Doxycycline and osteoarthritis: what does it show us?
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Journal Article↗
Biomedical subjects
Tim D Spector
Publications and source records attributed to Tim D Spector.
Two candidate genes for low platelet count identified in an Asian Indian kindred by genome-wide linkage analysis: glycoprotein IX and thrombopoietin.
A genome-wide linkage analysis of platelet count was carried out in a large Asian Indian kindred. Linkage analysis showed one marker (D3S1309) on chromosome 3q with a lod score of 3.26 and another (D3S1282) approximately 30 cM centromeric, with a lod score of 2.52. Multipoint analysis of chromosome 3q identified two peaks with maximum multipoint lod scores of 3.52 and 4.11 under markers D3S1309 and D3S1282, respectively. Two strong candidate genes for platelet variation were identified in the linked region; thrombopoietin (THPO) and glycoprotein IX (GPIX). Resequencing of four individuals revealed five single-nucleotide polymorphisms (SNPs) in THPO and one mutation in the transmembrane region of GPIX. Analysis of variance showed that the GPIX mutation and one THPO SNP accounted for 6 and 4% of the variation in platelet count, respectively. The THPO SNP lies in the 3' untranslated region of the gene and has not been previously reported. The G to A transition at nucleotide 653 resulted in an Ala 156 (GCC) to Thr (ACC) replacement in the GPIX protein. The GPIX mutation was recently identified in a Chinese patient with Bernard-Soulier syndrome (BSS), a rare recessive bleeding disorder characterized by thrombocytopenia and giant platelets. One copy of the GPIX mutation was found in 300 European individuals with platelet counts within the normal range. The results suggest that two QTLs on chromosome 3q influence platelet count variation in the Asian Indian kindred, with the GPIX transmembrane mutation and the 3' UTR SNP in THPO being strong candidates.
3' Untranslated Regions↗
Linkage and potential association of obesity-related phenotypes with two genes on chromosome 12q24 in a female dizygous twin cohort.
Obesity is a multifactorial disorder with a complex phenotype. It is a significant risk factor for diabetes and hypertension. We assessed obesity-related traits in a large cohort of twins and performed a genome-wide linkage scan and positional candidate analysis to identify genes that play a role in regulating fat mass and distribution in women. Dizygous female twin pairs from 1,094 pedigrees were studied (mean age 47.0+/-11.5 years (range 18-79 years)). Nonparametric multipoint linkage analyses showed linkage for central fat mass to 12q24 (141 cM) with LOD 2.2 and body mass index to 8q11 (67 cM) with LOD 1.3, supporting previously established linkage data. Novel areas of suggestive linkage were for total fat percentage at 6q12 (LOD 2.4) and for total lean mass at 2q37 (LOD 2.4). Data from follow-up fine mapping in an expanded cohort of 1243 twin pairs reinforced the linkage for central fat mass to 12q24 (LOD 2.6; 143 cM) and narrowed the -1 LOD support interval to 22 cM. In all, 45 single-nucleotide polymorphisms (SNPs) from 26 positional candidate genes within the 12q24 interval were then tested for association in a cohort of 1102 twins. Single-point Monks-Kaplan analysis provided evidence of association between central fat mass and SNPs in two genes - PLA2G1B (P = 0.0067) and P2RX4 (P = 0.017). These data provide replication and refinement of the 12q24 obesity locus and suggest that genes involved in phospholipase and purinoreceptor pathways may regulate fat accumulation and distribution.
Adolescent↗
Functional characterization of calcium sensing receptor polymorphisms and absence of association with indices of calcium homeostasis and bone mineral density.
