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R Rakotovao

Publications and source records attributed to R Rakotovao.

16 recordsLinked to original sources
PubMed1997

Segregation analysis of fat mass and fat-free mass with age- and sex-dependent effects: the Stanislas Family Study.

Segregation analysis using a regressive model with age- and sex-dependent effects was applied to family data of weight, fat mass (FM) and fat-free mass (FFM) to investigate the major gene hypothesis. The sample consisted of 220 nuclear families from the 'Stanislas Cohort' who volunteered for a free health examination (n = 913). FM and FFM were assessed by bioelectrical impedance. The data were adjusted for height2 and height prior to analysis. The spouse, father-offspring, mother-offspring and sib-sib correlations were: 0.16, 0.18, 0.25 and 0.32 for weight; 0.13, 0.20, 0.23 and 0.28 for FM; 0.18, 0.16, 0.29 and 0.41 for FFM. For the three phenotypes, models specifying a major gene with age- and sex-dependent effects and residual family correlations was better supported than models including only family correlations. For weight, the most parsimonious genetic model was a codominant model with a sex-dependent effect in parents and an age-increasing effect in offspring. For FM, the most parsimonious model was also a codominant model with sex-dependent effects in parents indicating higher effects in women than in men. For FFM, the most parsimonious model was a recessive model with no significant age or sex interaction, although the age interactions paralleled those observed on weight in offspring. For weight and FM, mendelian transmission was rejected. For FFM, the Mendelian and the environmental hypotheses were nearly equally supported and none was rejected when compared to general transmission. Then, evidence for a single major gene could not be inferred for any of the traits. This does not preclude the existence of several genes acting in a more complex way. However, our findings emphasize that weight is a composite phenotype reflecting different components which evolve in distinct ways during life span. For this reason, FM should be highly preferred to weight or BMI for the research of susceptibility genes to obesity.

Adolescent↗
PubMed1996

Family study of lipoprotein lipase gene polymorphisms and plasma triglyceride levels.

To better characterize the role of the lipoprotein lipase (LPL) gene in the determination of triglyceride levels in healthy subjects, a study was performed in 193 nuclear families (384 parents, means age = 42.0 +/- 5.2 years; 399 offspring, mean age = 14.6 +/- 4.3 years) volunteering to have a free health checkup examination. The pattern of familial resemblance was compatible with a zero correlation between spouses, a weak father-offspring correlation (0.099 +/- 0.054; P < 0.07), and significant mother-offspring (0.235 +/- 0.053; P < 10(-4)) and sib-sib (0.294 +/- 0.064; P < 10(-4)) correlations. Associations of triglyceride levels with the LPL HindIII and PvuII polymorphisms were investigated by a familial measured genotype analysis, specifying sex- and age-dependent polymorphism effects. The effects associated with both polymorphisms were significant only in fathers, the H+ and P+ alleles being associated with raised triglyceride levels. The HindIII and PvuII polymorphisms explained 3.5% and 3%, respectively, of the variability of triglycerides in fathers. The relationship was weakened after prior adjustment on body mass index, but remained significant for PvuII. Because of the lack of effect in mothers and offspring, the polymorphisms did not contribute to the covariance of triglyceride levels in relatives. In conclusion, this family study showed a weak relationship of the HindIII and PvuII polymorphisms to plasma triglyceride levels in young healthy male subjects. The effects detectable only in fathers suggest a possible modulation of the LPL expression by hormonal or lifestyle factors.

Adolescent↗
PubMed1996

Identification of new polymorphisms of the angiotensin I-converting enzyme (ACE) gene, and study of their relationship to plasma ACE levels by two-QTL segregation-linkage analysis.

