Familial Risk of Multiple Sclerosis: A Nationwide Cohort Study
Nielsen NM, Westergaard T, Rostgaard K, et al.;
Commented by , 27 Sep 2005
Background
Most MS cases occur sporadically although family history often reveals other cases. The familial risk has been calculated in various ways, ranging from 12- to 38-fold in siblings, seven- to 26-fold in parents, and six- to 26-fold in children of MS patients.
There is a need for more accurate counseling on this issue in clinical practice and the current study aims at providing relevant data using a unique nationwide database.
Aim
To estimate the relative and absolute risk of MS in a population-based cohort.
Methods
The authors identified all MS patients alive on April 1, 1968, or later (n=8,205) in the Danish Multiple Sclerosis Register. All first-degree relatives (n=19,615; offspring 13,316, parents 3,556, siblings 2,710 or twins 33) were then identified in the Danish Civil Registration System and followed from 1968 to 1997.
The ratio of observed to expected MS cases served as a measure of relative risk of MS. Lifetime risk of MS in first degree relatives to MS patients was expressed as the product of the relative risk and the national lifetime risk of MS.
Results
The authors observed 90 cases of MS among first-degree relatives versus 12.6 cases expected. The relative risk (RR) was 7.1 % (CI 5.8-8.8).
Stratification of the analysis by gender of relatives showed a lower RR in female (5.9 %; CI 4.5 – 7.9) compared with male (9.3 %; CI 6.8 – 12.5) relatives.
Stratification by gender of proband suggested a higher RR in relatives of male MS patients (8.8 %; CI 6.6-11.8) compared with relatives of female MS patients (6.0 %; CI 4.5-8.0).
Among the 33 twins two cases (monozygotic) was observed versus 0.02 cases expected (RR=85.8; CI 21.5-343).
Estimated lifetime risk was 0.5% in women and 0.3% in men, according to national age- and sex-specific incidence rates.
Lifetime risk of MS was calculated to be 2.9% in female and 2.8% in male first-degree relatives of MS patients.
Dr Blinkenberg's comments
It is the first study to provide nationwide data of familial risk of MS. The authors find a sevenfold increased risk of MS in relatives of MS patients, and kinship is associated with excess absolute risk of 2.5% in first degree relatives in a high incidence region.
This number is smaller than generally used estimates, and is therefore important and applicable in clinical counseling.
The study shows an increased relative risk of MS in relatives of males compared with females, which is in accordance with previous observations. The observed risk of MS was the same for both gender irrespective of the gender of the proband, which means that gender-specific variations in the background MS incidence rate is explained by sporadic risk factors.
A study bias was introduced since first-degree relatives of MS patients who died before April 1960, was not classified as familial cases but as sporadic cases, which lead to a more conservative estimate.
The authors did not find a major role of environmental factors in adulthood, since spouses of MS patients were not at increased risk of MS. In this way the study show a strong familial component and involvement of genetic factors in MS.