OBJECTIVES: Associations between calcium-sensing receptor (CaSR) polymorphisms and serum calcium, PTH and bone mineral density (BMD) have been reported by six studies. However, three other studies have failed to detect such associations. We therefore further investigated three CaSR coding region polymorphisms (Ala986Ser, Arg990Gly and Gln1011Glu) for associations with indices of calcium homeostasis and BMD and for alterations in receptor function. PATIENTS AND DESIGN: One hundred and ten adult, Caucasian, female, dizygotic twin pairs were investigated for associations between the three CaSR polymorphisms and serum calcium, albumin, PTH, 25-hydroxyvitamin D(3) (25OHD(3)), 1,25-dihydroxyvitamin D(3)[1,25(OH)(2)D(3)], urinary calcium excretion and BMD. Each polymorphic CaSR was also transfected into HEK293 cells and functionally evaluated. RESULTS: There was a lack of association between each of these three CaSR polymorphisms and serum calcium corrected for albumin, PTH, 25OHD(3), 1,25(OH)(2)D(3), urinary calcium excretion or BMD at the hip, forearm and lumbar spine. These findings were supported by a lack of functional differences in the dose-response curves of the CaSR variants, with the EC(50) values (mean +/- SEM) of the wild-type (Ala986/Arg990/Gln1011), Ser986, Gly990 and Glu1011 CaSR variants being 2.74 +/- 0.29 mm, 3.09 +/- 0.34 mm (P > 0.4), 2.99 +/- 0.23 mm (P > 0.4) and 2.96 +/- 0.30 mm (P > 0.5), respectively. CONCLUSIONS: Our study, which was sufficiently powered to detect effects that would explain up to 5%, but not less than 1%, of the variance has revealed that the three CaSR polymorphisms of the coding region have no major influence on indices of calcium homeostasis in this female population, and that they do not alter receptor function.
Adolescent↗
Heritability of the second to fourth digit ratio (2d:4d): A twin study.
The second to fourth finger length ratio (2d:4d) has been the subject of much recent work and is thought to be related to diverse gender and hormone-related traits including sports ability, disease susceptibility, attractiveness and sexuality. It is established in utero and remains constant in adulthood. Familial clustering has been thought to contribute to the development of 2d:4d from early studies but no twin studies exploring heritability have been reported to date. In this study, a sample of 456 female twin pairs (148 monozygotic [MZ], 308 dizygotic [DZ]) aged 18 to 79 years was used to estimate the heritability of 2d:4d for the right and left hands. Finger lengths were derived from hand x-rays. Variance components analysis was used to estimate and contrast genetic and environmental effects on this phenotype. The mean 2d:4d was 0.92 (SD = 0.001) for both hands. The MZ intraclass correlation was higher than in DZ (.66 vs. .35 for right 2d:4d, and .71 vs. .37 for left 2d:4d). The best fit model included additive polygenic and unique environmental effects ('AE' model), with no significant common environmental effects detected. Heritability was estimated to be approximately 66% for 2d:4d (95% confidence interval 0.5-0.78). These results suggest a substantial genetic contribution to the determination of this hormonally related skeletal ratio in women, which could be more influential than the effects of common prenatal environmental factors. However the current study design does not preclude the possibility of confounding between heritability estimates and unobserved prenatal effects.
Adolescent↗
Genetic influences on motion sickness susceptibility in adult women: a classical twin study.
BACKGROUND: Motion sickness is a common and potentially debilitating condition that characteristically occurs in situations of conflicting sensory input. While the precise stimuli that give rise to this trait are increasingly well characterized, the underlying determinants of individual susceptibility to motion sickness remain unclear. This study uses a classical twin design to assess the influence of genetic and environmental factors. METHODS: A postal survey was conducted in an age-matched sample of 3652 monozygotic (MZ) and dizygotic (DZ) adult female twins selected from the TwinsUK Registry. Study participants were asked to complete items from a validated questionnaire relating to their lifetime susceptibility to motion sickness. The relative contribution of genetic and environmental factors to motion sickness susceptibility was assessed using variance components analysis. RESULTS: The response rate to the questionnaire was 78%. Approximately 40% of respondents reported at least moderate susceptibility to motion sickness. The pattern of responses among twins indicated a significant genetic contribution with heritability for a motion sickness factor score estimated as 57% (95% CI: 51%, 63%). The heritability of recalled motion sickness was at its highest in childhood (70% [59%, 80%]) and declined through puberty and the early adult years. DISCUSSION AND CONCLUSIONS: The findings highlight the importance of genetic factors in determining an individual's underlying propensity to motion sickness and should stimulate the search for specific susceptibility genes.
Adult↗
Central retinal thickness is positively correlated with macular pigment optical density.
