP sequencing), gene expression arrays and RNA sequencing, telomere length measures, metabolomic profiles, and gut flora microbiomics. The scientific community now can freely access parts of the phenotype data from the ‘TwinsUK Resource’ and interested researchers are encouraged to contact us via our website ( for future collaborations.
PMCID: PMC3927054  PMID: 23088889
5.  Longitudinal study of variation in body mass index in middle-aged UK females 
Age  2011;34(5):1285-1294.
The importance of changing patterns of obesity in society and its implications for public health are well recognized. However, the adult life course of body mass index (BMI) changes in individuals over time is largely unknown and has mostly been extrapolated from cross-sectional studies. The present study examines individual specific variation of BMI during a 15-year follow-up period in a community-based sample of UK females. We attempted to establish whether there is a common, generalized pattern which captures variation in BMI over time. The participants of this study belong to a prospective population cohort of British women studied intensively since 1989: the Chingford Study. The sample originally consisted of 1,003 women aged 45–68 years, who were assessed annually for BMI during follow-up period. Polynomial regression models were used to assess longitudinal BMI variation. We observed a great stability in individual BMI variation during the follow-up period, reflected by high correlations between the baseline BMI and follow-up BMI 10 and 15 years later (r = 0.876, N = 810, and r = 0.824, N = 638, respectively). We also found that three different major age-related patterns in BMI could be clearly identified: no change in 30.6% in 58% it increased and in 11.4% it decreased with age. Thus, our data suggest that individual age-related changes in BMI are very different. Therefore, simply combining all individuals into groups by any other criteria (age, sex, etc.) and overlooking the distinctive patterns of BMI change may lead to biased inferences in epidemiologic and etiologic research of the future.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9299-0) contains supplementary material, which is available to authorized users.
PMCID: PMC3448995  PMID: 21853263
BMI; Follow-up, curve fitting; Age-dependent patterns; Longitudinal; Weight gain
6.  Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region 
Annals of the rheumatic diseases  2012;72(3):427-436.
Chronic widespread pain (CWP) is a common disorder affecting ~10% of the general population and has an estimated heritability of 48-52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP.
We conducted a GWAS meta-analysis in 1,308 female CWP cases and 5,791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1,480 CWP cases and 7,989 controls (P<1×10−5). Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain.
The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of CCT5 and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (MAF=43%; OR=1.30, 95%CI=1.19-1.42, P=1.2×10−8). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95%CI=1.10-1.24, P=4.7×10−7) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95%CI=1.14-1.32, P=3.4×10−8, I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (P>7.7×10−4).
We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain.
PMCID: PMC3691951  PMID: 22956598
Gene Polymorphism; Fibromyalgia/Pain Syndromes; Epidemiology
7.  A Role for PACE4 in Osteoarthritis Pain: Evidence from Human Genetic Association and Null Mutant Phenotype 
Annals of the rheumatic diseases  2012;71(6):1042-1048.
To assess if genetic variation in the PACE4 gene, PCSK6, influences the risk for symptomatic knee OA.
Ten PCSK6 single nucleotide polymorphisms (SNP) were tested for association in a discovery cohort of radiographic knee OA (n= 156 asymptomatic and 600 symptomatic cases). Meta-analysis of the minor allele at rs900414 was performed in three additional independent cohorts (total n=674 asymptomatic and 2068 symptomatic). Pcsk6 knockout (KO) mice and wildtype C57BL/6 mice were compared in a battery of algesiometric assays, including hypersensitivity in response to intraplantar substance P; pain behaviours in response to intrathecal substance P; and pain behaviour in the abdominal constriction test.
In the discovery cohort of radiographic knee OA, an intronic SNP at rs900414 was significantly associated with symptomatic OA. Replication in three additional cohorts confirmed that the minor allele at rs900414 was consistently increased among asymptomatic compared to symptomatic radiographic knee OA cases in all four cohorts. A fixed-effects meta-analysis yielded an odds ratio =1.35 (95% CI 1.17, 1.56; p-value 4.3×10−5 and no significant between-study heterogeneity). Studies in mice revealed that Pcsk6 knockout (KO) mice were significantly protected against pain in a battery of algesiometric assays.
