[Show abstract][Hide abstract] ABSTRACT: The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10-14), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10-11; ncases = 98,742 and ncontrols = 409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10-11). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.
[Show abstract][Hide abstract] ABSTRACT: Atraumatic subtrochanteric and diaphyseal (atypical) femoral fractures are a rare, but important adverse event in patients treated with potent anti-resortive agents. The mechanisms involved are unknown and particularly the association with genetic variants has not been explored. The aim of the study was to identify rare genetic variants that could be associated with the occurrence of these fractures. We performed a genome-wide analysis of up to 300,000 variants, mainly distributed in gene coding regions, in 13 patients with atypical femoral fractures and 268 control women, either healthy or with osteoporosis. Twenty one loci were more frequent in the fracture group, with a nominal p value between 1 × 10(-6) and 2.5 × 10(-3). Most patients accumulated two or more allelic variants, and consequently the number of risk variants was markedly different between patients and controls (p = 2.6 × 10(-22)). The results of this pilot study suggest that these fractures are polygenic and are associated with the accumulation of changes in the coding regions of several genes.
[Show abstract][Hide abstract] ABSTRACT: Abstract This paper assesses the temporal variations of surface ozone concentrations during the period 2001-2010 in 3 regions of Spain with different geographical and socioeconomic features (northern coastland, central inland and northeast inland), as well as its link with atmospheric circulation. Specifically, daily surface atmospheric patterns over the aforementioned regions are characterized using NCEP/NCAR reanalysis data and an objective classification scheme in order to study the relationship between synoptic weather types and daily ozone levels. The results show that tropospheric ozone concentration has a tendency towards an increase during the study period, both during daytime and nighttime. Moreover, in general, this upward trend is seen throughout all of the seasons. The observed trends are in line with a reported decrease of NOX emissions and increase in surface solar radiation during the 2000s in Spain. On the other hand, interestingly, median concentrations were statistically significantly lower in days with anticyclonic weather conditions than in the rest of meteorological situations, while days with a directional weather type showed higher median levels of ozone concentration, with maximum values in days with northern and eastern component. Due to the detrimental effect that ozone has on human health, the relationship between synoptic weather patterns and daily ozone levels shown in this work could potentially be used for implementing pollution level alert protocols depending on forecast weather types.
[Show abstract][Hide abstract] ABSTRACT: 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.Bone Marrow Transplantation advance online publication, 11 August 2014; doi:10.1038/bmt.2014.173.
Bone Marrow Transplantation 08/2014; 49(11). DOI:10.1038/bmt.2014.173 · 3.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Sclerostin, the product of the SOST gene, is a key regulator of bone homeostasis. Sclerostin interferes with the Wnt signalling pathway and, therefore, has a negative effect on bone formation. Although the importance of sclerostin in bone homeostasis is well established, many aspects of its biology are still unknown. Due to its restricted pattern of expression, in vitro studies of SOST gene regulation are technically challenging. Furthermore, a more profound investigation of the molecular mechanism controlling sclerostin expression has been hampered by the lack of a good human in vitro model. Here, we describe two cell lines derived from the human osteosarcoma cell line SaOS-2 that produce elevated levels of sclerostin. Analysis of the super-producer cell lines showed that sclerostin levels were still reduced in response to parathyroid hormone treatment or in response to mechanical loading, indicating that these regulatory mechanisms were not affected in the presented cell lines. In addition, we did not find differences between the promoter or ECR5 sequences of our clones and the SaOS-2 parental line. However, the methylation of the proximal CpG island located at the SOST promoter was lower in the super-producer clones, in agreement with a higher level of SOST transcription. Although the underlying biological causes of the elevated levels of sclerostin production in this cell line are not yet clear, we believe that it could be an extremely useful tool to study the molecular mechanisms driving sclerostin expression in humans.