Macular pigment (MP) has been suggested to have a protective role in age-related macular degeneration by reducing the amount of oxidative stress on the retina. MP levels peak at the foveal center, where it is found predominantly in the receptor axon and inner plexiform layers of the retina. The purpose of this study was to investigate the relationship between central retinal thickness and macular pigment optical density in a group of healthy subjects. We report that macular pigment optical density (MPOD) has a significant and positive relationship with central retinal thickness as measured by optical coherence tomography. The strength of the observed relationship (r approximately 0.30) was independent of the technique used to measure MPOD, whether heterochromatic flicker photometry (HFP) or 2-wavelength autofluorescence (AF). Of note, there was no statistically demonstrable relationship between MPOD at an eccentricity of 1- or 2-degrees and central retinal thickness. This finding has important implications for future studies investigating MPOD, and its response to dietary modification/supplementation.
Adult↗
Genome-wide scan for prospective memory suggests linkage to chromosome 12q22.
Prospective memory slips (forgetting to do something) are as part of everyday memory failure as retrospective complaints (forgetting a past event). The extent to which genes influence prospective and retrospective memory is so far unclear. This study aims to quantify the relative genetic and environmental influences on such memory slips and seeks to identify QTL's with the first genome-wide scan for such traits. A classic twin design was implemented: comprising 896 monozygotic (MZ) and 1008 dizygotic (DZ) female twin pairs aged between 19 and 85 (mean age, 51) participated. The prospective and retrospective memory questionnaire (PRMQ) consists of 16 items, eight asking about prospective memory failures and eight concerning retrospective failures. Heritability for prospective memory and retrospective memory were found to be 44% and 41%, respectively. A genome- wide scan of 489 female DZ twin pairs suggested a QTL on chromosome 12q22 for prospective memory (LOD 2.76, empirical p-value 0.0006). Within this QTL lies an obvious candidate-the SCAD gene. These results suggest that large-scale gene discovery studies are possible with self-report memory questionnaires.
Adult↗
Menopause modifies the association of leukocyte telomere length with insulin resistance and inflammation.
CONTEXT: Leukocyte telomere length is inversely correlated with age, insulin resistance, serum leptin, and smoking. OBJECTIVE: We explored whether menopausal status modifies the relations between leukocyte telomere length and insulin resistance. In addition, we examined the effect of menopause on the relation between leukocyte telomere length and C-reactive protein (CRP), an index of inflammation. DESIGN: This was an observational cohort study. SETTING: The study setting was community based. PARTICIPANTS: A total of 1517 women aged 18-79 yr selected only for belonging to a twin pair and representative of the general population participated in the study. MAIN OUTCOME MEASURE: Leukocyte telomere restriction fragment length (TRFL) was measured. RESULTS: Insulin resistance (expressed in the homeostasis model assessment), leptin, and CRP were inversely correlated with leukocyte TRFL in premenopausal but not postmenopausal women. Insulin resistance, CRP, but not leptin independently accounted for variation in white blood cell TRFL in premenopausal women. CONCLUSIONS: Menopausal status impacts leukocyte telomere length and its relation with insulin resistance and inflammation in women.
Adolescent↗
Radiographic progression of lumbar spine disc degeneration is influenced by variation at inflammatory genes: a candidate SNP association study in the Chingford cohort.
STUDY DESIGN: A candidate gene association study in a longitudinal cohort. OBJECTIVE: To investigate the association between polymorphisms at 25 candidate genes and progression of individual radiographic features of lumbar disc degeneration (LDD). SUMMARY OF BACKGROUND DATA: LDD is characterized radiographically by the presence of osteophytes and disc space narrowing and is known to have a genetic component. Because of the high prevalence of radiographic features, progression may be a more useful phenotype clinically to study than prevalence itself. METHODS: We tested the effect on radiographic progression of LDD of polymorphisms in 25 genes, 24 of which had been previously tested with regards to knee osteoarthritis. The progression traits used were the change in radiographic grade over 9 years in osteophytes, disc space narrowing, and summary Kellgren-Lawrence grade. Lumbar spine radiographs (L1-L5) at baseline and at follow-up were read for 720 women genotyped at the 25 genes participating in the Chingford study. RESULTS: Polymorphisms in MMP3, TIMP1, and COX2, which encode molecules involved in inflammatory pathways, were associated with radiographic progression of LDD. The strongest associations observed (statistically significant after correcting for multiple comparisons) were between COX2 and change in osteophyte grade (P < 0.001) and Kellgren-Lawrence grade (P < 2 x 10(-5)), and between the genes for vitamin D receptor (P < 0.002) and a thrombospondin (THSD2) (P < 0.002) and change in osteophyte grade. CONCLUSIONS: Our results suggest a role for genes regulating inflammatory pathways in the radiographic progression of spine degeneration. This could prove a fruitful area for future therapeutics for the spine and other joints.
