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Affected Sardinian families were studied to elucidate the genetic components of asthma by linkage and association analysis at chromosome 12q13-24. It was found that variants in the interleukin-1 receptor associated kinase-M gene are associated with early-onset persistent asthma and indicate interleukin-1 receptor associated kinase-M gene as a potential target for therapeutic intervention against asthma.

Background: Defective alleles within the PRF1 gene, encoding the pore-forming protein perforin, in combination with environmental factors, cause familial type 2 hemophagocytic lymphohistiocytosis (FHL2), a rare, severe autosomal recessive childhood disorder characterized by massive release of cytokines—cytokine storm. Objective: The aim of this study was to determine the function of hypomorph PRF1:p.A91V g.72360387 G > A on multiple sclerosis (MS) and type 1 diabetes (T1D). Methods: We cross-compare the association data for PRF1:p.A91V mutation derived from GWAS on adult MS and pediatric T1D in Sardinians. The novel association with T1D was replicated in metanalysis in 12,584 cases and 17,692 controls from Sardinia, the United Kingdom, and Scotland. To dissect this mutation function, we searched through the coincident association immunophenotypes in additional set of general population Sardinians. Results: We report that PRF1:p.A91V, is associated with increase of lymphocyte levels, especially within the cytotoxic memory T-cells, at general population level with reduced interleukin 7 receptor expression on these cells. The minor allele increased risk of MS, in 2903 cases and 2880 controls from Sardinia p = 2.06 × 10−4, odds ratio OR = 1.29, replicating a previous finding, whereas it protects from T1D p = 1.04 × 10−5, OR = 0.82. Conclusion: Our results indicate opposing contributions of the cytotoxic T-cell compartment to MS and T1D pathogenesis. [ABSTRACT FROM AUTHOR]

Abstract Background Genetic isolates with a history of a small founder population, long-lasting isolation and population bottlenecks represent exceptional resources in the identification of disease genes. In these populations the disease allele reveals Linkage Disequilibrium (LD) with markers over significant genetic intervals, therefore facilitating disease locus identification. In a previous study we examined the LD extension on the Xq13 region in three Corsican sub-populations from the inner mountainous region of the island. On the basis of those previous results we have proposed a multistep procedure to carry out studies aimed at the identification of genes involved in complex diseases in Corsica. A prerequisite to carry out the proposed multi-step procedure was the presence of different degrees of LD on the island and a common genetic derivation of the different Corsican sub-populations. In order to evaluate the existence of these conditions in the present paper we extended the analysis to the Corsican coastal populations. Methods Samples were analyzed using seven dinucleotide microsatellite markers on chromosome Xq13-21: DXS983, DXS986, DXS8092, DXS8082, DXS1225, DXS8037 and DXS995 spanning approximately 4.0 cM (13.3 Mb). We have also investigated the distribution of the DXS1225-DXS8082 haplotype which has been recently proposed as a good marker of population genetic history due to its low recombination rate. Results the results obtained indicate a decrease of LD on the island from the central mountainous toward the coastal sub-populations. In addition the analysis of the DXS1225-DXS8082 haplotype revealed: 1) the presence of a particular haplotype with high frequency; 2) the derivation from a common genetic pool of the sub-populations examined in the present study. Conclusion These results indicate the Corsican sub-populations useful for the fine mapping of genes contributing to complex diseases.

Background: Primary open-angle glaucoma encompasses a complex of potentially blinding ocular diseases characterized by a normal-appearing angle of the anterior chamber, a characteristic degeneration of the optic nerve with resultant typical visual field defects, and usually, an elevated intraocular pressure. It can be subdivided into 2 groups according to the age at onset: the more prevalent chronic open-angle glaucoma diagnosed after 40 years of age, and the less common juvenile form, which occurs between 3 years of age and early adulthood. A locus for primary openangle glaucoma (GLC1A) has been mapped to a 3-centimorgan region of the long arm of chromosome 1 (1q23-25). Recently, the myocilin (MYOC) gene, located in this chromosomal interval, has been found mutated in several patients affected by primary open-angle glaucoma. Objective: To describe the clinical and molecular genetic features of 4 pedigrees affected by autosomal dominant juvenile open-angle glaucoma, all from the Italian region of Puglia. Methods: Clinical study, gonioscopy, automated perimetry, and DNA analysis were performed on several members of the 4 families. Results: We identified a new molecular defect (1177GACA→T) in the third exon of the GLC1A gene. This mutation is present in all affected persons and in 2 still phenotypically normal persons. Conclusion: Our results are important for diagnostic purposes because it is now possible to identify asymptomatic carriers, for whom clinical surveillance for the early detection and treatment of glaucoma may be suggested. [ABSTRACT FROM AUTHOR]