Calcified Tissue International 06/2014; 95(2). DOI:10.1007/s00223-014-9880-5 · 3.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Short-tandem repeat (STR) genotyping is widely used for forensic purposes and it is also used to determine the proportions of donor and recipient cells after hematopoietic stem-cell transplantation. New STR multiplexes have recently been developed to analyze the complete CODIS plus D19S433 and D2S1338, such as AmpFℓSTR® Identifiler® Plus PCR Amplification kit (Applied Biosystems) and Investigator™ IDplex® (Qiagen). The objective of this study was to compare the sensitivity of both kits in the analysis of chimerism. The Investigator™ IDplex® allowed quimerism detection only in 10 (67%) of the 15 cases with chimerism detected by using the Identifiler® Plus kit, suggesting that the latter may have higher sensitivity.
Forensic Science International Genetics Supplement Series 01/2014; DOI:10.1016/j.fsigss.2011.09.084
[Show abstract][Hide abstract] ABSTRACT: Although their primary therapeutic indications are different, aminobisphosphonates and statins target enzymes in the mevalonate pathway, which is critical for bone homeostasis. Previous studies have shown that some polymorphisms of the gene encoding farnesyl diphosphate synthase (FDPS), the main target of aminobisphosphonates, modulate the response to these drugs. In this study, we explored whether those single nucleotide polymorphisms (SNPs) also influence the changes in bone mineral density (BMD) following therapy with statins. Sixty-six patients with coronary heart disease were studied at baseline and after 1-year therapy with atorvastatin. BMD was measured by DXA. Three SNPs of the FDPS gene (rs2297480, rs11264359 and rs17367421) were analyzed by using Taqman assays. The results showed that there was no association between the SNPs and basal BMD. However, rs2297480 and rs11264359 alleles, which are in linkage disequilibrium, were associated with changes in hip BMD following atorvastatin therapy. Thus, patients with AA genotype at the rs2297480 locus had a 0.8 ± 0.8 % increase in BMD at the femoral neck, whereas in patients with AC/CC genotypes, BMD showed a 2.3 ± 0.8 % decrease (p = 0.02). Similar results were obtained regarding changes of BMD at the femoral trochanter and when alleles at the rs11264359 locus were analyzed. However, there was no association between BMD and rs17367421 alleles. In conclusion, these results suggest that polymorphisms of the FDPS gene may influence the bone response to various drugs targeting the mevalonate pathway, including not only aminobisphosphonates but also statins.
Rheumatology International 12/2013; 34(8). DOI:10.1007/s00296-013-2914-x · 1.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We reported previously that the expression of Wnt-related genes is lower in osteoporotic hip fractures than in osteoarthritis. We aimed to confirm those results by analyzing β-catenin levels and explored potential genetic and epigenetic mechanisms involved. ß-catenin gene expression and nuclear levels were analyzed by real time PCR and confocal immunofluorescence. Increased nuclear β-catenin was found in osteoblasts isolated from patients with osteoarthritis (99±4 units vs. 76±12, p=0.01, n=10), without differences in gene transcription, which is consistent with a post-translational down-regulation of β-catenin and decreased Wnt pathway activity. Twenty four single nucleotide polymorphisms (SNPs) of genes showing differential expression between fractures and osteoarthritis (WNT4, WNT10A, WNT16 and SFRP1) were analyzed in DNA isolated from blood of 853 patients. The genotypic frequencies were similar in both groups of patients, with no significant differences. Methylation of Wnt pathway genes was analyzed in bone tissue samples (15 with fractures and 15 with osteoarthritis) by interrogating a CpG-based methylation array. Six genes showed significant methylation differences between both groups of patients: FZD10, TBL1X, CSNK1E, WNT8A, CSNK1A1L and SFRP4. The DNA demethylating agent 5-deoxycytidine up-regulated 8 genes, including FZD10, in an osteoblast-like cell line, whereas it down-regulated other 16 genes. In conclusion, Wnt activity is reduced in patients with hip fractures, in comparison with those with osteoarthritis. It does not appear to be related to differences in the allele frequencies of the Wnt genes studied. On the other hand, methylation differences between both groups could contribute to explain the differences in Wnt activity.