Cyclooxygenase 2↗
Reproducibility and sensitivity to change of various methods to measure joint space width in osteoarthritis of the hip: a double reading of three different radiographic views taken with a three-year interval.
Joint space width (JSW) and narrowing (JSN) measurements on radiographs are currently the best way to assess disease severity or progression in hip osteoarthritis, yet we lack data regarding the most accurate and sensitive measurement technique. This study was conducted to determine the optimal radiograph and number of readers for measuring JSW and JSN. Fifty pairs of radiographs taken three years apart were obtained from patients included in a structure modification trial in hip osteoarthritis. Three radiographs were taken with the patient standing: pelvis, target hip anteroposterior (AP) and oblique views. Two trained readers, blinded to each other's findings, time sequence and treatment, each read the six radiographs gathered for each patient twice (time interval > or = 15 days), using a 0.1 mm graduated magnifying glass. Radiographs were randomly coded for each reading. The interobserver and intraobserver cross-sectional (M0 and M36) and longitudinal (M0-M36) reproducibilities were assessed using the intraclass coefficient (ICC) and Bland-Altman method for readers 1 and 2 and their mean. Sensitivity to change was estimated using the standardized response mean (SRM = change/standard deviation of change) for M0-M36 changes. For interobserver reliability on M0-M36 changes, the ICCs (95% confidence interval [CI]) were 0.79 (0.65-0.88) for pelvic view, 0.87 (0.78-0.93) for hip AP view and 0.86 (0.76-0.92) for oblique view. Intraobserver reliability ICCs were 0.81 (0.69-0.89) for observer 1 and 0.97 (0.95-0.98) for observer 2 for the pelvic view; 0.87 (0.78-0.92) and 0.97 (0.96-0.99) for the hip AP view; and 0.73 (0.57-0.84) and 0.93 (0.88-0.96) for the oblique view. SRMs were 0.61 (observer 1) and 0.82 (observer 2) for pelvic view; 0.64 and 0.75 for hip AP view; and 0.77 and 0.70 for oblique view. All three views yielded accurate JSW and JSN. According to the best reader, the pelvic view performed slightly better. Both readers exhibited high precision, with SRMs of 0.6 or greater for assessing JSN over three years. Selecting a single reader was the most accurate method, with 0.3 mm precision. Using this cutoff, 50% of patients were classified as 'progressors'.
Aged↗
Genetic influences on variation in female orgasmic function: a twin study.
Orgasmic dysfunction in females is commonly reported in the general population with little consensus on its aetiology. We performed a classical twin study to explore whether there were observable genetic influences on female orgasmic dysfunction. Adult females from the TwinsUK register were sent a confidential survey including questions on sexual problems. Complete responses to the questions on orgasmic dysfunction were obtained from 4037 women consisting of 683 monozygotic and 714 dizygotic pairs of female twins aged between 19 and 83 years. One in three women (32%) reported never or infrequently achieving orgasm during intercourse, with a corresponding figure of 21% during masturbation. A significant genetic influence was seen with an estimated heritability for difficulty reaching orgasm during intercourse of 34% (95% confidence interval 27-40%) and 45% (95% confidence interval 38-52%) for orgasm during masturbation. These results show that the wide variation in orgasmic dysfunction in females has a genetic basis and cannot be attributed solely to cultural influences. These results should stimulate further research into the biological and perhaps evolutionary processes governing female sexual function.
Adult↗
Body odor similarity in noncohabiting twins.
