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In order to detect chimerism after allogeneic hematopoietic SCT (HSCT), several methods have been developed. In this study we describe the use of a set of insertion/deletion (Indel) polymorphic loci to determine the level of donor cell engraftment. We analyzed 50 DNA samples from patients who had undergone HSCT, and also several artificial chimeric samples created by mixing different DNA specimens from non-transplanted donors in various proportions. A specific set of 38 autosomic Indel polymorphisms were analyzed. For comparison purposes, a set of 15 short tandem repeats (STRs) were analyzed using the Identifiler Plus Amplification Kit. Our results suggest that Indel-based and STR-based procedures behave similarly in most cases. However, Indel analysis may provide additional information in some cases with a small minor chimeric component or when the presence of stutter bands complicates chimerism estimation.

Farnesyl diphosphate synthase (FDPS) is necessary for osteoclast survival and activity and is considered as a major molecular target of aminobisphosphonates. Our objective was to analyze the influence of FDPS polymorphisms on bone mineral density (BMD) and the response to antiresortive drugs. Three single-nucleotide polymorphisms of FDPS were analyzed in 1186 postmenopausal women. There was only a marginally significant association of baseline hip BMD with rs11264359 alleles ( P =0.043). However, among 191 women receiving antiresortive therapy, there was a very significant association between rs2297480 or rs11264359 alleles and the BMD changes after aminobisphosphonate therapy for an average period of 2.5 years ( P =0.001). The genotype explained 7.2% of the variance in the BMD response. On the other hand, there was no association between the BMD changes after raloxifene therapy and any of the polymorphisms studied. These results suggest that common polymorphisms of the FDPS gene influence the response to aminobisphosphonates.

BackgroundMild forms of adult hypophosphatasia may have subtle manifestations, and may go unrecognizedObjectivesTo get a better knowledge of its clinical spectrum.MethodsWe performed a computerized search of low total alkaline phosphatase among laboratory records. The diagnosis of hypophosphatasia was confirmed by measuring serum pyridoxal phosphate (PLP) and bone alkaline phosphatase. Carotid ultrasonography was performed in patients and controls with a MyLab 70 scanner (Esaote; Genoa, Italy), equipped with 7–12 MHz linear transducer.ResultsOver a 31 month period, we identified 130 individuals with at least one determination of serum alkaline phosphatase less than 26 u/l. After reviewing the clinical records, unexplained persistently low levels were found in 42 individuals who accepted to participate in the study (10 men, 32 women). Age range was 20-77 yr (mean 51). Total alkaline phosphatase levels were positively correlated with bone alkaline phosphatase (r=0.52, p<0.001). Serum PLP was inversely correlated with bone alkaline phosphatase. Ten individuals (24%) had PLP levels above the reference range of 175 nmol/l, consistent with hypophosphatasia. In comparison with those with normal PLP levels, these individuals had higher frequency of hypertension (50 vs 12%, p=0.02). Likewise, individuals with hypophosphatasia showed a trend to have early atherosclerotic disease. Carotid ultrasound showed bilateral plaques in 4 out of 9 patients (44%), and only in 26% of the age and sex-matched controls. The intima-media thickness also tended to be increased in the patients (670±70 vs. 648±110 microns; p=0.18).ConclusionsThese preliminary data suggest that individuals with adult hypophosphatasia may be at increased cardiovascular risk. The results should be confirmed in larger studies.Disclosure of InterestNone declared

