Discordant Monozygotic Twin Pairs Research Articles

Determinants of the Progression in Lumbar Degeneration

A 5-year follow-up study of exposure of discordant monozygotic twin pairs with repeated interviews and spine imaging. The primary goals were to record changes in the degenerative signs over a 5-year interval and to estimate the effects of familial influences and suspected environmental risk factors on the speed of lumbar degeneration. Traditionally, disc degeneration has been attributed to aging and environmental exposures; recently, a dominant effect of genetics has been revealed. Yet the etiopathogenesis of disc degeneration remains poorly understood and controversial despite being a primary target of diagnostic and therapeutic interventions. Among 116 monozygotic twin pairs, which had been examined 5 years earlier, 75 pairs (150 men) were reexamined. They were imaged using the same MRI scanner and examination protocol as at baseline. The data were analyzed using statistical methods for longitudinal studies. Progression in disc height narrowing, disc bulging, osteophytosis, and fatty degeneration in the lumbar spine was seen in about 7% to 13% of the discs in 7% to 46% of subjects during 5-year follow-up. Few degenerative findings appear to reverse; few disc height measures increased, some anular tears were no longer visible, and bulging/herniation diminished. New anular tears (in axial view) were detected in 1.5%, disappeared in 2%, and were unchanged in 5.3% of discs; in the sagittal view, new high intensity zones findings were identified in 0.5%, were no longer apparent in 1.6%, and were unchanged in 7.1% of discs. There were no clear changes in upper endplates: in 2.1% of discs, the irregularity score increased and in 1.8% it decreased. Familial aggregation, reflecting genetic, and shared environmental influences, explained 47% to 66% of the variance in progression of degenerative signs on lumbar MRI, and resistance training and occupational physical loading together explained 2% to 10% of the progression in the degenerative signs in lumbar MRIs. Progression of disc height narrowing, bulging, osteophytes, and fatty degeneration was detected in about 10% or less of the T12-S1 discs. Development and disappearance of anular lesions were rarer. No clear changes were seen in endplate irregularities. The results also confirm that hereditary effects have a dominant role in the progression of disc degeneration and suggest that occupational lifting and leisure time resistance training have modest additional effects.

Monozygotic twins clinically discordant for scleroderma show concordance for fibroblast gene expression profiles

Fewer than 5% of monozygotic (MZ) and dizygotic (DZ) twin pairs are clinically concordant for systemic sclerosis (SSc), yet the majority of MZ twins are concordant for antinuclear antibodies. To discover genetic versus nongenetic molecular pathways important to the pathogenesis of SSc, we compared global gene expression patterns in twins discordant for SSc. Total RNA from dermal fibroblasts of 15 discordant twin pairs (10 MZ and 5 DZ) and 5 normal controls were used in microarray analysis. Aberrantly expressed genes were confirmed using quantitative real-time reverse transcriptase-polymerase chain reaction. Lesional and nonlesional fibroblasts from SSc patients showed no significant differences in gene expression, while SSc patients had gene profiles that were significantly different from those of unaffected DZ twins and normal controls. Unaffected MZ twins, however, were not significantly different from SSc patients. Unsupervised hierarchical clustering segregated the fibroblast samples as originating from 2 major groups. Group A contained 5 discordant MZ twin pairs, 3 affected MZ twins, and 3 affected DZ twins. Group B contained all 5 normal population controls, all 5 healthy DZ twins, 2 discordant MZ twins, and 2 discordant DZ twin pairs. Normal fibroblasts incubated with serum from an SSc-affected patient or with serum from her unaffected MZ twin sister developed the increased expression of COL1A2, SPARC, and CTGF typically seen in SSc fibroblasts. These results demonstrate that dermal fibroblasts from SSc patients and from 40-50% of their genetically identical but clinically unaffected MZ twins exhibit a similar gene expression pattern which can be induced in normal fibroblasts by sera from both. Thus, a stronger genetic predisposition to SSc (than can be detected clinically) is apparent at the molecular level in skin fibroblasts.