Background: Hepcidin plays a key role in body iron metabolism by preventing the release of iron from macrophages and intestinal cells. Defective hepcidin synthesis causes iron loading, while overproduction results in defective reticuloendothelial iron release and iron absorption., Design and Methods: We studied a Sardinian family in which microcytic anemia due to defective iron absorption and utilization is inherited as a recessive character. Five members showed iron deficiency anemia that was not responsive to oral iron and only partially responsive to parenteral iron administration. To investigate the involvement of known genes implicated in iron metabolism we carried out linkage analysis with microsatellite markers mapping close to these genes. Afterwards, a genome-wide search was performed., Results: No linkage was found between the phenotype of the patients and several known human genes involved in iron metabolism (DMT1, TF, TFRC, ZIRTL, HAMP, HJV). Genome-wide scanning by microsatellites and single nucleotide polymorphisms showed a multipoint LOD score of 5.6 on chromosome 22q12.3-13.1, where the matriptase-2 (also known as transmembrane protease, serine 6 or TMPRSS6) gene is located. Its murine counterpart (Tmprss6) has recently been found to be an essential component of a pathway that detects iron deficiency and suppresses hepcidin production. Sequencing analysis of TMPRSS6 revealed a homozygous causal mutation, predicting a splicing error and a truncated TMPRSS6 protein in affected members. Homozygous subjects had inappropriately elevated levels of serum and urinary hepcidin., Conclusions: The findings of this study suggest that the observed TMPRSS6 mutation leads to overproduction of hepcidin and, in turn, to defective iron absorption and utilization. More generally, they confirm in humans the inhibitory effect of matriptase-2 on hepcidin synthesis already demonstrated in mice.

Background: It has been observed that in patients with ST-elevation myocardial infarction (STEMI) the presence of ST-segment depression (ST) in heterozonal electrocardiographic leads (remote STI) worsens the patient's prognosis. The aim of this study was to observe in an unselected population with a first STEMI the incidence of remote STI and the risk factors related to this condition., Methods: We evaluated retrospectively 350 patients with a first STEMI; we excluded from our analysis 139 patients because no data about their coronary anatomy was available. ST-segment depression in the heterozonal myocardium was considered significant if > 0.1 mV at 60 ms from the J point, in at least two electrocardiographic leads., Results: Patients were classified according to the presence (group 1, 117 patients) or absence (group II, 94 patients) of remote ST. The two groups did not differ for age, sex and coronary anatomy. In group I we found more heterozonal wall motion abnormalities than group II (32 vs. 18%, p = 0.018). In this group there was a higher incidence of smokers (56 vs. 33%, p = 0.025) and less patients were treated with statins when the STEMI occurred (6 vs. 14%, p = 0.047). Patients with remote ST had higher total cholesterol (214.6 +/- 48.9 vs. 192.3 +/- 29.8 mg/dl, p < 0.001) and low-density lipoprotein cholesterol (138.7 +/- 40.7 vs. 123.2 +/- 22.9 mg/dl, p < 0.0001) levels. Conclusions. In patients with STEMI the presence of remote ST is rather frequent, and seems to indicate a real heterozonal ischemia, independently of an epicardial coronary stenosis of the non-infarct-related artery. Remote ST. is associated with a higher incidence of risk factors related to microcirculatory dysfunction, such as cigarette smoking, a worse lipid profile and less protective factors, such as the use of statins prior to acute myocardial infarction.