David Karasik

Complex Segregation Analysis of the Radiographic Phalanges Bone Mineral Density and Their Age‐Related Changes

The complex segregation analyses performed in our previous studies revealed a significant major gene (MG) effect on the age‐adjusted cortical and cancellous bone mineral density (BMD) in two ethnically different populations, Chuvasha and Turkmenians. The aim of the present study was to test the hypothesis of pleiotropic MG control of three components of bone aging, that is, the baseline level of BMD (μgs), the age at onset of the bone mass loss (Tgs), and the rate of this loss over the years (αgs). Nuclear and more complex pedigrees from the same two ethnic samples were assessed for hand phalangeal BMD (Chuvasha, 1208 individuals, and Turkmenians, 643 individuals), and complex segregational analysis incorporating age and sex effects directly into MG penetrance function was carried out. The results of the present analysis clearly confirmed the existence of the putative MG and showed that the proportion of BMD variation attributable to this MG effect within the sex was remarkably similar in both populations and ranged between 34.7% and 35.2%. The most parsimonious model for BMD transmission in Chuvasha pedigrees additionally indicated significant residual correlation between siblings and clear sex differences in the annual rates of bone loss αgs. The latter was more than twice as high in females than that in males (0.086 SD vs. 0.033 SD per year). In Turkmenian pedigrees the most parsimonious model presented obvious evidence of the MG control of BMD baseline levels in both sexes with significantly lower baseline levels and younger age at onset (Tgs) in females. No clear MG effects were inferred on Tgs and/or αgs in either sample, either in males or in females. That is, the present study does not suggest MG × SEX × AGE interaction. We suppose that if the rate of age‐related changes in phalangeal BMD is genetically determined, then these are not the same genes as those affecting the BMD baseline levels.

Modelling of age-related bone loss using cross-sectional data

Background : Current applications of bone mineral density (BMD) data in age studies are not free of certain drawbacks. Since it is well established that age-related patterns of BMD changes involve three distinct periods (bone acquisition in youth, stabilization at maturity, and decrease with ageing), adjusting for age via an inappropriate mathematical function may lead to inconsistencies and wrong conclusions. Hypothesis : The piecewise model, which encompasses the above three periods, will accurately describe the BMD dependence on age. Objective : To examine age-related patterns of BMD changes using a number of possible mathematical functions and to find among them the best-fitting function. Next, to test whether the chosen function is universally applicable or if there are diverse population-specific functions. Material and methods : Thirteen ethnic samples from various regions of Europe and Asia, assigned into five ethnic-geographic groups, were examined. The total sample included 2430 males and 2515 females. Compact BMD of hand phalanges was measured by photodensitometry from plain radiographs of each individual studied. Statistical software was developed for the purposes of the present study; this software gave a maximum likelihood of the parameter estimates for various statistical models (functions). Results : In all samples of sufficient size and representative age range, a two-interval function was found as the best fitting and most parsimonious model to describe the BMD age-related changes. This two-interval function was characterized by age-related bone mass increase, positive slope g 1s in young age or a plateau ( g 1s = 0, i.e. no age-related changes) until a sex-specific age threshold, T 0, after which annual bone loss ensued with a slope coefficient g 2s. Threshold of BMD loss in women of different ethnic groups ranged between 37.85 and 47.77 years, and roughly coincided with perimenopausal age. In males, the age T 0 varied between 27.85 and 49.07 years. The ensuing cortical bone loss appeared to be linear in both sexes, averaging between 0.51% and 1.15% in men and between 0.74% and 1.77% per year of young age BMD value in females. Conclusions : The change of phalangeal BMD with age may be best described by a two-interval function, regardless of sex and ethnic background. However, specific parameter estimates depend both on gender and ethnic affiliation. This study has yielded a well-fitted model of BMD dependence on age suitable for further use in population studies.

Evidence of major gene control of cortical bone loss in humans.

Cortical index (CI) is the ratio of the combined cortical thickness to the total diameter of the bone. It serves for the assessment of the geometric properties of bone and for indirect evaluation of bone mass. CI is a useful predictor of osteoporosis. The aim of the present study was to test the hypothesis of major gene control of CI variation in a large sample of pedigrees from Chuvashia, Russia. Complex segregation analysis revealed that the major gene model of CI inheritance is the best fitting and most parsimonious for the present data. Parameters of the genotype‐gender specific dependence of CI variation on age were estimated simultaneously with other parameters in the segregation analysis. The results of analysis showed that not only the baseline level of CI but also the age at onset of the involutive bone changes (inflection point) and the rate of the CI decrease with age (slope coefficient) are under control of the same major gene. Non‐major gene effects shared by pedigree members (residual familial correlations) were found to be statistically insignificant. Approximately 73% of inter‐individual variation in CI was attributable to the effects explicitly included in the model. Genet. Epidemiol. 19:410–421, 2000.