[Show abstract][Hide abstract] ABSTRACT: Background
Several studies suggested that some vitamin D receptor (VDR) and estrogen receptor(ER) polymorphisms influence bone mass. However, others did not confirm these results.This study was undertaken to determine if the genotypes revealed by the combined analysis ofVDR and ER polymorphisms are associated with clinically significant differences in peak bone mass and the risk of osteoporotic fractures.
Patients and Methods
Restriction fragment length polymorphisms of VDR were determined withthe enzymes BsmI, ApaI, TaqI, and FokI. Enzymes XbaI and PvuII were used as polymorphicmarkers of the ER. The study group comprised 149 young control women (18-34 years), 66postmenopausal controls, 99 women with hip fracture and 76 women with osteoporotic vertebralfractures. Bone mineral density (BMD) was measured by DEXA.
We did not find significant differences in lumbar spine or hip BMD among young womenwith different genotypes (determined with either single or multiple polymorphic markers).Likewise, there were no differences in the frequency distributions of VDR or ER alleles betweencontrol and fractured women. The study had a 77% power to detect a fracture odds ratio of2 in case of genotypes present in at least 15% of the population.
These results suggest that the polymorphic markers used in this study do not haveenough discriminant power to be clinically useful in the assessment of fracture risk.
[Show abstract][Hide abstract] ABSTRACT: Osteoarthritis (OA) has a strong genetic component, and experimental evidence suggests the involvement of the Wnt pathway in its pathogenesis. Hence, we explored the association of common single nucleotide polymorphisms (SNPs) related to the Wnt pathway with hip and knee OA. Seventy-eight SNPs were analyzed in 606 patients undergoing joint replacement and in 680 control subjects. SNPs were located in WNT1, WNT10A, WNT16, DVL2, FZD5, BCL9, SFRP1, TCF7L1 and SFRP4 genes. SNPs significantly associated with OA were genotyped in an independent group of 369 patients and 407 controls. One SNP in WNT10A, rs3806557, was associated with hip OA in men (OR 0.65, 95 % CI 0.46-0.93; p = 0.017), but the association was not confirmed in the replication phase. The TCF7L1 polymorphism rs11547160 was also associated with hip OA in the discovery set, but not in the replication set. Similarly, the SFRP4 SNP rs1052981 was associated with knee OA in women with OR of 2.73 (95 % CI 1.29-5.8; p = 0.006), but the association was not replicated. The BCL9 polymorphism rs2353525 was associated with knee OA in women, both in the unadjusted and in the age- and BMI-adjusted analysis (OR 2.01; 95 % CI 1.34-2.98; p = 0.0006). A similar, but not statistically significant, trend was observed in the replication phase. In the combined analysis, OR was 3.13 (1.34-7.28; p = 0.009). These data suggest that some SNPs of genes related to the Wnt pathway and, specifically BCL9, influence the genetic predisposition to osteoarthritis of the large joints in a sex- and joint-specific way.
