Enrichment for Northern European-derived multiple sclerosis risk alleles in Sardinia.

BACKGROUND: The list of genomic loci associated with multiple sclerosis (MS) susceptibility outside the major histocompatibility complex (MHC) in patients of Northern European (NE) ancestry has increased to 103. Despite the extraordinarily high MS prevalence in the isolated Sardinian population, the contribution of genetic risk factors to MS in Sardinia is largely not understood. OBJECTIVE: The objective of this paper is to examine the relevance of non-MHC MS susceptibility variants in Sardinia. METHODS: We examined a log-additive MS-specific genetic burden score (MSGB) using 110 NE-derived risk alleles in a dataset of 75 Sardinian cases, 346 Sardinian controls and 177 cases and 1967 controls from the United States (US). RESULTS: Sardinian cases demonstrate a heavier non-MHC MSGB load than Sardinian controls and US cases (p = 2E-06, p = 1E-06, respectively). Furthermore, Sardinian controls carry a heavier burden than US controls (p = 2E-14). Our results confirm the limited ability of the 110-SNP MSGB to predict disease status in Sardinia (AUROC = 0.629). CONCLUSIONS: Risk alleles discovered in samples of NE ancestry are relevant to MS in Sardinia. Our results suggest a general enrichment of MS susceptibility alleles in Sardinians, encouraging the pursuit of further studies of MS in this population.

The increasing incidence and prevalence of MS in a Sardinian province.

OBJECTIVE: To verify incidence rates and their temporal trend in a homogeneous, ethnically, and genetically distinct population of central Sardinia (the Nuoro province). BACKGROUND: Intensive epidemiologic studies carried out in Sardinia since the 1970s have suggested that the prevalence and incidence of MS are much higher in this Mediterranean island compared with those found on mainland Italy. METHODS: The study area had a population of approximately 274, 000 people in the 1991 census. The authors adopted a complete enumerative approach by reviewing all possible sources of case collection available in the investigative area. RESULTS: Based on 469 MS patients, the mean annual incidence for 1955 to 1995 was 4.18 per 100,000 (or 4.3 per 100,000 if age- and sex-adjusted to the European population). The incidence, averaging 1.95 per 100,000 during 1955 to 1959, rose progressively over time, reaching rates of 6.6 in the quinquiennium 1985 to 1989 and 6.4 per 100,000 in 1990 to 1995. On December 31, 1994, the crude prevalence, based on 415 MS patients alive in the study area, was 151.9 per 100,000 (156.6 if adjusted to the European population). CONCLUSION: These incidence and prevalence rates are the highest to date that have been estimated for a large community in southern Europe, and they constitute some of the highest rates in the world. Based on other surveys, these results reinforce the position of Sardinia as a higher and rising prevalence area for MS compared with other Mediterranean populations. Genetic and social-historic data strengthen the hypothesis of the environmental role and genetic factors among Sardinians in determining the notable difference in MS frequency between Sardinians and other Mediterraneans.

An epidemiological study of multiple sclerosis in central Sardinia, Italy.

OBJECTIVES: To verify morbidity estimates in central Sardinia, Italy. METHODS: A prevalence study was performed in the province of Nuoro, Central Sardinia, which has a population of 273,768 inhabitants (135,383 men and 138,385 women). A complete enumeration approach was adopted by using all possible case-collection sources. RESULTS: On prevalence day, December 31, 1993, 394 subjects (124 men and 270 women) living in the study area were known to suffer from definite and probable MS, giving a crude prevalence rate of 143.9 cases per 100,000 people, 91.6 for males and 195.11 for females. The crude prevalence estimated on December 31, 1985, based on 282 MS cases alive in the study area, was 102.94 per 100,000. CONCLUSION: This study reinforced central Sardinia's position as a high and rising prevalence area for MS.

Association between the ancestral haplotype HLA A30B18DR3 and multiple sclerosis in central Sardinia.

Association and linkage studies have established the importance of the major histocompatibility complex (MHC) in the susceptibility for multiple sclerosis (MS). We carried out a case-control study to investigate the ancestral haplotype A30B18DR3 and MS in the Nuoro population of Sardinia, which is isolated and genetically distinct from other populations in the Mediterranean basin and characterized by genetic homogeneity, high level of inbreeding, low migration, high prevalence of MS, high frequency of the relevant haplotype, and high past malaria prevalence. Cases and controls were serologically typed for the currently recognized HLA-A, B, and DR antigens. We used a log-linear approach to fit a wide class of models. We tested our hypothesis comparing different models via a likelihood ratio test. We overcame the complication due to unknown gametic phase using expectation-maximization (EM) algorithm as the estimation method. We estimated confidence intervals for odds ratio by using a profile likelihood approach. We found that: (1) the ancestral haplotype A30B18DR3 was associated to MS after allowing for a possible stratification in cases and controls; (2) DR3 allele was conditional independent on disease status, given A30B18 haplotype; (3) there was a tendency for ORs for the high-risk haplotypes to be higher in the high malaria strata; however, this indication did not achieve statistical significance (P = 0.11).

An ecologic study of geographical variation in multiple sclerosis risk in central Sardinia, Italy.

We carried out an ecological study in the most archaic area of Sardinia to obtain a reliable estimate of the prevalence of multiple sclerosis (MS) and to investigate the geographical variation in the prevalence across the 100 administrative communes. To estimate the area-specific prevalence rate, we adopted a Bayesian approach that makes it possible to filter out the random variation from the estimates and to obtain a map that reflects the true geographical variation in MS prevalence. 428 resident cases were identified by the case register, including 69 multiplex families. The overall prevalence was 157 per 100,000 inhabitants. The Bayesian area-specific prevalence ranged from 143 to 262/100,000. The high prevalence and its moderate geographical variation in a genetically homogeneous population, as well as the high number of multiplex families observed in the communes with the highest prevalence, could be interpreted as representing a high susceptibility of the population to MS.