Behavioral Versus Genetic Correlates of Lipoproteins and Adiposity in Identical Twins Discordant for Exercise

Lipoprotein and weight differences between vigorously active and sedentary monozygotic (MZ) twins were used to (1) estimate the effects of training while controlling for genotype and (2) estimate genetic concordance (ie, similarity) in the presence of divergent lifestyles. Thirty-five pairs of MZ twins (25 male, 10 female) were recruited nationally who were discordant for vigorous exercise (running distances differed by > or =40 km in male and > or =32 km in female twins). The active twins ran an average (mean+/-SD) of 63.0+/-20.4 km/wk, whereas the mostly sedentary twins averaged 7.0+/-13.5 km/wk. The active twins had significantly lower body mass index (difference+/-SE, -2.12+/-0.57 kg/m2, P=0.0007) and significantly higher HDL cholesterol (0.14+/-0.04 mmol/L, P=0.004), HDL2 (2.71+/-1.04 U, P=0.01), and apolipoprotein (apo) A-I (0.10+/-0.03 g/L, P=0.004). Despite the difference in lifestyle, when adjusted for sex, the correlations between the discordant MZ twin pairs were significant (P<0.01) for HDL cholesterol (r=0.69), apoA-I (r=0.58), and HDL2 (r=0.67). There was no significant MZ twin correlation for body mass index (r=0.17). None of the active twins having an overweight twin were themselves overweight. Behavior (vigorous exercise) may reduce genetic influences on body mass index. In contrast, genetics (or shared environment) substantially influences HDL cholesterol and HDL subclasses, even in the presence of extreme behavioral differences. There may be greater individual control over moderate degrees of obesity, whereas low HDL cholesterol may be largely predetermined and less effectively treated by vigorous exercise.

Does marijuana use have residual adverse effects on self-reported health measures, socio-demographics and quality of life? A monozygotic co-twin control study in men.

To assess the effects of former heavy marijuana use on selected aspects of health. A monozygotic co-twin control design was used to compare the health of former heavy marijuana using male monozygotic twins to that of their co-twins who never used marijuana significantly. In-person survey and questionnaires. Fifty-six marijuana use discordant monozygotic twin pair members of the Vietnam Era Twin (VET) Registry. Current socio-demographic characteristics; current nicotine and alcohol use; life-time nicotine and alcohol abuse/dependence; past 5-year physical and mental health services utilization; and health-related quality of life. The mean number of days on which the marijuana user twin used marijuana in his life-time was 1085, while the non-marijuana user used marijuana a maximum of 5 days. Marijuana was last used a mean of 20 years previously. No significant differences were found between the former marijuana user twins and their siblings for current socio-demographic characteristics; current nicotine or alcohol use; life-time nicotine or alcohol abuse/dependence; past 5-year out-patient or emergency room visits, hospitalizations or medication use for medical problems; past 5-year mental health out-patient use or hospitalizations; or health-related quality of life. Previous heavy marijuana use a mean of 20 years earlier by a group of men who reported no other significant illicit drug use does not appear to be associated with adverse socio-demographic, physical or mental health adverse effects. The conclusions of the study are limited by possible participation and recall biases, relatively small sample size and the absence of a physical health examination.

Is the genetic liability in multifactorial disorders higher in concordant than discordant monozygotic twin pairs? A population-based family twin study of migraine without aura.

Migraine without aura (MO) is a multifactorial disorder. Expression of a disorder with multifactorial inheritance depends on the genetic liability and on environmental factors. A high liability is reflected by a high frequency of affected relatives. We have previously shown that monozygotic (MZ) twin pairs have a significant higher concordance of MO than dizygotic twin pairs. The incomplete concordance among MZ twin pairs may be due to a lower genetic liability among discordant than concordant MZ twin pairs. The present study analysed the genetic liability in MZ twin pairs concordant and discordant for MO by the population-relative risk of MO among parents and siblings. The twin pairs were from the population-based Danish Twin Register. First-degree relatives of 29 concordant and 34 discordant MZ twin pairs were blindly telephone interviewed by a physician. The participation rate of the eligible first-degree relatives was 96%. The population-relative risk of MO among parents and siblings was 2.73 (2.39-3.06) in concordant and 2.37 (2.03-2.71) in discordant MZ twin pairs. The relative risk of MO was significantly higher in female first-degree relatives of concordant than of discordant MZ male and female twin pairs. An opposite effect was observed in male first-degree relatives, although this was not significant for male first-degree relatives of female MZ twin pairs. The present study found no statistically significant difference in genetic liability to MO among concordant and discordant MZ twin pairs. However, a difference in genetic liability among MZ and DZ twin pairs is anticipated to be small. Thus, it may be possible to show the effect in a larger study population or by investigating a more frequent trait than MO.

Low birth weight is associated with NIDDM in discordant monozygotic and dizygotic twin pairs.