Rheumatology International 07/2013; 33(11). DOI:10.1007/s00296-013-2821-1 · 1.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The European genetic landscape has been shaped by several human migrations occurred since Paleolithic times. The accumulation of archaeological records and the concordance of different lines of genetic evidence during the last two decades have triggered an interesting debate concerning the role of ancient settlers from the Franco-Cantabrian region in the postglacial resettlement of Europe. Among the Franco-Cantabrian populations, Basques are regarded as one of the oldest and more intriguing human groups of Europe. Recent data on complete mitochondrial DNA genomes focused on macrohaplogroup R0 revealed that Basques harbor some autochthonous lineages, suggesting a genetic continuity since pre-Neolithic times. However, excluding haplogroup H, the most representative lineage of macrohaplogroup R0, the majority of maternal lineages of this area remains virtually unexplored, so that further refinement of the mtDNA phylogeny based on analyses at the highest level of resolution is crucial for a better understanding of the European prehistory. We thus explored the maternal ancestry of 548 autochthonous individuals from various Franco-Cantabrian populations and sequenced 76 mitogenomes of the most representative lineages. Interestingly, we identified three mtDNA haplogroups, U5b1f, J1c5c1 and V22, that proved to be representative of Franco-Cantabria, notably of the Basque population. The seclusion and diversity of these female genetic lineages support a local origin in the Franco-Cantabrian area during the Mesolithic of southwestern Europe, ∼10,000 years before present (YBP), with signals of expansions at ∼3,500 YBP. These findings provide robust evidence of a partial genetic continuity between contemporary autochthonous populations from the Franco-Cantabrian region, specifically the Basques, and Paleolithic/Mesolithic hunter-gatherer groups. Furthermore, our results raise the current proportion (≈15%) of the Franco-Cantabrian maternal gene pool with a putative pre-Neolithic origin to ≈35%, further supporting the notion of a predominant Paleolithic genetic substrate in extant European populations.
PLoS ONE 07/2013; 8(7):e67835. DOI:10.1371/journal.pone.0067835 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Atmospheric particulate matter (PM) is made up of a mixture of solid and
aqueous species which enter the atmosphere by anthropogenic and natural
pathways. The levels and composition of ambient air PM depend on the
climatology and on the geography (topography, soil cover, proximity to
arid zones or to the coast) of a given region. Spain has particular
difficulties in achieving compliance with the limit values established
by the European Union (based on recommendations from the World Health
Organization) for particulate matter on the order of 10 micrometers of
diameter or less (PM10), but not only antropogenical emissions are
responsible for this: some studies show that PM10 concentrations
originating from these kinds of sources are similar to what is found in
other European countries, while some of the geographical features of the
Iberian Peninsula (such as African mineral dust intrusion, soil aridity
or rainfall) are proven to be a factor for higher PM concentrations.
This work aims to describe PM10 concentration levels in Cantabria
(Northern Spain) and their relationship with the following
meteorological variables: rainfall, solar radiation, temperature,
barometric pressure and wind speed. Data consists of daily series
obtained from hourly data records for the 2000-2010 period, of PM10
concentrations from 4 different urban-background stations, and daily
series of the meteorological variables provided by Spanish National
Meteorology Agency. The method used for establishing the relationships
between these variables consists of several steps: i) fitting a
non-stationary probability density function for each variable accounting
for long-term trends, seasonality during the year and possible
seasonality during the week to distinguish between work and weekend
days, ii) using the marginal distribution function obtained, transform
the time series of historical values of each variable into a normalized
Gaussian time series. This step allows using consistently time series
models, iii) fitting of a times series model (Autoregressive moving
average, ARMA) to the transformed historical values in order to
eliminate the temporal autocorrelation structure of each stochastic
process, obtaining a white noise for each variable, and finally, iv) the
calculation of cross correlations between white noises at different time
lags. These cross correlations allow characterization of the true
correlation between signals, avoiding the problems induced by data
scaling or autocorrelations inherent to each signal. Results provide the
relationship and possible contribution to PM10 concentration levels
associated with each meteorological variable. This information can be
used to improve PM10 concentration levels forecasting using existing