These results suggest that a variant in PCSK6 is strongly associated with protection against pain in knee OA, offering some insight as to why in the presence of the same structural damage, some individuals develop chronic pain and others are protected. Studies in Pcsk6 null mutant mice further implicate PACE4 in pain.
PMCID: PMC3603144  PMID: 22440827
Knee osteoarthritis; pain; PACE4; genetic association; SNP
8.  Meta-analysis of genome-wide association studies confirms a susceptibility locus for knee osteoarthritis on chromosome 7q22 
Evangelou, Evangelos | Valdes, Ana M. | Kerkhof, Hanneke J.M | Styrkarsdottir, Unnur | Zhu, YanYan | Meulenbelt, Ingrid | Lories, Rik J. | Karassa, Fotini B. | Tylzanowski, Przemko | Bos, Steffan D. | Akune, Toru | Arden, Nigel K. | Carr, Andrew | Chapman, Kay | Cupples, L. Adrienne | Dai, Jin | Deloukas, Panos | Doherty, Michael | Doherty, Sally | Engstrom, Gunnar | Gonzalez, Antonio | Halldorsson, Bjarni V. | Hammond, Christina L. | Hart, Deborah J. | Helgadottir, Hafdis | Hofman, Albert | Ikegawa, Shiro | Ingvarsson, Thorvaldur | Jiang, Qing | Jonsson, Helgi | Kaprio, Jaakko | Kawaguchi, Hiroshi | Kisand, Kalle | Kloppenburg, Margreet | Kujala, Urho M. | Lohmander, L. Stefan | Loughlin, John | Luyten, Frank P. | Mabuchi, Akihiko | McCaskie, Andrew | Nakajima, Masahiro | Nilsson, Peter M. | Nishida, Nao | Ollier, William E.R. | Panoutsopoulou, Kalliope | van de Putte, Tom | Ralston, Stuart H. | Rivadeneira, Fernado | Saarela, Janna | Schulte-Merker, Stefan | Slagboom, P. Eline | Sudo, Akihiro | Tamm, Agu | Tamm, Ann | Thorleifsson, Gudmar | Thorsteinsdottir, Unnur | Tsezou, Aspasia | Wallis, Gillian A. | Wilkinson, J. Mark | Yoshimura, Noriko | Zeggini, Eleftheria | Zhai, Guangju | Zhang, Feng | Jonsdottir, Ingileif | Uitterlinden, Andre G. | Felson, David T | van Meurs, Joyce B. | Stefansson, Kari | Ioannidis, John P.A. | Spector, Timothy D.
Annals of the rheumatic diseases  2010;70(2):349-355.
Osteoarthritis (OA) is the most prevalent form of arthritis and accounts for substantial morbidity and disability, particularly in the elderly. It is characterized by changes in joint structure including degeneration of the articular cartilage and its etiology is multifactorial with a strong postulated genetic component. We performed a meta-analysis of four genome-wide association (GWA) studies of 2,371 knee OA cases and 35,909 controls in Caucasian populations. Replication of the top hits was attempted with data from additional ten replication datasets. With a cumulative sample size of 6,709 cases and 44,439 controls, we identified one genome-wide significant locus on chromosome 7q22 for knee OA (rs4730250, p-value=9.2×10−9), thereby confirming its role as a susceptibility locus for OA. The associated signal is located within a large (500kb) linkage disequilibrium (LD) block that contains six genes; PRKAR2B (protein kinase, cAMP-dependent, regulatory, type II, beta), HPB1 (HMG-box transcription factor 1), COG5 (component of oligomeric golgi complex 5), GPR22 (G protein-coupled receptor 22), DUS4L (dihydrouridine synthase 4-like), and BCAP29 (the B-cell receptor-associated protein 29). Gene expression analyses of the (six) genes in primary cells derived from different joint tissues confirmed expression of all the genes in the joint environment.
PMCID: PMC3615180  PMID: 21068099
9.  A Genome-Wide Association Study identifies a locus on chromosome 7q22 to influence susceptibility for osteoarthritis 
Arthritis and Rheumatism  2010;62(2):499-510.