BackgroundAccelerated aging may be a component of osteoarthritis (OA) as shown by changes observed at the level of cartilage (local) in multiple studies. Systemic changes of biological aging have been much less studied, but accelerated telomere shortening (a biomarker of biological aging) has been described in the blood of patients with hand OA (1). In addition, some studies report increases in age-related comorbidities, frailty and mortality in patients with OA, which are consistent with sytemic premature aging. The recent discovery of an epigenetic biomarker of biological age consisting in DNA methylation age measures (DmAM) provides a new opportunity to address these questions.ObjectivesWe aimed to explore the local and the systemic components of biological aging in OA using epigenetic DmAM biomarkers.MethodsThree tissues were investigated: blood with 890 samples (182 controls without OA, 206 clinical hand OA, 229 severe knee OA and 273 severe hip OA), bone from femoral heads (45 controls without OA and 33 severe hip OA) and cartilage from tibial plateau or femoral heads (31 controls without OA and 36 severe OA). Two DmAM were used: a novel DmAM based on 8 CpG selected from previous work (2) and analyzed by quantitative minisequencing for blood; and the multi-tissue age estimator by Horvath (3), which is based on 353 CpGs analyzed with Illumina Methylation arrays, for bone and cartilage. Accuracy of the 8 CpG DmAM was evaluated with correlation and mean absolute difference (MAD) to age. Differences in DmAM (ΔDmAM) between OA patients and controls were evaluated with ANOVA adjusting for age and sex.ResultsOA cartilage showed an accelerated epigenetic aging of 3.7 years in relation with cartilage from controls without OA (Table 1). By contrast, no significant difference was observed in bone from OA patients (Table 1).The new DmAM for blood based on 8 CpG was accurate as shown in data sets from controls, two from previous studies and the 182 controls without OA from the current study (R2≥0.52, p<10–16, MAD≤7.3 years). Therefore, it was applied to compare the controls without OA with the OA patients. None of the three groups of patients, hand OA, knee OA or hip OA, showed accelerated aging in blood (Table 1).Table 1.Specific accelerated DmAM in OA cartilage compared with control cartilageTissueOA setΔDmAM (95% CI)P-valueCartilageKnee/hip3.66 (1.06 to 6.26)0.008BoneHip0.04 (−1.80 to 1.87)0.34BloodHand0.01 (−1.10 to 1.12)0.98Knee0.04 (−0.94 to 1.02)0.93Hip−0.72 (−1.70 to 0.25)0.11ConclusionsOA cartilage showed premature biological (epigenetic) aging according to DNA methylation changes. This effect was cartilage-specific, excluding a systemic component, since it was not observed in bone tissue or in blood.ReferencesZhai G, et al. Ann Rheum Dis. 2006;65:1444Weidner CI, et al. Genome biology. 2014;15:R24Horvath S. Genome biology. 2013;14:R115AcknowledgementFunding was provided by the Instituto de Salud Carlos III (Spain) through grants PI12/01909, PI15/01651, RD12/009/008, and P12/615, which are partially financed by the European Regional Development Fund of the EU.Disclosure of InterestNone declared

A collaborative work was carried out by the Spanish and Portuguese ISFG Working Group (GEP‐ISFG) to estimate Y‐STR mutation rates. Seventeen Y chromosome STR loci (DYS19, DYS385, DYS389I and II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438, DYS439, DYS460, DYS461, DYS635 [GATA C4], GATA H4, and GATA A10) were analyzed in a sample of 3,026 father/son pairs. Among 27,029 allele transfers, 54 mutations were observed, with an overall mutation rate across the 17 loci of 1.998 × 10–3 (95% CI, 1.501 × 10–3 to 2.606 × 10–3). With just one exception, all of the mutations were single‐step, and they were observed only once per gametogenesis. Repeat gains were more frequent than losses, longer alleles were found to be more mutable, and the mutation rate seemed to increase with the father's age. Hum Mutat 26(6), 520–528, 2005. © 2005 Wiley‐Liss, Inc.

BackgroundIntima media thickness (IMT) and coronary artery calcification (CAC) quantification using multidetector computed tomography (MDCT) scanner are useful in detecting subclinical atherosclerosis and are good surrogate markers of cardiovascular morbidity and mortality in general population and in rheumatoid arthritis (RA)A good correlation between these methods has been reported in RA, being CAC a slightly more sensitive technique (1)ObjectivesOur aim is to determine the value of IMT that better predicts the presence of coronary atherosclerosis, using CAC as reference and assuming CAC value of 100 as the cut-off point indicating high cardiovascular risk.MethodsWe evaluated 127 RA patients without previous cardiovascular events. Carotid ultrasonography was performed by a MyLab 70 scanner (Esaote; Genoa, Italy), equipped with 7–12 MHz linear transducer and the automated software guided technique radiofrequency – Quality Intima Media Thickness in real-time (QIMT, Esaote, Maastricht, Holland). According to data from non-rheumatic patients and also from RA patients, an IMT≥0.90 mm is a good predictor of high cardiovascular risk. To determine CAC score, a CT Imaging of coronary arteries using a 32-slice MDCT scanner (Lightspeed, Pro 32, GE Healthcare, USA) was performed.ResultsPatients with IMT below 0.90 mm had CAC values of 88±210 whereas patients with IMT≥0.90 mm had mean CAC values of 190± 272 (p=0.066). We found a positive correlation between IMT and CAC (correlation coefficient 0,303; p=0.001).The IMT cut-off value ≥0.90 mm had a sensitivity of 32% for detecting CAC ≥100. ROC curve analysis showed and area under the curve of 0.664. The IMT cut-off value of 0.80 mm had a sensitivity of 40% and a specificity of 71.3%. Lowering the IMT cut-off point to 0.70, we reached a sensitivity of 76% and a specificity of 51.5% for CAC ≥100 detection. The positive predictive value for the IMT cut-off point of 0.70 mm was 76% in our population, being the negative predictive value 49.5%VariableVariableAge (mean ± SD)58. 57±9.7IMT ≥0.7 mm, n (%)71 (56)Female sex, n (%)92 (72.,4)CAC score (mean ± SD)103.4±222.6IMT ≥0,9 mm, n (%)19 (15)CAC score ≥100, n (%)26 (20.5)ConclusionsIMT values ≥0.70 mm predict coronary artery calcification score above 100 with a sensitivity of 76%. According to that, the IMT value considered as predictor of high cardiovascular risk would be 0.70 mm instead of 0.90 mm.ReferencesCorrales A et al. “Cardiovascular risk stratification in rheumatic diseases: carotid ultrasound is more sensitive than coronary artery calcification score to detect subclinical atherosclerosis in patients with rheumatoid arthritis” Ann Rheum Dis. 2013,72 1764–1770.Disclosure of InterestNone declared

