Multiple sclerosis recurrence risk for siblings in an isolated population of Central Sardinia, Italy

Studies of twins, adoptees, half siblings, and familial recurrence risk have shown that genetic and non-genetic factors are involved in multiple sclerosis (MS) etiology. Age at onset, gender, and parental MS status seem to influence sibling risk. We studied the recurrence risk in siblings of MS patients in an isolated population of Sardinia, Italy, which is genetically homogeneous, inbred, and very stable, with a high MS frequency. The Aalen-Nelson estimate of the recurrence risk in siblings is 4.7%, and the risk ratio compared with the general population is 31. Proportional hazards models were used to investigate the effect of sibling sex, sex, and age at onset of the proband, and number of affected relatives on a sibling's predicted MS risk. Sib's risk is influenced by age at onset (P = 0.02), and possibly by sex of the proband (P = 0.08). There is also a borderline significant interaction (P = 0.05) between the sex and age at onset of the proband: early age at onset influences sib's risk only if the proband is female. The number of affected relatives in the family is not found to influence sibling risk, but the power is lacking (95% CI 0.50-2.62). This result is consistent with a single dominant gene with an extremely low penetrance, a model that has not yet been disproved as a possible inheritance model for MS.