ABSTRACT
BACKGROUND: The Mediterranean island of Sardinia has a strikingly high incidence of the autoimmune disorders Type 1 Diabetes (T1D) and Multiple Sclerosis (MS). Furthermore, the two diseases tend to be co-inherited in the same individuals and in the same families. These observations suggest that some unknown autoimmunity variant with relevant effect size could be fairly common in this founder population and could be detected using linkage analysis. METHODS: To search for T1D and MS loci as well as any that predispose to both diseases, we performed a whole genome linkage scan, sequentially genotyping 593 microsatellite marker loci in 954 individuals distributed in 175 Sardinian families. In total, 413 patients were studied; 285 with T1D, 116 with MS and 12 with both disorders. Model-free linkage analysis was performed on the genotyped samples using the Kong and Cox logarithm of odds (LOD) score statistic. RESULTS: In T1D, aside from the HLA locus, we found four regions showing a lod-score > or =1; 1p31.1, 6q26, 10q21.2 and 22q11.22. In MS we found three regions showing a lod-score > or =1; 1q42.2, 18p11.21 and 20p12.3. In the combined T1D-MS scan for shared autoimmunity loci, four regions showed a LOD >1, including 6q26, 10q21.2, 20p12.3 and 22q11.22. When we typed more markers in these intervals we obtained suggestive evidence of linkage in the T1D scan at 10q21.2 (LOD = 2.1), in the MS scan at 1q42.2 (LOD = 2.5) and at 18p11.22 (LOD = 2.6). When all T1D and MS families were analysed jointly we obtained suggestive evidence in two regions: at 10q21.1 (LOD score = 2.3) and at 20p12.3 (LOD score = 2.5). CONCLUSION: This suggestive evidence of linkage with T1D, MS and both diseases indicates critical chromosome intervals to be followed up in downstream association studies.
Subject(s)
Diabetes Mellitus, Type 1/genetics , Genetic Linkage , Genetic Predisposition to Disease , Microsatellite Repeats/genetics , Multiple Sclerosis/genetics , Adolescent , Adult , Child , Chromosome Mapping , Diabetes Mellitus, Type 1/complications , Female , Genetic Markers/genetics , Haplotypes , Humans , Male , Mediterranean Islands , Middle Aged , Multiple Sclerosis/complications , Quantitative Trait Loci , Statistics, NonparametricABSTRACT
A male excess in Sardinian type 1 diabetic cases has previously been reported and was largely restricted to those patients carrying the HLA-DR3/nonDR4 genotype. In the present study, we have measured the male- to-female (M:F) ratio in a sample set of 542 newly collected, early-onset type 1 diabetic Sardinian patients. This data not only confirm the excess of male type 1 diabetic patients overall (M:F ratio = 1.3, P = 3.9 x 10(-3)) but also that the bias in male incidence is largely confined to patients with the DR3/nonDR4 genotype (M:F ratio = 1.6, P = 2.0 x 10(-4)). These sex effects could be due to a role for allelic variation of the Y chromosome in the susceptibility to type 1 diabetes, but to date this chromosome has not been evaluated in type 1 diabetes. We, therefore, established the frequencies of the various chromosome Y lineages and haplotypes in 325 Sardinian male patients, which included 180 cases with the DR3/nonDR4 genotype, and 366 Sardinian male control subjects. Our results do not support a significant involvement of the Y chromosome in DR3/nonDR4 type 1 diabetic cases nor in early-onset type 1 diabetes as a whole. Other explanations, such as X chromosome-linked inheritance, are thus required for the male bias in incidence in type 1 diabetes in Sardinia.