To identify genes involved in osteoarthritis (OA), the most prevalent form of joint disease, we performed a genome-wide association study (GWAS) in which we tested 500,510 Single Nucelotide Polymorphisms (SNPs) in 1341 OA cases and 3496 Dutch Caucasian controls. SNPs associated with at least two OA-phenotypes were analysed in 14,938 OA cases and approximately 39,000 controls. The C-allele of rs3815148 on chromosome 7q22 (MAF 23%, 172 kb upstream of the GPR22 gene) was consistently associated with a 1.14-fold increased risk (95%CI: 1.09–1.19) for knee- and/or hand-OA (p=8×10−8), and also with a 30% increased risk for knee-OA progression (95%CI: 1.03–1.64, p=0.03). This SNP is in almost complete linkage disequilibrium with rs3757713 (located 68 kb upstream of GPR22) which is associated with GPR22 expression levels in lymphoblast cell lines (p=4×10−12). GPR22 encodes an G-protein coupled receptor with unkown ligand (orphan receptor). Immunohistochemistry experiments showed absence of GPR22 in normal mouse articular cartilage or synovium. However, GPR22 positive chondrocytes were found in the upper layers of the articular cartilage of mouse knee joints that were challenged by in vivo papain treatment or in the presence of interleukin-1 driven inflammation. GRP22 positive chondrocyte-like cells were also found in osteophytes in instability-induced OA. In addition, GPR22 is also present in areas of the brain involved in locomotor function. Our findings reveal a novel common variant on chromosome 7q22 to influence susceptibility for prevalence and progression of OA.
PMCID: PMC3354739  PMID: 20112360
10.  Recommendations for standardization and phenotype definitions in genetic studies of osteoarthritis: the TREAT-OA consortium 
To address the need for standardization of osteoarthritis (OA) phenotypes by examining the effect of heterogeneity among symptomatic (SOA) and radiographic osteoarthritis (ROA) phenotypes.
Descriptions of OA phenotypes of the 28 studies involved in the TREAT-OA consortium were collected. To investigate whether different OA definitions result in different association results, we created hip OA definitions used within the consortium in the Rotterdam Study-I and tested the association of hip OA with gender, age and BMI using one-way ANOVA. For radiographic OA, we standardized the hip, knee and hand ROA definitions and calculated prevalence's of ROA before and after standardization in 9 cohort studies. This procedure could only be performed in cohort studies and standardization of SOA definitions was not feasible at this moment.
In this consortium, all studies with symptomatic OA phenotypes (knee, hip and hand) used a different definition and/or assessment of OA status. For knee, hip and hand radiographic OA 5, 4 and 7 different definitions were used, respectively. Different hip OA definitions do lead to different association results. For example, we showed in the Rotterdam Study-I that hip OA defined as “at least definite JSN and one definite osteophyte” was not associated with gender (p=0.22), but defined as “at least one definite osteophyte” was significantly associated with gender (p=3×10−9). Therefore, a standardization process was undertaken for radiographic OA definitions. Before standardization a wide range of ROA prevalence's was observed in the 9 cohorts studied. After standardization the range in prevalence of knee and hip ROA was small. Standardization of SOA phenotypes was not possible due to the case-control design of the studies.
Phenotype definitions influence the prevalence of OA and association with clinical variables. ROA phenotypes within the TREAT-OA consortium were standardized to reduce heterogeneity and improve power in future genetics studies.
PMCID: PMC3236091  PMID: 21059398
11.  Large Scale Replication Study of the Association between HLA Class II/BTNL2 Variants and Osteoarthritis of the Knee in European-Descent Populations 
PLoS ONE  2011;6(8):e23371.
Osteoarthritis (OA) is the most common form of arthritis and a major cause of disability. This study evaluates the association in Caucasian populations of two single nucleotide polymorphisms (SNPs) mapping to the Human Leukocyte Antigen (HLA) region and deriving from a genome wide association scan (GWAS) of knee OA in Japanese populations. The frequencies for rs10947262 were compared in 36,408 controls and 5,749 knee OA cases from European-descent populations. rs7775228 was tested in 32,823 controls and 1,837 knee OA cases of European descent. The risk (major) allele at rs10947262 in Caucasian samples was not significantly associated with an odds ratio (OR)  = 1.07 (95%CI 0.94 -1.21; p = 0.28). For rs7775228 the meta-analysis resulted in OR = 0.94 (95%CI 0.81-1.09; p = 0.42) for the allele associated with risk in the Japanese GWAS. In Japanese individuals these two SNPs are in strong linkage disequilibrium (LD) (r2 = 0.86) with the HLA class II haplotype DRB1*1502 DQA1*0103 DQB1*0601 (frequency 8%). In Caucasian and Chinese samples, using imputed data, these SNPs appear not to be in LD with that haplotype (r2<0.07). The rs10947262 and rs7775228 variants are not associated with risk of knee OA in European descent populations and they do not appear tag the same HLA class II haplotype as they do in Japanese individuals.