[Show abstract][Hide abstract] ABSTRACT: Two missense polymorphisms of WNT16 were associated with hip bone mineral density (BMD), the buckling ratio of the femoral neck, calcaneal ultrasound and hip fractures in individuals under 80 years of age. These results confirm the association of the WNT16 gene with bone mass and osteoporotic fractures. INTRODUCTION: Osteoporosis has a strong genetic component. Wnt ligands stimulate the differentiation of osteoblast precursors and play a major role in skeletal homeostasis. Therefore, the aim of this study was to explore the association of allelic variants of the WNT16 gene with BMD, other structural parameters of bone and osteoporotic hip fractures. METHODS: Six single nucleotide polymorphisms were analysed in 1,083 Caucasian individuals over 49 years of age. RESULTS: Two missense polymorphisms (rs2908004 and rs2707466) were associated with femoral neck BMD, with average differences across genotypes of 35 mg/cm(2) (p = 0.00037 and 0.0015, respectively). Likewise, the polymorphisms were associated with calcaneal quantitative ultrasound parameters (p = 0.00004 and 0.0014, respectively) and the buckling ratio, an index of cortical instability of the femoral neck (p = 0.0007 and 0.0029, respectively). Although there were no significant differences in the genotype frequency distributions between 294 patients with hip fractures and 670 controls, among the subgroup under 80 years of age, TT genotypes were underrepresented in patients with fractures (odds ratio 0.50; CI 0.27-0.94). CONCLUSION: Common missense polymorphisms of the WNT16 gene are associated with BMD at the hip, calcaneal ultrasound and the buckling ratio of the femoral neck, as well as with hip fractures in individuals under 80 years of age. Overall, these results confirm the association of the WNT16 locus with BMD identified in genome-wide association studies and support its role in determining the risk of osteoporotic fractures.
Osteoporosis International 02/2013; 24(9). DOI:10.1007/s00198-013-2302-0 · 4.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
To determine genome-wide methylation profiles of bone from patients with hip osteoarthritis (OA) and those with osteoporotic (OP) hip fractures.
Trabecular bone pieces were obtained from the central part of the femoral head of 27 patients with hip fractures and 26 patients with hip OA. DNA was isolated, and methylation was explored with Illumina methylation arrays. RNA was extracted, pooled, and deep-sequenced to obtain the whole transcriptome. Differentially methylated regions were identified, and connections between genes with differentially methylated regions were explored by pathway and text-mining analyses.
After quality control, methylation of 23,367 CpG sites (13,463 genes) was analyzed. There was a genome-wide inverse relationship between methylation and gene expression in both patient groups. Comparison of OP and OA bones revealed 241 CpG sites, located in 228 genes, with significant differences in methylation (false discovery rate<0.05). Of them, 217 were less methylated in OP than in OA. The absolute methylation differences were >5% in 128 CpG sites and >10% in 45 CpG sites. The differentially methylated genes were enriched for association with bone traits in the genome-wide association study catalog. Pathway analysis and text-mining analysis with Gene Relationships Across Implicated Loci software revealed enrichment in genes participating in glycoprotein metabolism or cell differentiation, and particularly in the homeobox superfamily of transcription factors.
Genome-wide methylation profiling of bone samples revealed differentially methylated regions in OP and OA. These regions were enriched in genes associated with cell differentiation and skeletal embryogenesis, such as those in the homeobox superfamily, suggesting the existence of a developmental component in the predisposition to these disorders.
[Show abstract][Hide abstract] ABSTRACT: We hypothesized that miRNAs present in vitreous humor could be a sort of "biological black box," storing information about physiological and environmental circumstances at death. As a proof of concept, we analyzed the vitreous humor miRNA signature to explore its forensic potential applications, such as determining the time of the day at death. The miRNAs present in vitreous humor from individuals who died at daytime or at nighttime were analyzed by quantitative real-time polymerase chain reaction (qPCR) array. Target miRNAs showing significant differences between groups were studied in a larger sample by individual qPCR assays. After array analysis of miRNAs in seven samples, significant expression differences were detected between individuals who died at daytime and at nighttime regarding mir-34c, mir-541, mir-888, mir-484, and mir-142-5p. miR-222 appeared as the best reference gene. The results were replicated in 34 vitreous humor samples, and the day-night differences were confirmed for miR-142-5p and miR-541, suggesting that miRNA levels may be related to either the ambient light or the circadian clock at the time of death. There was no correlation between miRNA levels and the time elapsed after death, suggesting that they were stable at least for 24 h. In conclusion, this report supports the potential forensic utility of the analysis of miRNAs in the vitreous humor in applications such as determining the time of death.