Plasma angiotensin I-converting enzyme (ACE) levels are highly genetically determined. A previous segregation-linkage analysis suggested the existence of a functional mutation located within or close to the ACE locus, in almost complete linkage desequilibrium (LD) with the ACE insertion/deletion (I/D) polymorphism and accounting for half the ACE variance. In order to identify the functional variant at the molecular level, we compared ACE gene sequences between four subjects selected for having contrasted ACE levels and I/D genotypes. We identified 10 new polymorphisms, among which 8 were genotyped in 95 healthy nuclear families, in addition to the I/D polymorphism. These polymorphisms could be divided into two groups: five polymorphisms in the 5' region and three in the coding sequence and the 3' UTR. Within each group, polymorphisms were in nearly complete association, whereas polymorphisms from the two groups were in strong negative LD. After adjustment for the I/D polymorphism, all polymorphisms of the 5' group remained significantly associated with ACE levels, which suggests the existence of two quantitative trait loci (QTL) acting additively on ACE levels. Segregation-linkage analyses including one or two ACE-linked QTLs in LD with two ACE markers were performed to test this hypothesis. The two QTLs and the two markers were assumed to be in complete LD. Results supported the existence of two ACE-linked QTLs, which would explain 38% and 49% of the ACE variance in parents and offspring, respectively. One of these QTLs might be the I/D polymorphism itself or the newly characterized 4656(CT)2/3 polymorphism. The second QTL would have a frequency of approximately .20, which is incompatible with any of the yet-identified polymorphisms. More extensive sequencing and extended analyses in larger samples and in other populations will be necessary to characterize definitely the functional variants.

Adolescent↗
PubMed1994

[Measurement errors and linear regression].

The consequences of a measurement error of known variance in the explanatory variable of a linear regression were assessed. On the average, the ordinary least squares (OLS) method underestimated the regression slope, the bias increasing with the variance of the measurement error and the strength of the relationship. Simulation results showed that the corrected-for-the-error estimate slightly overestimated the slope, the bias increasing with the variance of the measurement error and the strength of the relationship, but rapidly decreasing when the number of observations increased. In all cases the corrected estimate has a larger variance than the OLS estimate, Nevertheless, the mean square deviation of the corrected estimate to the "true" slope value can be smaller than the OLS one, even for a relatively small number of observations (< or = 100). In those conditions, the corrected estimate might be preferred when a "good estimation" of the regression slope is needed. Whereas a measurement error in the dependent variable, does not bias the slope estimator, when it is independent of the error in the explanatory variable, this is not the case when both measurement errors are correlated. An example of the need to correct for such a correlation is given.

Bias↗
PubMed1993

Effect of ignoring genotype-environment interaction on segregation analysis of quantitative traits.

Thirty replicates of 200 nuclear families (6 members each) were generated under three GxE interaction models. Segregation analyses of these data were performed using a regressive model taking into account an interaction effect or not. Results showed that ignoring the GxE interaction markedly decreased the power for accepting a major gene and led to serious bias in parameter estimates.

Adult↗
PubMed1992

Segregation analysis of height-adjusted weight with generation- and age-dependent effects: the Nancy Family Study.

A segregation analysis using a regressive model with generation- and age-dependent effects was applied to familial data of height-adjusted weight to investigate the major gene hypothesis. The sample included 629 nuclear families with 2,534 members volunteering for a free health check-up in the Preventive Medicine Center of Vandoeuvre-lès-Nancy, France. The familial correlations were 0.094 +/- 0.040 between spouses, 0.198 +/- 0.023 between parent and offspring, and 0.327 +/- 0.034 between siblings. The variability of the trait was higher in parents than in offspring. The most parsimonious genetic model indicated a codominant major effect increasing with age in childhood, then stabilizing in adulthood. The same data were analyzed using the classical mixed model, assuming equality of variances between parents and offspring, no resemblance between spouses, similar parent-offspring and sib-sib correlations, and identical effects in parents and offspring. This analysis indicated a recessive solution. In both analyses, mendelian transmission was rejected. However, the mixture of two distributions in the recessive model, instead of three in the codominant one, was less constraining with respect to the test of transmission probabilities, and the rejection of mendelian transmission was due to a single family in the recessive case, instead of several families in the codominant one. This could possibly explain why previous studies, all using the mixed model, found evidence for a recessive major gene. Although the major gene hypothesis cannot be definitely ruled out from our results, the mechanism appears more complex than the effect of one single gene.