PMCID: PMC3154440  PMID: 21853121
12.  Association between DHEAS and Bone Loss in Postmenopausal Women: A 15-Year Longitudinal Population-Based Study 
Calcified Tissue International  2011;89(4):295-302.
Our aim was to examine the association between serum dehydroepiandrosterone sulfate (DHEAS) at baseline and BMD change at the femoral neck (FN) and lumbar spine (LS) in postmenopausal women during a 15-year follow-up. All participants were from the Chingford Study. BMD at the FN and LS were measured eight times during the 15-year follow-up by dual-energy X-ray absorptiometry. DHEAS at baseline was measured using radioimmunoassay. Data on height, weight, and hormone-replacement therapy (HRT) status were obtained at each visit. Multilevel linear regression modeling was used to examine the association between longitudinal BMD change at the FN and LS and DHEAS at baseline. Postmenopausal women (n = 1,003) aged 45–68 years (mean 54.7) at baseline were included in the study. After adjustment for baseline age, estradiol, HRT, and BMI, BMD at the FN decreased on average 0.49% (95% CI 0.31–0.71%) per year; and the decline was slowed down by 0.028% per squared year. Increase of DHEAS (each micromole per liter) was associated with 0.49% less bone loss at the FN (95% CI 0.21–0.71%, P = 0.001). However, this strong association became slightly weaker over time. Similar but weaker results were obtained for LS BMD. Our data suggest that high serum DHEAS at baseline is associated with less bone loss at both FN and LS and this association diminishes over time. The nature of the association is unclear, but such an association implies that, in managing BMD loss, women might benefit from maintaining a high level of DHEAS.
PMCID: PMC3175043  PMID: 21789637
BMD; DHEAS; Osteoporosis; Longitudinal study; Postmenopausal
13.  Meta-Analysis of Genome-Wide Scans for Human Adult Stature Identifies Novel Loci and Associations with Measures of Skeletal Frame Size 
PLoS Genetics  2009;5(4):e1000445.
Recent genome-wide (GW) scans have identified several independent loci affecting human stature, but their contribution through the different skeletal components of height is still poorly understood. We carried out a genome-wide scan in 12,611 participants, followed by replication in an additional 7,187 individuals, and identified 17 genomic regions with GW-significant association with height. Of these, two are entirely novel (rs11809207 in CATSPER4, combined P-value = 6.1×10−8 and rs910316 in TMED10, P-value = 1.4×10−7) and two had previously been described with weak statistical support (rs10472828 in NPR3, P-value = 3×10−7 and rs849141 in JAZF1, P-value = 3.2×10−11). One locus (rs1182188 at GNA12) identifies the first height eQTL. We also assessed the contribution of height loci to the upper- (trunk) and lower-body (hip axis and femur) skeletal components of height. We find evidence for several loci associated with trunk length (including rs6570507 in GPR126, P-value = 4×10−5 and rs6817306 in LCORL, P-value = 4×10−4), hip axis length (including rs6830062 at LCORL, P-value = 4.8×10−4 and rs4911494 at UQCC, P-value = 1.9×10−4), and femur length (including rs710841 at PRKG2, P-value = 2.4×10−5 and rs10946808 at HIST1H1D, P-value = 6.4×10−6). Finally, we used conditional analyses to explore a possible differential contribution of the height loci to these different skeletal size measurements. In addition to validating four novel loci controlling adult stature, our study represents the first effort to assess the contribution of genetic loci to three skeletal components of height. Further statistical tests in larger numbers of individuals will be required to verify if the height loci affect height preferentially through these subcomponents of height.
