-
E Sánchez,
M García-Bermúdez,
J Jiménez-Alonso,
E de Ramón,
J Sánchez-Román,
N Ortego-Centeno,
T Witte, S D'Alfonso,
B Pons-Estel,
H-J Anders,
Me Alarcón-Riquelme,
J Martín
[show abstract]
[hide abstract]
ABSTRACT: Objective: The aim of this study was to evaluate the relevance of genetic variants of interleukin receptor-associated kinase-M (IRAK-M) (rs11465955, rs1624395, rs1152888 and rs1370128) and single immunoglobulin IL1-1R-related molecule (SIGIRR) (rs3210908) genes in systemic lupus erythematosus (SLE) in four independent European-descent populations. Methods: Our study population consisted of a total of 2033 SLE patients and 2357 healthy controls from Spain, Germany, Italy and Argentina. The genotyping was performed using a polymerase chain reaction (PCR) system with pre-developed TaqMan allelic discrimination assay. Genetic association between the genotyped markers was determined by PLINK v1.07. Results: After a meta-analysis including these four populations, a trend of association between rs11465955 (P(meta) (-analysis) = 0.06), rs1370128 (P(meta) (-analysis) = 0.07) and rs1624395 (P(meta) (-analysis) = 0.06) polymorphisms was found. However, these differences did not reach statistical significance. In addition, we did not find any association between SLE and the rs1152888 IRAK-M (P(meta) (-analysis) = 0.13) and the rs3210908 SIGIRR (P(meta) (-analysis) = 0.40) polymorphisms after the meta-analysis. No evidence of association with IRAK-M haplotypes was found. Conclusion: These results suggest that the tested variations of IRAK-M and SIGIRR genes do not confer a relevant role in the susceptibility to SLE in European-descent populations.
Lupus 05/2012; 21(11):1166-71. · 2.34 Impact Factor
-
S E Löfgren,
J Frostegård,
L Truedsson,
B A Pons-Estel, S D'Alfonso,
T Witte,
B R Lauwerys,
E Endreffy,
L Kovács,
C Vasconcelos,
B Martins da Silva,
S V Kozyrev,
M E Alarcón-Riquelme
[show abstract]
[hide abstract]
ABSTRACT: A recent genome-wide association study revealed a variant (rs2431697) in an intergenic region, between the pituitary tumor-transforming 1 (PTTG1) and microRNA (miR-146a) genes, associated with systemic lupus erythematosus (SLE) susceptibility. Here, we analyzed with a case-control design this variant and other candidate polymorphisms in this region together with expression analysis in order to clarify to which gene this association is related. The single-nucleotide polymorphisms (SNPs) rs2431697, rs2910164 and rs2277920 were genotyped by TaqMan assays in 1324 SLE patients and 1453 healthy controls of European ancestry. Genetic association was statistically analyzed using Unphased. Gene expression of PTTG1, the miRNAs miR-3142 and primary and mature forms of miR-146a in peripheral blood mononuclear cells (PBMCs) were assessed by quantitative real-time PCR. Of the three variants analyzed, only rs2431697 was genetically associated with SLE in Europeans. Gene expression analysis revealed that this SNP was not associated with PTTG1 expression levels, but with the microRNA-146a, where the risk allele correlates with lower expression of the miRNA. We replicated the genetic association of rs2341697 with SLE in a case-control study in Europeans and demonstrated that the risk allele of this SNP correlates with a downregulation of the miRNA 146a, potentially important in SLE etiology.
Genes and immunity 01/2012; 13(3):268-74. · 4.22 Impact Factor
-
R Del Bo,
C Tiloca,
V Pensato,
L Corrado,
A Ratti,
N Ticozzi,
S Corti,
B Castellotti,
L Mazzini,
G Sorarù,
C Cereda, S D'Alfonso,
C Gellera,
G P Comi,
V Silani
[show abstract]
[hide abstract]
ABSTRACT: Optineurin (OPTN), a causative gene of hereditary primary open-angle glaucoma, has been recently associated with amyotrophic lateral sclerosis (ALS) with mainly autosomal recessive, but also dominant, traits. To further define the contribution of OPTN gene in ALS, we performed a mutational screening in a large cohort of Italian patients.
A group of 274 ALS patients, including 161 familial (FALS) and 113 sporadic (SALS) cases, were screened for OPTN mutations by direct sequencing of its coding sequence. All patients fulfilled the El Escorial criteria for probable or definite ALS and were negative for mutations in SOD1, ANG, TARDBP and FUS/TLS genes.