Adolescent↗
PubMed1991

Testing for association between disease and linked marker loci: a log-linear-model analysis.

One approach frequently used for identifying genetic factors involved in the process of a complex disease is the comparison of patients and controls for a number of genetic markers near a candidate gene. The analysis of such association studies raises some specific problems because of the fact that genotypic and not gametic data are generally available. We present a log-linear-model analysis providing a valid method for analyzing such studies. When studying the association of disease with one marker locus, the log-linear model allows one to test for the difference between allelic frequencies among affected and unaffected individuals, Hardy-Weinberg (H-W) equilibrium in both groups, and interaction between the association of alleles at the marker locus and disease. This interaction provides information about the dominance of the disease susceptibility locus, with dominance defined using the epidemiological notion of odds ratio. The degree of dominance measured at the marker locus depends on the strength of linkage disequilibrium between the marker locus and the disease locus. When studying the association of disease with several linked markers, the model becomes rapidly complex and uninterpretable unless it is assumed that affected and unaffected populations are in H-W equilibrium at each locus. This hypothesis must be tested before going ahead in the analysis. If it is not rejected, the log-linear model offers a stepwise method of identification of the parameters causing the difference between populations. This model can be extended to any number of loci, alleles, or populations.

Alleles↗
PubMed1990

Familial resemblance of plasma apolipoprotein B: the Nancy study.

The familial resemblance of plasma apolipoprotein B (apo B) was investigated in a sample of 102 families including 419 members who volunteered for a free health checkup in the Preventive Center of Vandoeuvre-lès-Nancy, France. The mean levels (+/- SD) of apo B were 141.0 (+/- 32.6), 121.8 (+/- 27.7), and 98.6 (+/- 22.6) mg/dl in fathers, mothers, and offspring, respectively. The familial correlations were 0.04, 0.13, 0.21 (P less than .01), and 0.47 (P less than .001) between spouses, father-offspring, mother-offspring, and siblings, respectively, after adjustment on age, body mass index, and sex. A genetic analysis was performed using the approach proposed by Bonney, which indicated that a recessive and a dominant major-locus model appeared nearly equally supported by the data. Under the recessive model, the frequency q of the most common allele was estimated as 0.825, with a mean difference of 60.4 mg/dl between high and low homozygotes. Under the dominant model, q was estimated as 0.875, with a mean increase of 34.2 mg/dl in heterozygotes and high homozygotes. However, the hypothesis of Mendelian transmission and the environmental hypothesis could not be formally tested because of great numeric difficulties encountered in the estimation of the three transmission probabilities. Given these analytical restrictions, we cannot conclude in favor of a major locus influencing apo B level in our population, even though the evidence is suggestive. The genetic heterogeneity underlying the familial aggregation of apo B level, suggested by several recent publications, might explain the difficulty in discerning a single major locus in a population sample of small nuclear families, not ascertained through patients enriching the sample in high values of apo B. These findings call into question the relevance of the approach through "healthy" populations in the search for major loci influencing biological traits.

Adult↗
PubMed1988

Familial resemblance of plasma angiotensin-converting enzyme level: the Nancy Study.

Plasma angiotensin I-converting enzyme (ACE) activity has been measured in a sample of 87 healthy families participating in a study of cardiovascular risk factors. The mean +/- SD levels of plasma ACE were 34.1 +/- 10.7, 30.7 +/- 10.4 and 43.1 +/- 17.2 units/liter in fathers (n = 87), mothers (n = 87) and offspring (n = 169), respectively. Plasma ACE was uncorrelated with age, height, weight, or blood pressure in the parents, but a negative correlation with age was observed in offspring (r = -.32). The age-adjusted familial correlations of plasma ACE were .038, .166, .323 and .303 for spouses, father-offspring, mother-offspring, and siblings, respectively. The results of the genetic analysis suggest that a major gene may affect the interindividual variability of plasma ACE, with different codominant effects in parents and offspring. According to this model, the major gene effect accounts for 4.8, 4.0, and 10.8 units/liter of the overall mean and for 29%, 29% and 75% of the variance of age-adjusted ACE in fathers, mothers, and offspring, respectively. The estimate of the probability of the less frequent allele is .26, and the major gene effect is approximately twice as great in high homozygotes than in heterozygotes and in offspring than in parents. The results of this study demonstrate the occurrence of a familial resemblance of plasma ACE activity in healthy families and suggest that this observation can be explained by the segregation of a major gene.