Author Summary
The first genetic association studies of adult height have confirmed a role of many common variants in influencing human height, but to date, the genetic basis of differences between different skeletal components of height have not been addressed. Here, we take advantage of recent technical and methodological advances to examine the role of common genetic variants on both height and skeletal components of height. By examining nearly 20,000 individuals from the UK and the Netherlands, we provide statistically significant evidence that 17 genomic regions are associated with height, including four novel regions. We also examine, for the first time, the association of these 17 regions with skeletal size measurements of spine, femur, and hip axis length, a measurement of hip geometry known to influence the risk of osteoporotic fractures. We find that some height loci are also associated with these skeletal components, although further statistical tests will be required to verify if these genetic variants act differentially on the individual skeletal measurements. The knowledge generated by this and other studies will not only inform the genetics of human quantitative variation, but will also lead to the potential discovery of many medically important polymorphisms.
PMCID: PMC2661236  PMID: 19343178
14.  Adiponectin gene ADIPOQ SNP associations with serum adiponectin in two female populations and effects of SNPs on promoter activity 
Journal of human genetics  2008;53(8):718-727.
Adiponectin is an insulin sensitizer in muscle and liver and low serum levels characterise obesity and insulin resistance. Eight tagging SNPs in the ADIPOQ gene and promoter were selected and association with serum adiponectin was tested in two independent samples of Caucasian females: the Chingford Study (n=808, mean age 62.8±5.9 years) and Twins UK (n=2718, mean age 47.4±12.6 years). In the Chingford cohort, −11391 G/A, −10066 G/A (rs182052), −7734 C/A (rs16861209), +276 G/T (rs1501299) and +3228 C/T (rs1063537) were significantly associated with fasting serum adiponectin (Ps=1.00 × 10−4 to 1.40 × 10−2). Associations with all except +3228 C/T were replicated in the Twins UK cohort (Ps=3.19 × 10−9 to 6.00 × 10−3). In Chingford subjects, the twelve most common 8-SNP haplotypes (freq. 1.90%) explained 2.85% (p=5.00 × 10−2) and in Twins UK subjects, the four most common 5-SNP haplotypes (freq. >5.00%) explained 1.66% of the variance (p=5.83 × 10−7). To investigate effects of −11391 G/A (rs17300539) and −11377 C/G (rs266729) on promoter activity, 1.2 kb of the ADIPOQ promoter region was cloned in a luciferase reporter plasmid and the four haplotypes were transfected in differentiated 3T3-L1 adipocytes. No significant allelic effects on promoter activity were found.
PMCID: PMC2564110  PMID: 18523726
adiponectin; gene transfection; genetic epidemiology; metabolic syndrome; single nucleotide polymorphism
15.  Interleukin-6 is a significant predictor of radiographic knee osteoarthritis: The Chingford study 
Arthritis and Rheumatism  2009;60(7):2037-2045.
There is a great need for identification of biomarkers that could improve the prediction of early osteoarthritis (OA). We undertook this study to determine whether circulating levels of interleukin-6 (IL-6), tumor necrosis factor α (TNFα), and C-reactive protein (CRP) can serve as useful markers of radiographic knee OA (RKOA) in a normal human population.
RKOA data were obtained from the cohort of the Chingford Study, a prospective population-based study of healthy, middle-aged British women. The RKOA-affected status of the subjects was assessed using the Kellgren/Lawrence (K/L) grade as determined on radiographs obtained at baseline (n = 908) and at 10 years and 15 years thereafter. Serum levels of CRP, IL-6, and TNFα were assayed at 5, 8, and 15 years, using high-sensitivity commercial assays. A K/L grade of ≥2 in either knee was used as the outcome measure. Statistical analyses included analysis of variance for repeated measurements and logistic regression models, together with longitudinal modeling of dichotomous responses.