Deutsche Zeitschrift für die Gesamte Gerichtliche Medizin 12/2012; 127(3). DOI:10.1007/s00414-012-0811-6 · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report the development of an effective system for analyzing X chromosome-linked mini short tandem repeat loci with reduced-size amplicons (less than 220 bp), useful for analyzing highly degraded DNA samples. To generate smaller amplicons, we redesigned primers for eight X-linked microsatellites (DXS7132, DXS10079, DXS10074, DXS10075, DXS6801, DXS6809, DXS6789, and DXS6799) and established efficient conditions for a multiplex PCR system (miniX). The validation tests confirmed that it has good sensitivity, requiring as little as 20 pg of DNA, and performs well with DNA from paraffin-embedded tissues, thus showing potential for improved analysis and identification of highly degraded and/or very limited DNA samples. Consequently, this system may help to solve complex forensic cases, particularly when autosomal markers convey insufficient information.
Deutsche Zeitschrift für die Gesamte Gerichtliche Medizin 11/2012; 127(4). DOI:10.1007/s00414-012-0795-2 · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction:
During routine analysis of chimerism in bone marrow transplant patients pre-transplant genotype of the recipient or the donor might lack. We aimed to develop a new method to analyze DNA results suitable when reference genotypes are not available.
The method was based on the balance between heterozygotes. It was implemented in a standard computer spreadsheet, and considered the hypothetical donor-recipient genotype combinations. Hypotheses with peak height ratios and allele sharing tendency above a critical threshold were accepted. The results were compared with those obtained with prior knowledge of reference genotypes.
The algorithm predicted correctly the proportion of donor/recipient chimerism, even in the absence of reference genotypes. In fact, the predicted values were closely correlated (r(2)>0.98) and free of systematic bias (slope 0.98-1.04), in comparison with the reference values obtained with prior knowledge of the donor and recipient genetic profiles.
This study constitutes a proof-of-concept of the application of the heterozygote balance for the quantitative study of chimerism. The algorithm computes post-transplant chimerism in an easy and time-efficient way, even when the donor and recipient reference genotypes are unavailable. Therefore, it can be a useful tool for laboratories involved in chimerism analysis.
Clinica chimica acta; international journal of clinical chemistry 09/2012; 414C:85-90. DOI:10.1016/j.cca.2012.08.023 · 2.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Sirtuin 1, encoded by the SIRT1 gene, is an emerging modulator of carbohydrate and lipid metabolism and may also influence the differentiation of bone cells. Our objective was to test the hypothesis that polymorphisms of SIRT1 are associated with body mass index (BMI) and bone mineral density (BMD).
We carried out a cross-sectional genetic association study with genotyping of ten single nucleotide polymorphisms of the SIRT1 region. The discovery cohort included 1394 individuals (342 males, 1052 females). Significant results were replicated in an independent cohort of 408 males.
We did not find a significant association of genotypes with BMD. There were also no significant BMI differences across genotypes in females. However, in males, two polymorphisms tended to be associated with BMI in the discovery cohort (p 0.03 and 0.05). A similar trend was also observed in the replication cohort. Thus, in the combined analysis of both cohorts, males with C alleles at the rs12049646 locus had a lower BMI than TT homozygotes, with a mean difference of 0.82 kg/m(2) (95% confidence interval 0.15-1.48; p = 0.016). Differences in the DNA binding of nuclear proteins between C and T alleles were also observed in vitro.
These results suggest that common variants of the SIRT1 gene influence BMI but not BMD.
Archives of medical research 07/2012; 43(5):363-8. DOI:10.1016/j.arcmed.2012.06.012 · 2.65 Impact Factor