There is currently considerable interest in biometric approaches using human odor as a marker of disease or genetic individuality. Body odor is also thought to be used during mate choice to select genetically compatible mates. The idea that body odor reveals information about both genetic identity and genetic similarity is most readily tested by examining odor in twin pairs. However, although this idea can be traced back 130 years to Francis Galton in 1875, most studies using dogs fail to control for shared environmental effects associated with cohabitation. Here we show that odors of identical twins (but not dizygotic twins) can be matched by human sniffers at rates better than chance, even when the twins are living apart. In addition, matching frequencies for identical twin odors were not significantly different from those for duplicate odors from the same individual. These results indicate an important genetic influence on body odor and the potential for developing technologies for human odor printing in relation to underlying genotype.
Adult↗
Identification of QTLs for serum lipid levels in a female sib-pair cohort: a novel application to improve the power of two-locus linkage analysis.
Using a novel approach for a two-locus model that provides a greatly increased power to detect multiple quantitative trait loci (QTLs) in simulated data, we identified in a sample of 961 female sib-pairs, three genome-wide significant QTLs for apolipoprotein A1 on chromosomes 8p21.1-q13.1 (LOD score 3.71), 9q21.32-33.1 (LOD score 3.28) and 10p15.1-p13 (LOD score 5.51), two for lipoprotein (a) on chromosomes 6q25.2-q27 (LOD score 10.18) and 21q21.1-q21.3 (LOD score 4.57) and two for triglycerides on chromosomes 4q28.3-32.1 (LOD score 3.71) and 5q23.1-q32 (LOD score 3.60). The two-locus ordered-subset analysis has led to the confirmation of known and likely identification of novel regions linked to serum lipid levels that would have otherwise been missed and deserves wider application in linkage analyses of quantitative traits. Given the relative lack of power for the sample sizes commonly used in human genetics linkage studies, minor QTL effects often go undetected and those that are detected will be upwardly biased. We show through simulation that the discrepancy between the real and estimated QTL-effects is often likely to generate an unpredictable source of false-negative errors, using multi-locus models, reducing the power to detect multiple QTLs through oligogenic linkage analysis. The successful simultaneous modelling of the identified QTLs in a multi-locus context helps to eliminate false positives and increases the power to detect linkages, adding compelling evidence that they are likely to be reliable QTLs for these lipid traits.
Chromosome Mapping↗
Epigenetic differences arise during the lifetime of monozygotic twins.
Monozygous twins share a common genotype. However, most monozygotic twin pairs are not identical; several types of phenotypic discordance may be observed, such as differences in susceptibilities to disease and a wide range of anthropomorphic features. There are several possible explanations for these observations, but one is the existence of epigenetic differences. To address this issue, we examined the global and locus-specific differences in DNA methylation and histone acetylation of a large cohort of monozygotic twins. We found that, although twins are epigenetically indistinguishable during the early years of life, older monozygous twins exhibited remarkable differences in their overall content and genomic distribution of 5-methylcytosine DNA and histone acetylation, affecting their gene-expression portrait. These findings indicate how an appreciation of epigenetics is missing from our understanding of how different phenotypes can be originated from the same genotype.
5-Methylcytosine↗
Effect of risedronate on joint structure and symptoms of knee osteoarthritis: results of the BRISK randomized, controlled trial [ISRCTN01928173].
To determine the efficacy and safety of risedronate in patients with knee osteoarthritis (OA), the British study of risedronate in structure and symptoms of knee OA (BRISK), a 1-year prospective, double-blind, placebo-controlled study, enrolled patients (40-80 years of age) with mild to moderate OA of the medial compartment of the knee. The primary aims were to detect differences in symptoms and function. Patients were randomized to once-daily risedronate (5 mg or 15 mg) or placebo. Radiographs were taken at baseline and 1 year for assessment of joint-space width using a standardized radiographic method with fluoroscopic positioning of the joint. Pain, function, and stiffness were assessed using the Western Ontario and McMaster Universities (WOMAC) OA index. The patient global assessment and use of walking aids were measured and bone and cartilage markers were assessed. The intention-to-treat population consisted of 284 patients. Those receiving risedronate at 15 mg showed improvement of the WOMAC index, particularly of physical function, significant improvement of the patient global assessment (P < 0.001), and decreased use of walking aids relative to patients receiving the placebo (P = 0.009). A trend towards attenuation of joint-space narrowing was observed in the group receiving 15 mg risedronate. Eight percent (n = 7) of patients receiving placebo and 4% (n = 4) of patients receiving 5 mg risedronate exhibited detectable progression of disease (joint-space width >or= 25% or >or= 0.75 mm) versus 1% (n = 1) of patients receiving 15 mg risedronate (P = 0.067). Risedronate (15 mg) significantly reduced markers of cartilage degradation and bone resorption. Both doses of risedronate were well tolerated. In this study, clear trends towards improvement were observed in both joint structure and symptoms in patients with primary knee OA treated with risedronate.