During 15 years of followup, the prevalence of RKOA (K/L grade ≥2) increased from 14.7% to 48.7% (P < 0.00001 versus baseline). The body mass index (BMI) and circulating levels of CRP and IL-6 were consistently and significantly higher in subjects diagnosed as having RKOA. When multiple logistic regression was applied to the data, the variables of older age (P = 3.93 × 10−5), higher BMI at baseline (P = 0.0003), and increased levels of IL-6 at year 5 (P = 0.0129) were determined to be independent predictors of the appearance of RKOA at year 10. The results were fully confirmed using longitudinal modeling of repeated measurements of the data obtained at 3 visits. The odds ratio for RKOA in subjects whose IL-6 levels were in the fourth quartile of increasing levels (versus the first quartile) was 2.74 (95% confidence interval 1.94–3.87).
This followup study showed that individuals were more likely to be diagnosed as having RKOA if they had a higher BMI and increased circulating levels of IL-6. These results should stimulate more work on IL-6 as a potential therapeutic target.
PMCID: PMC2841820  PMID: 19565477
16.  The Ile585Val TRPV1 variant is involved in risk of painful knee osteoarthritis 
Annals of the Rheumatic Diseases  2011;70(9):1556-1561.
To assess if a coding variant in the gene encoding transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is associated with genetic risk of painful knee osteoarthritis (OA).
The Ile585Val TRPV1 variant encoded by rs8065080 was genotyped in 3270 cases of symptomatic knee OA, 1098 cases of asymptomatic knee OA and 3852 controls from seven cohorts from the UK, the USA and Australia. The genetic association between the low-pain genotype Ile–Ile and risk of symptomatic and asymptomatic knee OA was assessed.
The TRPV1 585 Ile–Ile genotype, reported to be associated with lower thermal pain sensitivity, was associated with a lower risk of symptomatic knee OA in a comparison of symptomatic cases with healthy controls, with an odds ratio (OR) of 0.75 (95% CI 0.64 to 0.88; p=0.00039 by meta-analysis) after adjustment for age, sex and body mass index. No difference was seen between asymptomatic OA cases and controls (OR=1.02, 95% CI 0.82 to 1.27 p=0.86) but the Ile–Ile genotype was associated with lower risk of symptomatic versus asymptomatic knee OA adjusting for covariates and radiographic severity (OR=0.73, 95% CI 0.57 to 0.94 p=0.0136). TRPV1 expression in articular cartilage was increased by inflammatory cytokines (tumour necrosis factor α and interleukin 1). However, there were no differences in TRPV1 expression in healthy and arthritic synovial tissue.
A genotype involved in lower peripheral pain sensitivity is significantly associated with a decreased risk of painful knee OA. This indicates a role for the pro-nociceptive gene TRPV1 in genetic susceptibility to symptomatic knee OA, which may also be influenced by a role for this molecule in cartilage function.
PMCID: PMC3147243  PMID: 21616913
17.  The association between hip morphology parameters and nineteen-year risk of end-stage osteoarthritis of the hip: A nested case–control study 
Arthritis and Rheumatism  2011;63(11):3392-3400.
Subtle deformities of the hip joint are implicated in the etiology of osteoarthritis (OA) of the hip. Parameters that quantify these deformities may aid understanding of these associations. We undertook this study to examine relationships between such parameters and the 19-year risk of total hip arthroplasty (THA) for end-stage OA.
A new software program designed for measuring morphologic parameters around the hip was developed and validated in a reliability study. THA was the outcome measure for end-stage OA. A nested case–control study was used with individuals from a cohort of 1,003 women who were recruited at year 1 in 1989 and followed up to year 20 (the Chingford Study). All hips with THA by year 20 and 243 randomly selected control hips were studied. Pelvis radiographs obtained at year 2 were analyzed for variations in hip morphology. Measurements were compared between the THA case group and the control group.
Patients with THA had a higher prevalence of cam deformity than did their respective controls (median alpha angle 62.4° versus 45.8° [P = 0.001]; mean modified triangular index height 28.5 mm versus 26.9 mm [P = 0.001]) as well as a higher prevalence of acetabular dysplasia (mean lateral center edge angle 29.5° versus 34.3° [P = 0.001]; median extrusion index 0.25 versus 0.185 [P = 0.009]). Logistic regression analyses clustering by subject and adjusting for radiographic hip OA at year 2 showed that these morphologic parameters were still significantly associated with THA by year 20. The alpha angle and lateral center edge angle predicted the risk of THA independently when included in the same model.
