Search PubMed⌕ Search

Biomedical subjects

F Rousseau

Publications and source records attributed to F Rousseau.

At least 19 recordsLinked to original sources
PubMed2002

Characterisation of the BRCT domains of the breast cancer susceptibility gene product BRCA1.

The breast cancer susceptibility gene product BRCA1 is a tumour suppressor but the biochemical and biological functions that underlie its role in carcinogenesis remain to be determined. Here, we characterise the solution properties of the highly conserved C terminus of BRCA1, consisting of a tandem repeat of the BRCT domain (BRCT-tan), that plays a critical role in BRCA1-mediated tumour suppression. The overall free energy of unfolding of BRCT-tan is high (14.2 kcal mol(-1) at 20 degrees C in water) but unfolding occurs via an aggregation-prone, partly folded intermediate. A representative set of cancer-associated sequence variants was constructed and the effects on protein stability were measured. All of the mutations were highly destabilising and they would be expected to cause loss of function for this reason. Over half could not be purified in a soluble form, indicating that these residues are critical for maintaining structural integrity. The remaining mutants exhibited much greater aggregation propensities than the wild-type, which is most likely a consequence of their reduced thermodynamic stability relative to the partly folded intermediate. The mutations characterised here are located at different sites in the BRCT-tan structure that do not explain fully their effects on the protein's stability. Thus, the results indicate an important role for biophysical studies in assessing the significance of sequence variants and in determining how they cause disease.

BRCA1 Protein↗
PubMed2002

Premutation and intermediate-size FMR1 alleles in 10572 males from the general population: loss of an AGG interruption is a late event in the generation of fragile X syndrome alleles.

We previously reported a 1:259 prevalence of female carriers of FMR1 premutation-size alleles (greater than 54 triplet repeats) in the general population. We now have screened 10 572 independent males from the same population for similar alleles using high-throughput Southern blotting. We identified 13 male carriers of an allele with more than 54 repeats. This corresponds to a prevalence of 1:813 males (95% confidence interval 1:527 to 1:1781). Haplotype analysis of four markers flanking the triplet array revealed that the prevalence of the major fragile X mutation-associated haplotype was increased among FMR1 alleles of 40-54 repeats. Although sequencing of highly unstable premutation alleles from fragile X families revealed only pure CGG tracts, this was not the case for alleles of similar size that were identified in males from the general population. Forty-eight out of forty-nine alleles of 40 or more triplets had one or two AGG interruptions. This observation, combined with the observation of the enrichment of major fragile X syndrome haplotypes in all alleles of this size, is evidence that the loss of an AGG interruption in the triplet repeat array is not necessary for expansion of normal alleles of 29-30 triplets to intermediate size. The loss of AGG interruptions thus appears to be a late event that leads to greatly increased instability and may be related to the haplotype background of specific FMR1 alleles.

Fragile X Messenger Ribonucleoprotein 1↗
PubMed2002

[Evaluation of the efficacy of a multiresistant bacteria control programme in a teaching hospital, studying the evolution of methicillin-resistant Staphylococcus aureus incidence].

Methicillin-resistant Staphylococcus aureus (MRSA) constitute the most important multiresistant bacteria (MRB) recovered in French hospitals. Our objective was to measure these MRSA diffusion in our hospital to evaluate the MRB control programme which had been implemented in the beginning of 1999. This study was conducted in a teaching hospital containing 1800 beds, from February 1999 to January 2001. All MRSA isolated in clinical samples were included. Duplicates (same bacteria in the same patient) were excluded. The detection of methicillin-resistance was performed at 30 degrees C, by disk diffusion method. Incidence densities were determined with their 95% confidence interval (CI 95%). Their evolution by four-month period was evaluated with the chi-square test for trend. During the two-year period, 866 MRSA were isolated. The global incidence was 0,88 per 1000 patient-days (PD) (IC 95% = left open bracket 0,83-0,93 right open bracket ). For cases acquired in our hospital the incidence was 0,66 per 1000 PD, whereas it was 0,26 per 1000 PD for imported cases. Concerning the evolution of incidences, no significant trend was observed for global incidence. The incidence of acquired MRSA decreased during the first year, but increased thereafter. The incidence of imported MRSA increased with a significant trend (p < 10(-5)). The number of these imported MRSA isolated in our hospital was twice fold higher in 2000. This study emphasizes an important actual problem : the increase of patient colonization pressure at the time of admission in hospitals. This increase, which can be due in part to a community transmission, is responsible for a reduction of the efficacy of MRSA control programmes.

