Multiple sclerosis complexity in selected populations: the challenge of Sardinia, insular Italy¹

Abstract

Several lines of evidence indicate a genetic contribution to multiple sclerosis (MS) both in terms of predisposition to the disease and of immunological mechanisms which are known to play crucial roles in MS pathogenesis. The presence of high- and low-risk areas for MS in neighbouring regions supports the theory that MS predisposition is influenced by a complex interaction of genetic and environmental factors. Therefore, the use of genetically homogeneous and geographically isolated populations becomes an increasing requirement to reduce biasing biological variables. Sardinians fulfil these conditions well because of their different phylogeny from Europeans and the unique selective pressures which shaped their genome. Sardinians display amongst the highest MS prevalence rates world-wide and increasing MS incidence rates over time. Also, MS in Sardinia is linked to distinct human leucocyte antigen (HLA) alleles and associated to different patterns of cytokine production from lymphoid cells of different HLA subtypes. In this context, recent findings and future perspectives on the peculiarities of Sardinian MS concerning genetic, immunological and epidemiological aspects are presented. So far, our results indicate that variations at the level of territorial distribution and HLA-association are present which render MS heterogeneous even in this ethnically homogeneous population.

High Prevalence and Fast Rising Incidence of Multiple Sclerosis in Caltanissetta, Sicily, Southern Italy

“…A similar phenomenon had already been described in Sardinia where clusters of particularly high prevalence and incidence rates have been reported [12] . The case for MS parallels that of other complex diseases with known immunopathogenesis and definite genetic component like type I diabetes [13] . In Italy, a south-to-north increasing gradient for young-onset diabetes had been previously described [14] , but unexpectedly, a high frequency of type I diabetes has recently been reported in Sicily [15] .…”

Seasonal fluctuation of multiple sclerosis births in Sardinia

“…In this genetically distinct population [5,27,31] MS incidence has increased in the last 40 years and is among the highest rates in the world despite the location within the Mediterranean basin [20][21][22] perhaps as a genetic result of founder effect [16]. However, since a temporal cluster of MS in this island occurred after the breaking of historical isolation [23] and four decades are too short a lag for any change of Sardinians' genetic pool to occur, an explanatory environmental influence should not be a priori rejected [29][30][31].…”

“…Although a genetic influence is thought to have the predominant role [16], past and recent evidence suggests the environment to be also influential in determining MS temporal increase in this island [21,23,[29][30][31]. To this purpose, we analysed on a case-control basis the seasonality of Sardinian MS births as compared with that of two control populations: the MS siblings, sharing genetic material with patients, and the general population of the Northern province of Sassari (study area).…”

Risk for Relatives of Patients with Multiple Sclerosis in Central Sardinia, Italy

“…Malaria was also the reason for selecting some human leucocyte antigen alleles [8] and possibly some ancestral haplotypes which are particularly frequent in Sardinia but not in other parts of the world [9]. A high prevalence of MS (157/100,000 inhabitants, 103/ 100,000 inhabitants) and a high proportion of MS cases in the young age groups are reported in Sardinia, in particular in the Nuoro province and in the north-western part of the island [10,11]. An association between the ancestral haplotype A30B18DR3 and MS was also observed [12].…”