Fluctuating asymmetry and morphometric variation of hand bones

The major aim of this study was to test three hypotheses: 1) more complex traits of the hand are less prone to developmental insults and therefore show lower fluctuating asymmetry (FA) as compared with simple traits; 2) the manifestation of FA correlates with the variability of the trait (i.e., CV); and 3) FA is an organ-wide property, and therefore a concordance exists between the FA measures of different traits in hand bones. Seventy-two bilateral measurements of hand bones, were made from plain-film radiographs of 365 cadavers. A complex trait was considered as the total length of the three phalanges of a finger and their contiguous metacarpals. Simple traits were considered to be the lengths of individual bone that made up the complex trait. The following results were obtained: 1) on the average simple traits, composing the complex trait, show much higher FA than the corresponding complex trait, but this result is expected if there is no correlation (or low correlation) between FA of simple traits within the complex trait, due to random direction of right-left differences; 2) strong and highly significant correlation was observed between FA and CV of studied traits, regardless of sex and age of individuals; and 3) the majority of FA measurements of hand bones showed no correlation. However, correlations between some sets of FA traits were highly significant. They were interpreted, although not specifically tested, as the result of a tight relationship between traits related not only developmentally but also by active performance of the same function.

Genes play an important role in bone aging

Pathological changes in bones like osteoarthritis and osteoporosis are among the most frequent outcomes of age and aging. Presently, little is known about the genetic basis of peak bone mass or rate of bone loss, or on the genetics of bone formation and resorption. This paper reviews modern studies, dealing with the genetic aspects of bone formation and bone aging. The currently most popular measures of bone aging are: osteometric measurements (OSM) including measures of cortical thickness, bone mineral density (BMD), and osteographic scores (OSS) basing on descriptive criteria of bone age. These three are important clinical tools for predicting chronic degenerative disease and estimating biological age of individuals. Despite abundant data on ethnic and racial differences in these bone aging measures, modern knowledge regarding the genetics of the processes came primarily from family studies of BMD which point to strong familial and probably also genetic effects on bone mass. Regardless of the measurement technique or skeletal site selected, heritability estimates of BMD in most studies account for about 60% of the total variation in bone mass. Similarity of heritability estimates in most studies suggests that the same genetic factors operate on both weight‐bearing and nonweight‐bearing bones. However, genetic heritability may be overestimated in some family studies due to underestimation of common environmental effects. Segregation analysis, performed to date, reveals strong effect of potential major locus on BMD of both compact and trabecular bone, but much remains to be clarified. Genetic factors affecting BMD may be mediated through biochemical turnover of bone. Hence, segregation, linkage, and molecular biology are the staples of any genetic analysis of BMD, while the study of biochemical factors regulating bone turnover should elucidate the full picture of bone formation and aging. Am. J. Hum. Biol. 10:421–438, 1998.

Genetic variation and covariation of parathyroid hormone levels and bone density in the human population.

Abstract. The present study was an attempt to evaluate the relative importance of familial/genetic factors in interindividual variation of plasma concentrations of parathyroid hormone (PTH) and bone mineral density (BMD). We also examined to what extent common genetic and environmental factors may be involved in covariation between the hormone concentrations and BMD levels.Ninety-five nuclear pedigrees (consisting of 187 males and 168 females, aged 18–91 and 18–86 years old, respectively), from several small villages in the Chuvasha Autonomy, Russia, were assessed for PTH, sex hormones, and BMD. PTH plasma levels were measured in duplicate by immunoradiometric assay using an N-tact PTH SP kit. Standard roentgenography was done from the second and third phalanges of the middle finger on both hands for assessment of compact and cancellous bone BMD separately. The present study clearly confirmed the results of the previous genetic analyses of BMD which indicated that between 47% and 60% of the total variance of BMD, adjusted for sex and age effects, were attributable to genetic factors. Genetic factors also contributed significantly to interindividual variation of PTH. Constraining these additive genetic effects to zero dramatically increased the likelihood ratio (P < 0.001), indicating that at least 30% of the hormone plasma variation was attributable to genetic sources. The results of bivariate decomposition analysis were not clear cut. Two types of bivariate analyses showed that PTH-BMD genetic correlations according to sex and between the opposite sexes were consistently negative, but only marginally significant.

Bone ageing: genetics versus environment.