The genetic analysis revealed six novel variants in both FALS and SALS patients, all occurring in an heterozygous state. We identified three missense (c.844A→C p.T282P, c.941A→T p.Q314L, c.1670A→C p.K557T), one nonsense (c.67G→T p.G23X) and two intronic mutations (c.552+1delG, c.1401+4A→G). The intronic c.552+1delG variant determined a splicing defect as demonstrated by mRNA analysis. All mutations were absent in 280 Italian controls and over 6800 worldwide glaucoma patients and controls screened so far. The clinical phenotype of OPTN-mutated patients was heterogeneous for both age of onset and disease duration but characterised by lower-limb onset and prevalence of upper motor neuron signs.
In this cohort, OPTN mutations were present both in FALS (2/161), accounting for 1.2% cases, and in SALS patients (4/113), thereby extending the spectrum of OPTN mutations associated with ALS. The study further supports the possible pathological role of optineurin protein in motor neuron disease.
Journal of neurology, neurosurgery, and psychiatry 05/2011; 82(11):1239-43. · 4.87 Impact Factor
-
M Ban,
J L McCauley,
R Zuvich,
A Baker,
L Bergamaschi,
M Cox,
A Kemppinen, S D'Alfonso,
F R Guerini,
J Lechner-Scott, [......],
D A Hafler,
L F Barcellos,
A J Ivinson,
D Sexton,
J R Oksenberg,
S L Hauser,
M A Pericak-Vance,
J Haines,
A Compston,
S Sawcer
[show abstract]
[hide abstract]
ABSTRACT: Several single-nucleotide polymorphism (SNP) genome-wide association studies (GWASs) have been completed in multiple sclerosis (MS). Follow-up studies of the variants with the most promising rankings, especially when supplemented by informed candidate gene selection, have proven to be extremely successful. In this study we report the results of a multi-stage replication analysis of the putatively associated SNPs identified in the Wellcome Trust Case Control Consortium non-synonymous SNP (nsSNP) screen. In total, the replication sample consisted of 3444 patients and 2595 controls. A combined analysis of the nsSNP screen and replication data provides evidence implicating a novel additional locus, rs3748816 in membrane metalloendopeptidase-like 1 (MMEL1; odds ratio=1.16, P=3.54 × 10⁻⁶) in MS susceptibility.
Genes and immunity 12/2010; 11(8):660-4. · 4.22 Impact Factor
-
European Journal of Neurology 11/2010; 18(4):e41-2. · 3.69 Impact Factor
-
L Bergamaschi,
M A Leone,
M E Fasano,
F R Guerini,
D Ferrante,
E Bolognesi,
N Barizzone,
L Corrado,
P Naldi,
C Agliardi, [......],
M Salvetti,
A Visconti,
D Galimberti,
E Scarpini,
M Vercellino,
R Bergamaschi,
F Monaco,
D Caputo,
P Momigliano-Richiardi, S D'Alfonso
[show abstract]
[hide abstract]
ABSTRACT: Previous studies reported an association with multiple sclerosis (MS) of distinct HLA-class I markers, namely HLA-A*02, HLA-Cw*05 and MOG-142L. In this work, we tested the association with MS of A*02 and Cw*05 in 1273 Italian MS patients and 1075 matched controls, which were previously analyzed for MOG-142, and explored the relationship among these three markers in modulating MS risk. HLA-A*02 conferred a statistically robust MS protection (odds ratio, OR=0.61; 95% confidence intervals, CI=0.51-0.72, P<10(-9)), which was independent of DRB1*15 and of any other DRB1* allele and remained similar after accounting for the other two analyzed class I markers. Conversely, the protective effect we previously observed for MOG-142L was secondary to its linkage disequilibrium with A*02. Cw*05 was not associated considering the whole sample, but its presence significantly enhanced the protection in the HLA-A*02-positive group, independently of DRB1: the OR conferred by A*02 in Cw*05-positive individuals (0.22, 95% CI=0.13-0.38) was significantly lower than in Cw*05-negative individuals (0.69, 95% CI=0.58-0.83) with a significant (P=4.94 x 10(-5)) multiplicative interaction between the two markers. In the absence of A*02, Cw*05 behaved as a risk factor, particularly in combination with DRB1*03 (OR=3.89, P=0.0006), indicating that Cw*05 might be a marker of protective or risk haplotypes, respectively.
