Association of age-dependent height and bone mineral density decline with increased arterial stiffness and rate of fractures in hypertensive individuals.

OBJECTIVE: Hypertension and osteoporosis are age-related health risks differentially expressed in men and women. Here we have analysed their prevalence in a randomly selected cross-sectional cohort [CARTaGENE (CaG) of Quebec, Canada and explored their existing relationships along with height, arterial stiffness and bone fractures. METHODS: The principal cohort CaG included 20 007 individuals of age 40-70 years. Participants were subjected to an extensive phenotyping and a questionnaire of medical history and habits. RESULTS: We determined the differences in height of participants and their relation to hypertension status and sex in this cohort and validated it in two other cohorts (The Canadian Heart Health Study and a family cohort from the Saguenay Lac Saint-Jean, a region of Quebec). In all three cohorts, we found that at younger age individuals with hypertension are taller than normotensive individuals, but they have a shorter stature at an older age compared with normotensive individuals. In CaG, we observed that hypertension, low bone mineral density (BMD) and arterial stiffness are strongly associated with height when adjusted for antihypertensive medications (P < 0.0001). Fractures are the net outcome of low BMD, and a significant association is observed (odds ratio = 2.34, confidence interval = 2.12-2.57); this relation was stronger in hypertensive individuals compared with normotensive individuals particularly in younger hypertensive individuals. In addition, we observed that increased arterial stiffness was significantly correlated with a low BMD in both men and women at all ages. CONCLUSION: Shorter stature in elderly, low BMD and fractures correlated with increased arterial stiffness and hypertension. We propose that hypertension and osteoporosis share components of accelerated aging.

Cohort profile of the CARTaGENE study: Quebec's population-based biobank for public health and personalized genomics.

The CARTaGENE (CaG) study is both a population-based biobank and the largest ongoing prospective health study of men and women in Quebec. In population-based cohorts, participants are not recruited for a particular disease but represent a random selection among the population, minimizing the need to correct for bias in measured phenotypes. CaG targeted the segment of the population that is most at risk of developing chronic disorders, that is 40-69 years of age, from four metropolitan areas in Quebec. Over 20,000 participants consented to visiting 1 of 12 assessment sites where detailed health and socio-demographic information, physiological measures and biological samples (blood, serum and urine) were captured for a total of 650 variables. Significant correlations of diseases and chronic conditions are observed across these regions, implicating complex interactions, some of which we describe for major chronic conditions. The CaG study is one of the few population-based cohorts in the world where blood is stored not only for DNA and protein based science but also for gene expression analyses, opening the door for multiple systems genomics approaches that identify genetic and environmental factors associated with disease-related quantitative traits. Interested researchers are encouraged to submit project proposals on the study website (www.cartagene.qc.ca).

Community engagement in genetic research: results of the first public consultation for the Quebec CARTaGENE project.

OBJECTIVE: This paper presents the results of the first public consultation for the creation of a large-scale genetic database, the Quebec CARTaGENE project. A consultation has been undertaken in order to gauge whether the general public is receptive to the project. An integral part of the approach of the researchers is to establish a dialogue with the public. METHODS: Two independent expert groups have carried out qualitative and quantitative studies measuring knowledge of and interest in genetics, incentives and obstacles to CARTaGENE participation and comprehension and evaluation of the communication tools. RESULTS: CARTaGENE is seen to hold promise for the greater population. However, reported across qualitative and quantitative studies is the concern for confidentiality and respect for the individual, transparency, the donor's right to feedback and governance. Participation would be conditional on a response to those concerns and a greater dissemination of information. CONCLUSION: Community engagement in genetic research requires targeted communications, with an appropriate proportioning of information and communication, and a consideration of the 'values and personal interests' of individuals according to different societal segments.

Anatomy of a founder effect: myotonic dystrophy in Northeastern Quebec.