Adult↗
Association between a variation in the phosphodiesterase 4D gene and bone mineral density.
BACKGROUND: Fragility fractures caused by osteoporosis are a major cause of morbidity and mortality in aging populations. Bone mineral density (BMD) is a useful surrogate marker for risk of fracture and is a highly heritable trait. The genetic variants underlying this genetic contribution are largely unknown. METHODS: We performed a large-scale association study investigating more than 25,000 single nucleotide polymorphisms (SNPs) located within 16,000 genes. Allele frequencies were estimated in contrasting DNA pools from white females selected for low (<0.87 g/cm2, n = 319) and high (> 1.11 g/cm2, n = 321) BMD at the lumbar spine. Significant findings were verified in two additional sample collections. RESULTS: Based on allele frequency differences between DNA pools and subsequent individual genotyping, one of the candidate loci indicated was the phosphodiesterase 4D (PDE4D) gene region on chromosome 5q12. We subsequently tested the marker SNP, rs1498608, in a second sample of 138 white females with low (<0.91 g/cm2) and 138 females with high (>1.04 g/cm2) lumbar spine BMD. Odds ratios were 1.5 (P = 0.035) in the original sample and 2.1 (P = 0.018) in the replication sample. Association fine mapping with 80 SNPs located within 50 kilobases of the marker SNP identified a 20 kilobase region of association containing exon 6 of PDE4D. In a second, family-based replication sample with a preponderance of females with low BMD, rs1498608 showed an opposite relationship with BMD at different sites (p = 0.00044-0.09). We also replicated the previously reported association of the Ser37Ala polymorphism in BMP2, known to interact biologically with PDE4D, with BMD. CONCLUSION: This study indicates that variants in the gene encoding PDE4D account for some of the genetic contribution to bone mineral density variation in humans. The contrasting results from different samples indicate that the effect may be context-dependent. PDE4 inhibitors have been shown to increase bone mass in normal and osteopenic mice, but up until now there have been no reports implicating any member of the PDE4 gene family in human osteoporosis.
3',5'-Cyclic-AMP Phosphodiesterases↗
Proopiomelanocortin gene variants are associated with serum leptin and body fat in a normal female population.
A major quantitative trait locus (QTL) determining leptin levels has been linked to the proopiomelanocortin (POMC) region on chromosome 2. Most studies, based on under 350 lean or obese subjects, have shown no association between POMC SNP 8246 C/T and serum leptin, but significant associations have been reported with RsaI 8246 C/T SNP haplotypes. We have investigated association of four POMC SNPs with body composition and serum leptin in 2758 normal Caucasian female subjects (mean age 47.4+/-12.5 years), from the St Thomas' UK Adult Twin Registry (Twins UK): RsaI and 51 G/C in the 5'UTR and 8246 C/T and 7965 C/T in the 3'UTR. Under the recessive model, the 8246 T allele (freq. 0.18) was significantly associated with higher mean BMI (P=0.032) and total fat (P=0.046, both after age adjustment). Significant associations were maintained in sib-TDT with waist (P=0.049), total fat (P=0.037) and emerged with serum leptin (P=0.016). Initial significant associations between RsaI (-) allele (freq. 0.30) and higher waist (P=0.04) or % central fat (P=0.02) were not maintained in sib-TDT. No significant associations were found between body composition or serum leptin and RsaI/8246 C/T haplotype and none with 51 G/C (freq. 0.01) or 7965 C/T (freq. 0.004). There was minimal pairwise LD between the four loci, apart from RsaI and 8246 C/T (D'=-0.78 (P<0.0001)). Associations of BMI, weight and total fat with SNPs in regions flanking the POMC gene in this powerful study suggest that regulation of POMC expression may be influential in determining body weight.
Adipose Tissue↗