Chi-Square Distribution↗
PubMed2002

Dose range study of pharmacokinetics, safety, and preliminary antiviral activity of emtricitabine in adults with hepatitis B virus infection.

A multicenter, open-label study was performed to evaluate the safety, anti-hepatitis B virus (anti-HBV) activity, and pharmacokinetics of emtricitabine therapy administered once daily for 8 weeks to patients infected with HBV. Clinical and virologic evaluations were completed at the baseline; at 7, 14, 28, 42, and 56 days during treatment; and at 24, 48, and 28 days posttreatment. Forty-nine patients were enrolled in five dose cohorts (doses of 25, 50, 100, 200, and 300 mg, all of which were administered once daily [q.d.]). Peak plasma emtricitabine concentrations occurred within 1.5 h following dosing. Plasma emtricitabine concentrations (maximum concentrations of drug in plasma and areas under the concentration-time curves) increased nearly dose proportionally over the 25- to 300-mg dose range, with relatively small intersubject variabilities. The plasma half-life of emtricitabine ranged from 6 to 9 h. HBV DNA levels were measured by the Digene HBV Hybrid Capture II assay. Viral suppression (reduction in log(10) serum HBV DNA levels) occurred in all dose cohorts. All doses demonstrated potent and rapid antiviral activities, with a trend toward a greater suppression with daily doses of 100 mg or greater. At 2 months, the median change in the serum HBV DNA level from the baseline level ranged from -1.7 log(10) for the 25-mg dose administered q.d. to -3.3 log(10) for the 300 mg dose administered q.d. Emtricitabine was well tolerated over the 2-month dosing period. These results support further clinical development of emtricitabine for the treatment of chronic hepatitis B infection.

Adolescent↗
PubMed2001

Short polyglutamine tracts in the androgen receptor are protective against breast cancer in the general population.

We studied the association of breast cancer with the polymorphic polyglutamine repeat of the androgen receptor (AR) in 255 incident cases of breast cancer and 461 matched controls from the Quebec City metropolitan area. Women for whom the sum of both of the AR (CAG)n-repeats alleles is 39 or less (short-allele AR genotypes) have one-half the risk of breast cancer compared with women for whom the sum of AR (CAG)n-repeats is 40 or more [odds ratio (OR), 0.5; 95% confidence interval (CI), 0.3-0.83; P = 0.007]. This association is stronger in postmenopausal women (180 cases, 297 controls; OR, 0.36; 95% CI, 0.19-0.7; P = 0.003). We also observed an interaction between the type of menopause (natural versus surgical) and the AR genotype on breast cancer risk. Alternately, when subjects were grouped according to their (CAG)n-repeat genotype [homozygous for short alleles (CAG)n < or = 20; other genotypes ("long allele")], results were similar (OR. 0.5; 95% CI, 0.27-0.82; P = 0.007). Thus, women with short-alleles AR genotypes appear to be protected against breast cancer. Short-alleles AR genotypes were observed in 16% of the general population as represented by the control group. Short polyglutamine repeats in the AR protein have been reported to be associated with an increase in the capacity of the receptor to activate transcription of reporter genes in vitro. Furthermore, androgens have been previously shown to inhibit in vitro the growth of breast cancer cell lines. This suggests that differences in the number of polyglutamines in the AR protein may influence individual risk of breast cancer, especially in postmenopausal women, and that this apparent protection could be the consequence of an increased response/sensitivity to androgens.

Breast Neoplasms↗
PubMed2001

Overview of the effectiveness of triple combination therapy in antiretroviral-naive HIV-1 infected adults.