Alleles↗
PubMed1980

Coronary heart disease in middle-aged Frenchmen. Comparisons between Paris Prospective Study, Seven Countries Study, and Pooling Project.

A systematic comparison was made of the incidence rates of major coronary heart disease (CHD), defined as fatal and non-fatal myocardial infarction and probable CHD deaths, observed in the Paris Prospective Study, the European and American cohorts of the Seven Countries Study, and the populations of the Pooling Project. The Paris study results were adjusted to the age-distribution and follow-up duration of the other studies. The major CHD incidence rate in the Paris study proved to be intermediate between those observed in Northern and Southern European populations and half to one-third those observed in the American populations. Mean risk-factor levels were of the same order of magnitude as in the whole European group and were lower than in the Pooling Project population, particularly for cholesterol and smoking. The coefficients of risk factors in the multivariate analysis of risk among the four studies showed similar gradients of risk except for a steeper gradient with smoking in the Paris Prospective Study. After adjustment to the risk-factor levels, major CHD incidence in the Paris study was comparable with that in the European population but lower than those in the U.S. Railroad population (ratio of predicted numbers of cases=1.56) and the pooling project population (ratio of predicted numbers of cases=2.24).

Adult↗
PubMed1976

Estimation of risk as a function of risk factors.

This paper describes a model which makes allowance for unequal follow-up times in estimating the risk as a function of risk factors. It is the usual exponential model with an instantaneous risk which is assumed to be an exponential function of the risk factors. Computing methods and an extension of the model are given.

Mathematics↗
PubMedDate not supplied

Family resemblance in body circumferences and their ratios: the Nancy family study.

The purpose of this study was to investigate the familial resemblance for individual body circumferences (suprailiac, waist, thigh and arm) and for the waist/suprailiac (as surrogate for the waist/hip) and the waist/thigh circumference ratios, in a sample of 216 unselected nuclear families with children aged 10-25 years. Familial correlations were jointly computed, using the maximum-likelihood method. The highest familial resemblance was observed for the waist circumference and for the waist/suprailiac and the waist/thigh circumference ratios. There was no significant difference between father-offspring and mother-offspring correlations when considering individual body circumferences. In contrast, when considering the two ratios there was a stronger mother-child than father-child similarity. Furthermore, there was a higher resemblance of the mother with her daughter than with her son, but no significant sib sex difference in the father-offspring relationship. There was also a heterogeneity of sibling correlations for the two ratios, the like-sex pairs exhibiting higher correlations than the unlike-sex pairs. Lastly, the similarity observed between spouses, of similar magnitude to the father-offspring correlation, suggests the contribution of environmental rather than genetic factors for explaining the familial resemblance of the two ratios. In conclusion, the great family resemblance for the waist/suprailiac and the waist/thigh circumference ratios (correlations ranging from 0.23 to 0.68) appears remarkable, and should be taken in consideration, given the predictive value of these indices for disease in adulthood.

Adolescent↗
PubMedDate not supplied

[Estimation of risk as a function of risk factors. II.--Application to the multivariate analysis of coronary heart disease in a middle aged male population (author's transl)].

The annual incidence of coronary heart disease (CHD) in a 8000 male professionnal group, aged 42-53, is computed from the model of LELLOUCH and al. described in the first part of this work. It is shown that each of five risk factors (cholesterol, blood pressure, cigarettes consumption, diabetes history and abnormal electrocardiogram) brings its own contribution to the CHD risk, which may be estimated by an exponential function of a linear combination of the levels of the five factors. "Risk tables" useful in current practice are described.

Adult↗