Founder effects are largely responsible for changes in frequency profiles of genetic variants in local populations or isolates. They are often recognized by elevated incidence of certain hereditary disorders as observed in regions of Charlevoix and Saguenay-Lac-Saint-Jean (SLSJ) in Northeastern Quebec. Dominantly transmitted myotonic dystrophy (DM1) is highly prevalent in SLSJ where its carrier rate reaches 1/550, compared with 1/5,000 to 1/50,000 elsewhere. To shed light on the origin of DM1 in this region, we have screened 50 nuclear DM1 families from SLSJ and studied the genetic variation in a 2.05 Mb (2.9 cM) segment spanning the site of the expansion mutation. The markers analyzed included 22 biallelic SNPs and two microsatellites. Among 50 independent DM1 chromosomes, we distinguished ten DM1-associated haplotypes and grouped them into three haplotype families, A, B and C, based on the relevant extent of allele sharing between them. To test whether the data were consistent with a single entry of the mutation into SLSJ, we evaluated the age of the founder effect from the proportion of recombinant haplotypes. Taking the prevalent haplotype A1_21 (58%) as ancestral to all the disease-associated haplotypes in this study, the estimated age of the founder effect was 19 generations, long predating the colonization of Nouvelle-France. In contrast, considering A1_21 as ancestral to the haplotype family A only, yielded the estimated founder age of nine generations, consistent with the settlement of Charlevoix at the turn of 17th century and subsequent colonization of SLSJ. We conclude that it was the carrier of haplotype A (present day carrier rate of 1/730) that was a "driver" of the founder effect, while minor haplotypes B and C, with corresponding carrier rates of 1/3,000 and 1/10,000, respectively, contribute DM1 to the incidence level known in other populations. Other studies confirm that this might be a general scenario in which a major "driver" mutation/haplotype issued from a founder effect is found accompanied by distinct minor mutations/haplotypes occurring at background population frequencies.

Psychosocial impact of predictive testing for myotonic dystrophy type 1.

In the Saguenay-Lac-Saint-Jean region (Quebec, Canada), a predictive DNA-testing program for myotonic dystrophy type 1 (DM1) has been available as a clinical service since 1988. From 1 to 12 years (median, 5 years) after receiving predictive testing, a total of 308 participants (44 carriers and 264 non-carriers) answered a questionnaire to determine the psychosocial impact of this genetic testing. The main reasons for wanting to be tested were to learn if children are at risk for DM1 or for reproductive decision making (75%) and to relieve the uncertainty for themselves (17%). The majority of participants (96.1%) remembered correctly their test result. At the time of the survey, the perception of the general well-being, the psychological distress (Psychiatric Symptom Index), and the self-esteem (Rosenberg Self-Esteem Scale) were similar in carriers, in non-carriers, and in the reference (Quebec) population. When participants indicated a change in different aspects of their lives following predictive testing, it was perceived as a change for the better by non-carriers and as a change for the worse by carriers. Nevertheless, for a majority of carriers and of non-carriers, the test result did not bring changes in their lives. All respondents believed that predictive testing should be available for the at-risk population and the vast majority of carrier and of non-carriers would recommend the use of predictive testing to their family members. Predictive testing for individuals at-risk of DM1 can be offered safely within a well-organized clinical and genetic counseling program that includes careful pre-test counseling, pre-test clinical assessment, post-test psychological support, and follow-up for those identified as carriers.

Rationale for an integrated approach to genetic epidemiology.

CONCLUSION: Genetic knowledge is now in the public domain and its interpretation by the media and the citizens brings the issues into the public forum of discussion for the necessary ethical, legal and socio-cultural evaluation of its application. Science is being perceived by some as dangerous and as requiring international regulation. Others feel that genetic knowledge will be the breakthrough that will permit medical progress and individual autonomy with regards to personal health and lifestyle choices. The mapping of the human genome has already yielded valuable information on an increasing number of diseases and their variants. Prevailing popular and journalistic archetypes ("imaginaires") used in the media are perceived by the producers as slowing down the possible application of genetic knowledge. The answers to these dilemmas are not readily apparent nor are they prescribed by classical philosophy of medicine. Since genetic knowledge eventually resides with the individual who carries the genes of disease and/or susceptibility, a logical approach to integration of this knowledge at a societal level would seem to reside with individual education and decision-making. The politics of the ensuing social debate could transform the current social contract since an individual's interests need to be balanced against those of his or her immediate family in the sharing of information. The ethical foundations of such a contract requires the genetic education of "Everyone" as a matter of urgent priority. Genetic education should not serve ideological power struggles between the medical establishment and the ethical-legal alliance. Instead, it should ensure the transfer of knowledge to physicians, to patients, to users, to planners, to social science and humanities researchers and to politicians, so that they may make "informed" and free decisions....

Newborn genetic screening: ethical and social considerations for the nineties.

As we head into the next decade, the impact of the use of genetic screening programs for immunological surveillance purposes (such as for HIV) and for possible DNA typing should not be underestimated. The authors present ten principles which seek to reaffirm the basic tenents of neonatal screening programs -- the benefit of newborns. These principles are both protective and yet open to the complex ethical and social considerations raised by such new uses of newborn genetic screening programs.