BackgroundCarotid ultrasonography (CU) and coronary artery calcification score (CAC) evaluated by multidetector computed tomography (MDCT) scanner are useful in detecting subclinical atherosclerosis and are good surrogate markers of cardiovascular morbidity and mortality in general population and in rheumatoid arthritis (RA). In RA, a good correlation between both diagnostic methods has been demonstrated, being CU more sensitive for detecting subclinical atherosclerosis.ObjectivesOur aim is to determine the association between the presence of carotid plaque and CAC quantification, and, using the presence of carotid plaque as a reference, to determine the cut-off value of CAC score that better predicts subclinical carotid atherosclerosis.MethodsWe evaluated 127 RA patients without previous cardiovascular events. Carotid ultrasonography was performed by a MyLab 70 scanner (Esaote; Genoa, Italy), equipped with 7–12 MHz linear transducer and the automated software guided technique radiofrequency – Quality Intima Media Thickness in real-time (QIMT, Esaote, Maastricht, Holland). Carotid plaque was defined according to the Manheim Conference Consensus criteria. To determine CAC score, a CT Imaging of coronary arteries using a 32-slice MDCT scanner (Lightspeed, Pro 32, GE Healthcare, USA) was performed. A CAC score ≥100 was considered as a surrogate marker of very high cardiovascular risk.ResultsUnilateral and bilateral carotid plaque frequency and the mean CAC score in the different groups are summarized in table 1. Patients without carotid plaques had a mean CAC value of 23 ±49 [range 0–250], being 50 ±116 [0–569] in patients with unilateral plaque and 192± 302 [0–1205] in patients with bilateral plaques, being these differences statistically significant (p<0.001). Using a CAC score ≥100 as a marker of very high cardiovascular risk, the sensitivity to detect carotid plaques was very low (28%).A ROC curve comparing the presence of carotid plaque and CAC quantification was performed, being the area under the curve 0.692. When we used CAC score value score ≥1 as the cut-off value to predict high cardiovascular risk, the sensitivity and specificity for the presence of carotid plaques increased (69.3% and 64.1%, respectively). Positive predictive value for CAC ≥1 was 81.3% in our population, being 48.1% the negative predictive value.Regarding bilateral carotid plaques, the CAC score ≥100 had a sensitivity of 40%. ROC curve showed an area under the curve of 0.712. Using a CAC score value score ≥1 as the cut-off value to predict high cardiovascular risk, the sensitivity to determine the presence of carotid plaques increased to 76.4% but the specificity decreased to 54.2%.VariableVariableAge (mean ± SD)58, 57±9,7Bilateral plaque, n (%)55 (43,3)Female, n (%)92 (72,4)CAC (media ± DE)103,4±222,6Plaque No, n (%)39 (30,7)CAC ≥1, n (%)75 (59)Plaque Yes, n (%)88 (69,3)CAC ≥100, n (%)26 (20,5)Unilateral plaque, n (%)33 (26)ConclusionsA CAC score value score ≥1 is good predictors of carotid plaques, showing sensitivity close to 70%. Our data support the use of a CAC score value score ≥1 instead of a CAC score ≥100 as the cut-off value to predict high cardiovascular risk in patients with RA.Disclosure of InterestNone declared