AIM: To estimate the effectiveness of triple combination therapy in antiretroviral-naive adults. METHODS: A systematic overview of results from clinical trials involving triple combination therapy with dual nucleoside reverse transcriptase inhibitors (NRTI) and: a protease inhibitor (PI triple); a non-nucleoside reverse transcriptase inhibitor (NNRTI triple); or a third NRTI (triple NUC). Data from 23 clinical trials involving 31 independent treatment groups, 19 unique antiretroviral regimens, and 3257 enrolled patients were included in this study. RESULTS: Median log(10) baseline plasma HIV RNA and CD4 cell count over all trials averaged 4.69 (49,329 copies/ml) and 375 x 10(6) cells/l, respectively. The overall estimated percentage of patients with plasma HIV RNA < or = 400 copies/ml at 24 weeks was 64% [95% confidence interval (CI), 60 to 67%]. The percentages of patients with plasma HIV RNA < or = 50 copies/ml at 48 weeks by drug class were: PI triple, 46% (95% CI, 41 to 52%); NNRTI triple, 51% (95% CI, 43 to 59%); triple NUC, 45% (95% CI, 36 to 54%). The CD4 cell count increase over all trials at 24 and 48 weeks averaged +123 x 10(6) cells/l (95% CI, 111 x 10(6) to 135 x 10(6) cells/l) and +160 x 10(6) cells/l (95% CI, 146 x 10(6) to 175 x 10(6) cells/l), respectively and did not differ between drug classes. In multivariable regression analysis, neither baseline plasma HIV RNA level and CD4 cell count nor treatment regimen predicted plasma HIV RNA < or = 50 copies/ml at week 48. However, pill count was significantly negatively associated with plasma HIV RNA < or = 50 copies/ml at week 48 (P = 0.0085). CONCLUSIONS: The results suggest that three drug regimens containing two NRTI with a PI, a NNRTI, or a third NRTI may provide comparable activity, and practical issues such as daily pill burden should be considered when choosing a treatment regimen.

CD4 Lymphocyte Count↗
PubMed2001

Three-dimensional domain swapping in p13suc1 occurs in the unfolded state and is controlled by conserved proline residues.

p13suc1 has two native states, a monomer and a domain-swapped dimer. We show that their folding pathways are connected by the denatured state, which introduces a kinetic barrier between monomer and dimer under native conditions. The barrier is lowered under conditions that speed up unfolding, thereby allowing, to our knowledge for the first time, a quantitative dissection of the energetics of domain swapping. The monomer-dimer equilibrium is controlled by two conserved prolines in the hinge loop that connects the exchanging domains. These two residues exploit backbone strain to specifically direct dimer formation while preventing higher-order oligomerization. Thus, the loop acts as a loaded molecular spring that releases tension in the monomer by adopting its alternative conformation in the dimer. There is an excellent correlation between domain swapping and aggregation, suggesting they share a common mechanism. These insights have allowed us to redesign the domain-swapping propensity of suc1 from a fully monomeric to a fully dimeric protein.

Amino Acid Substitution↗
PubMed2001

[Spread of Enterobacteriaceae producing broad-spectrum beta-lactamase and the development of their incidence over a 16-month period in a university hospital center].

Enterobacteriaceae producing extended-spectrum beta-lactamases (ESBLE) constitute with methicillin-resistant Staphylococcus aureus the main multiresistant bacteria recovered in French hospitals. Our objectives were to evaluate these ESBLE diffusion in our teaching hospital and to follow their incidence during a 16-month period, whereas a control programme (barrier precautions) had been implemented in the beginning of 1999. This study was conducted in a teaching hospital containing 1800 beds, from February 1999 to May 2000. All ESBLE isolated in clinical or screening samples were included. Duplicates (same bacteria in the same patient) were excluded. The detection of the ESBL was performed with the double-disk diffusion test. Incidence densities were determined with their 95% confidence interval (CI95%). Their evolution by four-month period was evaluated with the chi-square test for trend. During the 16-month period, 229 ESBLE were isolated. The incidence was 0.35 per 1000 patient-days (PD) (CI95% = [0.30-0.40]) for the whole hospital. It was 0.47/1000 PD (CI95% = [0.38-0.56]) in medical wards, 0.29/1000 PD (CI95% = [0.20-0.38]) in surgical wards and 1.32/1000 PD (CI95% = [0.90-1.74]) in intensive care units. Enterobacter aerogenes strains represented more than 75% of all ESBLE, whereas Klebsiella pneumoniae stains represented only 8.6%. During the study, the incidence of ESBLE and the proportion of strains acquired in our hospital decreased significantly (p < 0.0001 and p < 0.001 respectively). Indeed, between the first eight-month period and the last one, the incidence of ESBLE acquired in our hospital decreased by 55%, whereas the incidence of imported strains increased slightly. This study shows that the diffusion of ESBLE concerns the entire hospital. The implementation of a control programme of the spread of multiresistant bacteria allowed us to reduce significantly the incidence of ESBLE. This incidence seemed to be stable for several months. The implementation of a policy which restricts antimicrobial use would allow us to complete the the efficacy of barrier precautions.