Bone ageing results from a complex interaction between genetic and environmental factors (such as diet, climate and physical exercise) throughout human life. According to current literature, the most popular measures of bone ageing are osseometric measurements (OSM), bone mineral density (BMD) and osseographic scores (OSS), based on descriptive criteria of bone age. Plain roentgenography allows simultaneous assessment of all three measures. Ethnic differences with regard to these bone ageing characteristics have prompted us to study to the process anew, with the aim of elucidation the nature of the genetic and environmental components involved, and the possible interaction(s) between them. Despite abundant data on ethnic differences regarding these measures, modern knowledge on the genetics of these processes has derived primarily from the family studies of BMD, which pointed to strong involvement of the familial factors on bone mass. Segregation analysis performed by us in two ethnically different samples of pedigrees revealed a significant effect of the putative major gene on BMD of both compact and cancellous bone. The major finding of our bivariate segregation analysis was that it lead to the acceptance of the hypothesis predicating a single major locus with pleiotropy to both cancellous and compact BMD, but clearly rejecting the polygenic hypotheses. Our study of cortical index (CI) provided evidence that a single potential major gene controls not only the baseline trait level, but also the age at onset of the involutive bone changes, and the rate of the CI change with age. When we examined the environmental vs genetic influences on OSS variation in 32 human populations, we found very little environmental effect on the rate of bone change (r2 = 0.107), but a substantial effect on this rate of the genetic differences between populations (r = 0.480). Clarification of the genetic basis of bone ageing could have wide-ranging applications in the prevention and treatment of bone degenerative diseases such as osteoporosis and osteoarthritis, before irreversible damage takes place. There is thus a need to target the genetic analysis of BMD and the biochemical regulating factors of bone turnover through the use of molecular genetic techniques.Bone ageing results from a complex interaction between genetic and environmental factors (such as diet, climate and physical exercise) throughout human life. According to current literature, the most popular measures of bone ageing are osseometric measurements (OSM), bone mineral density (BMD) and osseographic scores (OSS), based on descriptive criteria of bone age. Plain roentgenography allows simultaneous assessment of all three measures. Ethnic differences with regard to these bone ageing characteristics have prompted us to study to the process anew, with the aim of elucidation the nature of the genetic and environmental components involved, and the possible interaction(s) between them. Despite abundant data on ethnic differences regarding these measures, modern knowledge on the genetics of these processes has derived primarily from the family studies of BMD, which pointed to strong involvement of the familial factors on bone mass. Segregation analysis performed by us in two ethnically different samples of pedigrees revealed a significant effect of the putative major gene on BMD of both compact and cancellous bone. The major finding of our bivariate segregation analysis was that it lead to the acceptance of the hypothesis predicating a single major locus with pleiotropy to both cancellous and compact BMD, but clearly rejecting the polygenic hypotheses. Our study of cortical index (CI) provided evidence that a single potential major gene controls not only the baseline trait level, but also the age at onset of the involutive bone changes, and the rate of the CI change with age. When we examined the environmental vs genetic influences on OSS variation in 32 human populations, we found very little environmental effect on the rate of bone change (r2 = 0.107), but a substantial effect on this rate of the genetic differences between populations (r = 0.480). Clarification of the genetic basis of bone ageing could have wide-ranging applications in the prevention and treatment of bone degenerative diseases such as osteoporosis and osteoarthritis, before irreversible damage takes place. There is thus a need to target the genetic analysis of BMD and the biochemical regulating factors of bone turnover through the use of molecular genetic techniques.

Comparative analysis of age prediction by markers of bone change in the hand assessed by roentgenography.

The major aim of this study was to develop an accurate method of age prediction for a wide range of ages based on the roentgenographic assessment of the hand bones. Such a method may be of particular interest in paleoanthropology and forensic medicine. The present paper provides the results of an analysis of individuals belonging to two ethnically different population samples: 1) Chuvasha (the Russian Federation), 293 males and 254 females, aged 18–91 and 18–86 years, respectively; and 2) Turkmenians (the Republic of Turkmenia), 257 males and 386 females, aged 18–82 and 17–83 years, respectively. The hands of study participants were roentgenographed with standard methodology. For each roentgenogram an equidistant osseographic score (OSS) including the descriptive criteria of bone age was estimated. In addition, an osteoarthritic and an osteoporotic score (OA and OP, respectively) were assigned to each individual. OA was a modification of the Kellgren/Lawrence scale, whereas the OP was locally developed. Results of the multiple logistic regression analysis clearly indicated that OSS is a strong predictor variable of an individuals age, with R reaching 0.93 in Chuvasha and 0.89 in Turkmenians (P < 0.001). The standard errors of estimate were approximately ±5–7 years and compared favorably with most known methods of age assessment using bones. This study provides an efficient method of age prediction, with acceptable accuracy, and extends the upper limit of prediction to the age of 70 years. An additional finding of interest was the coexistence of OA and OP in the bones of the same hand. The observed correlation between these two conditions reached 0.8 (P < 0.001). Am. J. Hum. Biol. 11:31–43, 1999.

Violent mortality patterns in immigrants in Israel (1990-95).

Since 1989, a large number of immigrants, mostly from the former Soviet Union, have arrived in Israel, increasing the local population (c. 5 million) by 700,000. The morbidity and mortality of this immigant population have been the concern of many investigations. In the present study we examine the mortality pattern of a sample of 1,000 immigrants, whose deaths occurred during the years 1990–95 and were examined at the L. Greenberg (National) Institute of Forensic Medicine. The sample was divided into two subgroups, natural and unnatural, according to manner of death. Seventy-five per cent of the victims in the violent death subgroup were males with a mean age of 44.6 (SD 17.3) years, while the females of the same category were 52.7 years old on average (SD 19.9). The age distribution of the whole sample showed peaks in the 25–34-year-old group for males and the 35–44-year-old group for females. The most frequent causes of death were accident (44.1%), suicide (12.6%) and homicide (7%). In 5% of cases the cause of death could not be determined. The pattern of mortality from violent causes in the immigrant population differed from that of the country of origin in all parameters. The incidence of unnatural death in immigrants resembled the local pattern in Israel, and was significantly lower than that of their homeland.