We have evaluated genetic and environmental influences in multiple sclerosis (MS) by comparing age of onset in 99 sibling pairs concordant for the disease. We used three methods of analysis: (1) comparison of mean differences in age of onset and year of onset, (2) linear regression of differences in age or year of onset vs difference in ages, and (3) intraclass correlation of age of onset which is also used for monozygotic twins concordant for MS. Comparison of the mean differences in age of onset or year of onset is found to be inappropriate and potentially misleading. No significant results were found in linear regression of the age of onset or year of onset vs differences in ages, although a trend towards onset at the same age is present. However, nontwin siblings show a significant intraclass correlation for age of onset (P less than 0.01) as is seen in genetic disorders. A stronger intraclass correlation in age of onset in concordant monozygotic twins vs concordant sibling pairs further suggests that age of onset is partly under genetic control, assuming common exposure to an environmental agent. The results give little support for common exposure to an environmental trigger in concordant MS sibling pairs. They are consistent with a mixture of random independent exposures and common exposures leading to the development of the disease, with the former predominating.
Microchimerism, the persistence of foreign cells thought to derive from previous pregnancies, has been associated with autoimmune diseases. A maternal parent-of-origin effect in MS remains unexplained. We tested for microchimerism in monozygotic and dizygotic twin-pairs with MS. Microchimerism was associated with MS in affected females from monozygotic concordant pairs when compared to both affected (p=0.020) and unaffected (p=0.025) females in monozygotic discordant pairs. Microchimerism was increased in affected females of dizygotic discordant pairs (p=0.059). The rate of microchimerism was significantly higher in affected twins than in unaffected co-twins (p=0.0059). These observations show an association in twins between the presence of microchimerism and having MS.
Results from studies of twin concordance in multiple sclerosis have not conclusively differentiated between environmental and genetic factors that determine susceptibility to the disease. Published studies that have been based on case finding by public appeal have been characterized by difficulties in ascertainment. The data reported here are from a large population-based study of multiple sclerosis in twins, in which ascertainment has been relatively unbiased and the cooperation of patients nearly complete. A total of 5463 patients attending 10 multiple sclerosis clinics across Canada were surveyed. Twenty-seven monozygotic and 43 dizygotic twin pairs were identified, and the diagnosis of multiple sclerosis was verified by examination and laboratory investigation. Seven of 27 monozygotic pairs (25.9 percent) and 1 of 43 dizygotic pairs (2.3 percent) were concordant for multiple sclerosis. The concordance rate for 4582 nontwin siblings of patients at two multiple sclerosis clinics was 1.9 percent, closely paralleling the concordance rate in dizygotic twins. To the extent that the difference in concordance rates between monozygotic and dizygotic twins indicates genetic susceptibility, the results of this study show a major genetic component in susceptibility to multiple sclerosis.
This study is a 7.5-year follow-up of a population-based series of twins with multiple sclerosis (MS) whose mean age now exceeds 50 years. The twin pairs were identified through the Canadian nationwide system of MS clinics and were drawn from a population of 5,463 patients. After 7.5 years, the monozygotic concordance rate increased from 25.9 to 30.8% and the dizygotic-like sex concordance rate from 2.4 to 4.7%. These results are very similar to those of other population-based studies and to our own modified replication twin data reported here. We interpret the data to mean that MS susceptibility is genetically influenced, and a single dominant or even a single recessive gene is unlikely to account for this effect. The difference in concordance rates suggests that at least two or more genes are operative. These data also have important implications for the nature of the environmental effect(s) in MS susceptibility. Most monozygotic twins are discordant even after a correction for age and magnetic resonance imaging findings. This unambiguously demonstrates the powerful effect of nonheritable factors.