Academic Medical Centers↗
PubMed2001

A comprehensive phylogeny of the Phaeophyceae based on nrDNA sequences resolves the earliest divergences.

The present study is the first comprehensive phylogeny of the class of the Phaeophyceae. For 67 species representing all orders of the class, the sequences of the 3'-end of the small and the 5'-end of the large subunit nrRNA genes were aligned and analysed. A further analysis based on sequences of the 3'-end of the small and of the complete sequences of the 28S gene of the large subunits was also performed, but for only eight taxa. In both analyses, Tribonema marinum (Xanthophyceae) was used as outgroup. The analyses showed the Dictyotales as diverging first, followed by the Sphacelariales, then the Syringodermatales. Most of the orders currently accepted were confirmed as monophyletic groups but the Laminariales and Tilopteridales remained polyphyletic. The relationships of the remaining orders to each other were not resolved with the present data set. Ascoseira, included for the first time in a molecular study, appeared as a separate lineage without any clear relationship with other algae possessing conceptacles (Splachnidium and Fucales). Algae with stellate plastids, never studied in a global context, were polyphyletic; this result is consistent with their plastid ultrastructure and is discussed in detail. As further result of the present study, the South African genus Bifurcariopsis appeared as the sister taxon of the North Atlantic genus Himanthalia, and Xiphophora appeared as the sister taxon of Hormosira rather than as a member of the Fucaceae; the taxonomic position of these genera is discussed.

DNA, Ribosomal↗
PubMed2001

Observation of signal transduction in three-dimensional domain swapping.

p13suc1 (suc1) has two native states, a monomer and a domain-swapped dimer. The structure of each subunit in the dimer is identical to that of the monomer, except for the hinge loop that connects the exchanging domains. Here we find that single point mutations at sites throughout the protein and ligand binding both shift the position of the equilibrium between monomer and dimer. The hinge loop was shown previously to act as a loaded molecular spring that releases tension present in the monomer by adopting an alternative conformation in the dimer. The results here indicate that the release of strain propagates throughout the entire protein and alters the energetics of regions remote from the hinge. Our data illustrate how the signal conferred by the conformational change of a protein loop, elicited by domain swapping, ligand binding or mutation, can be sensed by a distant active site. This work highlights the potential role of strained loops in proteins: the energy they store can be used for both signal transduction and allostery, and they could steer the evolution of protein function. Finally, a structural mechanism for the role of suc1 as an adapter molecule is proposed.

Ligands↗
PubMed2001

Evaluation of the contribution of isolation precautions in prevention and control of multi-resistant bacteria in a teaching hospital.

From February 1999 to January 2000, a control programme to prevent the spread multi-resistant bacteria (MRB) was implemented in a French teaching hospital. This programme focused on methicillin-resistant Staphylococcus aureus (MRSA) and Enterobacteriaceae producing extended-spectrum beta-lactamases (ESBL), and was based on the application of barrier precautions (washing hands with antiseptic soaps, wearing disposable gloves and gowns, identifying MRB carriers). No changes in antibiotic policy occurred during the year. Our aim was to conduct an evaluation of this programme by measuring incidence rates. Concurrently, the effect of barrier precautions was estimated in an indirect way, by documenting the availability of barrier precautions in MRB carriers' rooms and by analysing the monthly correlation between the supply of such material and the theoretical cumulated length of MRB carriers' isolation in six randomized wards. All MRB isolated in hospitalized patients were recorded, and differentiated between acquisition in our hospital or from elsewhere. For the analysis of trends, the year was divided in three periods of four months. Over the year, the global MRB incidence was 1.26 per 1000 patient-days (PD) [95% confidence interval (95%CI)=1.16-1.36]. The MRSA incidence was 0.89 per 1000 PD (95%CI=0.81- 0.97) and the ESBL incidence was 0.38 per 1000 PD (95% CI=0.33-0.43). The MRB incidence decreased significantly in all types of specialties except for surgical wards. The incidence decreased by 17.9% for MRSA, 54.9% for ESBL and 34.8% for both MRB. Concurrently, the proportion of strains acquired in our hospital decreased for MRSA (P for trend > or = 0.05) and ESBL (P for trend > or = 0.01), whereas the incidence of imported strains increased slightly. The proportion of multiresistant strains in S. aureus (36.8%) and Enterobacter aerogenes (37.0%) remained similar throughout the year. Thus, the decrease of the incidence concerned both resistant and susceptible strains. The availability of antiseptic soaps increased significantly (P for trend > or = 0.01). The amount of antiseptic soap ordered and the theoretical lengths of isolation were correlated on a monthly basis (Spearman coefficient = 0.72; P > or = 0.02). These results shows the efficacy of such a programme of MRB containment in a large hospital, provided barrier nursing is instigated, together with the availability of such material as antiseptic soap, to allow implementation.