Previous studies have demonstrated an association between low weight at birth and risk of later development of non-insulin-dependent diabetes mellitus (NIDDM). It is not known whether this association is due to an impact of intrauterine malnutrition per se, or whether it is due to a coincidence between the putative "NIDDM susceptibility genotype" and a genetically determined low weight at birth. It is also unclear whether differences in gestational age, maternal height, birth order and/or sex could explain the association. Twins are born of the same mother and have similar gestational ages. Furthermore, monozygotic (MZ) twins have identical genotypes. Original midwife birth weight record determinations were traced in MZ and dizygotic (DZ) twins discordant for NIDDM. Birth weights were lower in the NIDDM twins (n = 2 x 14) compared with both their identical (MZ; n = 14) and non-identical (DZ; n = 14) non-diabetic co-twins, respectively (MZ: mean +/- SEM 2634 +/- 135 vs 2829 +/- 131 g, p < 0.02; DZ: 2509 +/- 135 vs 2854 +/- 168 g, p < 0.02). Using a similar approach in 39 MZ and DZ twin pairs discordant for impaired glucose tolerance (IGT), no significantly lower birth weights were detected in the IGT twins compared with their normal glucose tolerant co-twins. However, when a larger group of twins with different glucose tolerance were considered, birth weights were lower in the twins with abnormal glucose tolerance (NIDDM + IGT; n = 106; 2622 +/- 45 g) and IGT (n = 62: 2613 +/- 55 g) compared with twins with normal glucose tolerance (n = 112: 2800 +/- 51 g; p = 0.01 and p = 0.03, respectively). Furthermore, the twins with the lowest birth weights among the two co-twins had the highest plasma glucose concentrations 120 min after the 75-g oral glucose load (n = 86 pairs: 9.6 +/- 0.6 vs 8.0 +/- 0.4 mmol/l, p = 0.03). In conclusion, the association between low birth weight and NIDDM in twins is at least partly independent of genotype and may be due to intrauterine malnutrition. IGT was also associated with low birth weight in twins. However, the possibility cannot be excluded that the association between low birth weight and IGT could be due to a coincidence with a certain genotype causing both low birth weight and IGT in some subjects.

Discordance and concordance of dementia of the Alzheimer type (DAT) in monozygotic twins indicate heritable and sporadic forms of Alzheimer's disease

Monozygotic (MZ) twin pairs concordant for dementia of the Alzheimer type (DAT) or for proven Alzheimer's disease (AD) have a significantly higher frequency of a positive family history (DAT or AD in at least one first-degree relative, p less than 0.002) than do discordant MZ twin pairs, consistent with a lesser predicted distribution of proportions of surviving first-degree relatives without DAT (or AD) (p less than 0.001). The results suggest that concordant MZ twin pairs with DAT (or AD) have a heritable form of disease. AD in discordant twins may result from environmental influences or from a somatic chromosomal change following zygotic division.

Concordance for Dyslipidemic Hypertension in Male Twins

Sixty cases of dyslipidemic hypertension were identified in the 1028 middle-aged, white, male twin participants in the first examination of the National Heart, Lung, and Blood Institute Twin Study (1969 to 1973). The prevalence of dyslipidemic hypertension was similar by zygosity but proband concordance was three times greater in monozygotic than dizygotic twins (0.44 [seven concordant and 18 discordant pairs] vs 0.14 [two concordant and 24 discordant pairs]), suggesting a genetic effect on the condition. Low high-density lipoprotein cholesterol level was the most common lipid abnormality in concordant pairs. Mortality from ischemic heart disease was significantly higher in individuals with dyslipidemic hypertension. Obesity and glucose intolerance were closely associated with the syndrome. Moreover, within the 18 discordant monozygotic twin pairs, the twins with dyslipidemic hypertension had gained significantly more weight as adults and were significantly heavier than their unaffected cotwins. Thus, although genetic factors may influence development of dyslipidemic hypertension, nongenetic, potentially modifiable aspects of obesity are also closely related to expression of this clinically important syndrome.

Obstetric complications and physical size of offspring of schizophrenic, schizophrenic-like, and control mothers.

The question whether schizophrenic mothers have increased risk for obstetric complications (OCs) has practical relevance to fertility recommendations and obstetric surveillance for such women. From a theoretical viewpoint the study of OCs in schizophrenic women concerns the possible relationship between tension-anxiety and OCs, and, additionally, whether the offspring have an increased risk for disturbance based at least partially upon an increased incidence of OCs. Recent evidence suggests a relationship or interaction between genetic factors contributed through family lineage and OCs attending the gestation of genetically-high-risk offspring. Increased OC rates have been found to be differentially characteristic of the pre-schizophrenics or the pre-disturbed persons within discordant monozygotic twin pairs (27), discordant regular sibling pairs (23), and offspring of schizophrenic mothers (18). Mednick (15, p. 56) has suggested that the OCs ‘trigger some characteristic which may be genetically predisposed’.