This investigation describes measurements that predict the risk of THA for end-stage OA by year 20, independently of the presence of radiographic hip OA at year 2. These measurements can be made on an anteroposterior pelvis radiograph, which is an inexpensive and commonly used clinical method of investigation.
PMCID: PMC3494291  PMID: 21739424
18.  The effect of FTO variation on increased osteoarthritis risk is mediated through body mass index: a mendelian randomisation study 
Annals of the Rheumatic Diseases  2013;73(12):2082-2086.
Variation in the fat mass and obesity-associated (FTO) gene influences susceptibility to obesity. A variant in the FTO gene has been implicated in genetic risk to osteoarthritis (OA). We examined the role of the FTO polymorphism rs8044769 in risk of knee and hip OA in cases and controls incorporating body mass index (BMI) information.
5409 knee OA patients, 4355 hip OA patients and up to 5362 healthy controls from 7 independent cohorts from the UK and Australia were genotyped for rs8044769. The association of the FTO variant with OA was investigated in case/control analyses with and without BMI adjustment and in analyses matched for BMI category. A mendelian randomisation approach was employed using the FTO variant as the instrumental variable to evaluate the role of overweight on OA.
In the meta-analysis of all overweight (BMI≥25) samples versus normal-weight controls irrespective of OA status the association of rs8044769 with overweight is highly significant (OR[CIs] for allele G=1.14 [01.08 to 1.19], p=7.5×10−7). A significant association with knee OA is present in the analysis without BMI adjustment (OR[CIs]=1.08[1.02 to 1.14], p=0.009) but the signal fully attenuates after BMI adjustment (OR[CIs]=0.99[0.93 to 1.05], p=0.666). We observe no evidence for association in the BMI-matched meta-analyses. Using mendelian randomisation approaches we confirm the causal role of overweight on OA.
Our data highlight the contribution of genetic risk to overweight in defining risk to OA but the association is exclusively mediated by the effect on BMI. This is consistent with what is known of the biology of the FTO gene and supports the causative role of high BMI in OA.
PMCID: PMC4251538  PMID: 23921993
Osteoarthritis; Knee Osteoarthritis; Gene Polymorphism; Epidemiology
19.  Osteophytes, Enthesophytes, and High Bone Mass: A Bone-Forming Triad With Potential Relevance in Osteoarthritis 
Previous studies of skeletal remains have suggested that both enthesophytes and osteophytes are manifestations of an underlying bone-forming tendency. A greater prevalence of osteophytes has been observed among individuals with high bone mass (HBM) compared with controls. This study was undertaken to examine the possible interrelationships between bone mass, enthesophytes, and osteophytes in a population of individuals with extreme HBM.
Cases of HBM (defined according to bone mineral density [BMD] Z scores on dual x-ray absorptiometry) from the UK-based HBM study were compared with a control group comprising unaffected family members and general population controls from the Chingford and Hertfordshire cohort studies. Pelvic radiographs from cases and controls were pooled and evaluated, in a blinded manner, by a single observer, who performed semiquantitative grading of the radiographs for the presence and severity of osteophytes and enthesophytes (score range 0–3 for each). Logistic regression analysis was used to identify significant associations, with a priori adjustment for age, sex, and body mass index.
In this study, 226 radiographs from HBM cases and 437 radiographs from control subjects were included. Enthesophytes (grade ≥1) and moderate enthesophytes (grade ≥2) were more prevalent in HBM cases compared with controls (adjusted odds ratio [OR] 3.00 [95% confidence interval (95% CI) 1.96–4.58], P < 0.001 for any enthesophyte; adjusted OR 4.33 [95% CI 2.67–7.02], P < 0.001 for moderate enthesophytes). In the combined population of cases and controls, the enthesophyte grade was positively associated with BMD at both the total hip and lumbar spine (adjusted P for trend < 0.001). In addition, a positive association between osteophytes and enthesophytes was observed; for each unit increase in enthesophyte grade, the odds of any osteophyte being present were increased >2-fold (P < 0.001).
Strong interrelationships were observed between osteophytes, enthesophytes, and HBM, which may be helpful in defining a distinct subset of patients with osteoarthritis characterized by excess bone formation.
PMCID: PMC4288267  PMID: 24910132

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