Bacterial Infections↗
PubMed2000

Prevalence and detection of delirium in elderly emergency department patients.

BACKGROUND: Delirium is a complex medical disorder associated with high morbidity and mortality among elderly patients. The goals of our study were to determine the prevalence of delirium in emergency department (ED) patients aged 65 years and over and to determine the sensitivity and specificity of a conventional clinical assessment by an ED physician for the detection of delirium in the same population. METHODS: All elderly patients presenting to the ED in a primary acute care, university-affiliated hospital who were triaged to the observation room on a stretcher because of the severity of their illness were screened for delirium by a research psychiatrist using the Mini-Mental State Examination and the Confusion Assessment Method. The diagnosis of "delirium" or an equivalent term by the ED physician was determined by 2 methods: completion of a mental status checklist by the ED physician and chart review. The prevalence of delirium and the sensitivity and specificity of the ED physician's clinical assessment were calculated with their 95% confidence intervals. The demographic and clinical characteristics of patients with detected delirium and those with undetected delirium were compared. RESULTS: A sample of 447 patients was screened. The prevalence of delirium was 9.6% (95% confidence interval 6.9%-12.4%). The sensitivity of the detection of delirium by the ED physician was 35.3% and the specificity, 98.5%. Most patients with delirium had neurologic or pulmonary diseases, and most patients with detected delirium had neurologic diseases. INTERPRETATION: Despite the relatively high prevalence of delirium in elderly ED patients, the sensitivity of a conventional clinical assessment for this condition is low. There is a need to improve the detection of delirium by ED physicians.

Age Factors↗
PubMed2000

Cloning and functional characterization of a cation-Cl- cotransporter-interacting protein.

To date, the cation-Cl(-) cotransporter (CCC) family comprises two branches of homologous membrane proteins. One branch includes the Na(+)-K(+)-Cl(-) cotransporters (NKCCs) and the Na(+)-Cl(-) cotransporter, and the other branch includes the K(+)-Cl(-) cotransporters. Here, we have isolated the first member of a third CCC family branch. This member shares approximately 25% identity in amino acid sequence with each of the other known mammalian CCCs. The corresponding cDNA, obtained from a human heart library and initially termed WO(3.3), encodes a 914-residue polypeptide of 96.2 kDa (calculated mass). Sequence analyses predict a 12-transmembrane domain (tm) region, two N-linked glycosylation sites between tm(5) and tm(6), and a large intracellular carboxyl terminus containing protein kinase C phosphorylation sites. Northern blot analysis uncovers an approximately 3.7-kilobase pair transcript present in muscle, placenta, brain, and kidney. With regard to function, WO(3. 3) expressed either in HEK-293 cells or Xenopus laevis oocytes does not increase Rb(+)-, Na(+)-, and Cl(-)-coupled transport during 5- or 6-h fluxes, respectively. In the oocyte, however, WO(3.3) specifically inhibits human NKCC1-mediated (86)Rb(+) flux. In addition, coimmunoprecipitation studies using lysates from WO(3. 3)-transfected HEK-293 cells suggest a direct interaction of WO(3.3) with endogenous NKCC. Thus, we have cloned and characterized the first putative heterologous CCC-interacting protein (CIP) known at present. CIP1 may be part of a novel family of proteins that modifies the activity or kinetics of CCCs through heterodimer formation.

Amino Acid Sequence↗
PubMed2000

Significant linkage for Tourette syndrome in a large French Canadian family.

Family and twin studies provide strong evidence that genetic factors are involved in the transmission of Gilles de la Tourette syndrome (TS) and related psychiatric disorders. To detect the underlying susceptibility gene(s) for TS, we performed linkage analysis in one large French Canadian family (127 members) from the Charlevoix region, in which 20 family members were definitely affected by TS and 20 others showed related tic disorders. Using model-based linkage analysis, we observed a LOD score of 3.24 on chromosome 11 (11q23). This result was obtained in a multipoint approach involving marker D11S1377, the marker for which significant linkage disequilibrium with TS recently has been detected in an Afrikaner population. Altogether, 25 markers were studied, and, for level of significance, we derived a criterion that took into account the multiple testing arising from the use of three phenotype definitions and three modes of inheritance, a procedure that yielded a LOD score of 3.18. Hence, even after adjustment for multiple testing, the present study shows statistically significant evidence for genetic linkage with TS.

Adult↗
PubMed2000

Sequence conservation provides the best prediction of the role of proline residues in p13suc1.

The unique nature of the proline side-chain imposes severe constraints on the polypeptide backbone, and thus it seems likely that it plays a special structural or functional role in the architecture of proteins. We have investigated the role of proline residues in suc1, a member of the cyclin-dependent kinase (cks) family of proteins, whose known function is to bind to and regulate the activity of the major mitotic cdk. The effect on stability of mutation to alanine of all but two of the eight proline residues is correlated with their conservation within the family. The remaining two proline residues are located in the hinge loop between two beta-strands that mediates a domain-swapping process involving exchange of a beta-strand between two monomers to form a dimer pair. Mutation of these proline residues to alanine stabilises the protein. cdk binding is unaffected by these mutations, but dimerisation is altered. We propose, therefore, that the double-proline motif is conserved for the purpose of domain swapping, which suggests that this phenomenon plays a role in the function of cks proteins. Thus, the conservation of the proline residues is a good indicator of their roles in suc1, either in the stabilisation of the native state or in performing functions that are as yet unknown. In addition, the strain resulting from two of the proline residues was relieved successfully by mutation of the preceeding residue to glycine, suggesting a general method for designing more stable proteins.

Amino Acid Motifs↗
PubMed2000

The folding pathway of the cell-cycle regulatory protein p13suc1: clues for the mechanism of domain swapping.

BACKGROUND: The 113-residue alpha+beta protein suc1 is a member of the cyclin-dependent kinase subunit (cks) family of proteins that are involved in regulation of the eukaryotic cell cycle. In vitro, suc1 undergoes domain swapping to form a dimer by the exchange of a C-terminal beta strand. We have analysed the folding pathway of suc1 in order to determine the atomic details of how strand-exchange occurs in vitro and thereby obtain clues as to the possible mechanism and functional role of dimerisation in vivo. RESULTS: The structures of the rate-determining transition state for the folding/unfolding of suc1 and of the intermediate that is populated during refolding were probed using phi values determined for 57 mutants with substitutions at 43 sites throughout the protein. The majority of phi values are fractional in the intermediate and transition state, indicating that interactions build up in a concerted manner during folding. In the transition state, phi values of greater than 0.5 are clustered around the inner strands beta2 and beta4 of the beta sheet. This part of the structure constitutes the nucleus for folding according to a nucleation-condensation mechanism. Molecular dynamics simulations of unfolding of suc1, performed independently in a blind manner, are in excellent agreement with experiment (proceeding paper). CONCLUSIONS: Strand beta4 is the exchanging strand in the dimer and yet it forms an integral part of the folding nucleus. This suggests that association is an early event in the folding reaction of the dimer. Therefore, interchange between the monomer and dimer must occur via an unfolded state, a process that may be facilitated in vivo by accessory proteins.

Cell Cycle Proteins↗
PubMed2000

The genetics of osteoporosis: 'complexities and difficulties'.

Osteoporosis is characterized by a decrease in bone mass as well as a deterioration of the bone architecture resulting in an increased risk of fracture. Although the disease is multifactorial, twin studies have shown that genetic factors account for up to 80% of the variance in bone mineral density, the best known predictor of the risk of osteoporosis. Some loci, such as the vitamin D and estrogen receptor genes, as well as the collagen type Ialpha1 locus, are promising genetic determinants of bone mass, and possibly other bone phenotypes, but this is controversial and the molecular basis of osteoporosis remains largely undefined. Considering that the effect of each candidate gene is expected to be modest, discrepancies between allelic association studies may have arisen because different populations carry different genetic backgrounds and exposure to environmental factors. Also, we realize the importance of gene-gene as well as gene-environment interactions as significant determinants of bone density and risk of osteoporosis. The use of new tools such as small nucleotide polymorphism maps now allows the possibility to perform allelic association studies in the context of whole-genome search. However, specific study design strategies in large epidemiological studies as well as the best statistical approach will need to be established. We may expect the development of population-specific at-risk profiles for osteoporosis that would include genetic and environmental factors, as well as their interactions. This should eventually lead to better prevention strategies and more adapted therapies against osteoporosis.

Aged↗