Genes and immunity 11/2009; 11(2):173-80. · 4.22 Impact Factor
-
A Brussino, S D'Alfonso,
C Cagnoli,
E Di Gregorio,
M Barberis,
S Padovan,
G Vaula,
L Pinessi,
S Squadrone,
M C Abete,
L Collimedaglia,
F R Guerini,
N Migone,
A Brusco
[show abstract]
[hide abstract]
ABSTRACT: Whole gene duplication of the lamin B1 gene (LMNB1), encoding for a protein of the nuclear lamina, causes an adult-onset autosomal dominant leukodystrophy (ADLD). Clinical features of ADLD (onset in adult life, dysautonomic symptoms, followed by pyramidal and cerebellar dysfunctions) partially resemble those of multiple sclerosis (MS), particularly the primary-progressive form. Our aim was to test whether LMNB1 gene mutations were present amongst patients with a diagnosis of MS.
One hundred eighty-two MS patients were screened for copy number variations of the LMNB1 gene using a qPCR assay. Point mutations in the LMNB1 gene were searched by denaturing high-performance liquid chromatography and direct sequencing in a subgroup of 16 patients with familial MS.
No duplication/deletion of the lamin B1 gene was found amongst MS patients, and no point mutation was identified in the familial cases.
Our work indicates that lamin B1 defects are probably not responsible for signs and symptoms resembling multiple sclerosis.
European Journal of Neurology 05/2009; 16(4):544-6. · 3.69 Impact Factor
-
Lucia Corrado,
A Ratti,
C Gellera,
E Buratti,
B Castellotti,
Y Carlomagno,
N Ticozzi,
L Mazzini,
L Testa,
F Taroni,
F E Baralle,
V Silani, S D'Alfonso
[show abstract]
[hide abstract]
ABSTRACT: Recent studies identified rare missense mutations in amyotrophic lateral sclerosis (ALS) patients in the TARDBP gene encoding TAR DNA binding protein (TDP)-43, the major protein of the ubiquitinated inclusions (UBIs) found in affected motor neurons (MNs). The aim of this study was to further define the spectrum of TARDBP mutations in a large cohort of 666 Italian ALS patients (125 familial and 541 sporadic cases). The entire coding region was sequenced in 281 patients, while in the remaining 385 cases only exon 6 was sequenced. In 18 patients, of which six are familial, we identified 12 different heterozygous missense mutations (nine novel) all locating to exon 6, which were absent in 771 matched controls. The c.1144G>A (p.A382T) variation was observed in seven patients, thus representing the most frequent TARDBP mutation in ALS. Analysis of microsatellites surrounding the TARDBP gene indicated that p.A382T was inherited from a common ancestor in 5 of the 7 patients. Altogether, the frequency of TARDBP gene mutations appears to be particularly high in Italian ALS patients compared to individuals of mainly Northern European origin (2.7% vs. 1%). Western blot analysis of lymphocyte extracts from two patients carrying the p.A382T and p.S393L TARDBP mutations showed the presence of lower molecular weight TDP-43 bands, which were more abundant than observed in healthy controls and patients negative for TARDBP mutations. In conclusion, this report contributes to the demonstration of the causative role of the TARDBP gene in ALS pathogenesis and indicates that mutations may affect the stability of the protein even in nonneuronal tissues.
Human Mutation 02/2009; 30(4):688-94. · 5.69 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The tumor necrosis factor ligand superfamily member 4 gene (TNFSF4) encodes the OX40 ligand (OX40L), a costimulatory molecule involved in T-cell activation. A recent study demonstrated the association of TNFSF4 haplotypes located in the upstream region with risk for or protection from systemic lupus erythematosus (SLE). To replicate this association, five single nucleotide polymorphisms (SNPs) tagging the previously associated haplotypes and passing the proper quality-control filters were tested in 1312 cases and 1801 controls from Germany, Italy, Spain and Argentina. The association of TNFSF4 with SLE was replicated in all the sets except Spain. There was a unique risk haplotype tagged by the minor alleles of the SNPs rs1234317 (pooled odds ratio (OR)=1.39, P=0.0009) and rs12039904 (pooled OR=1.38, P=0.0012). We did not observe association to a single protective marker (rs844644) or haplotype as the first study reported; instead, we observed different protective haplotypes, all carrying the major alleles of both SNPs rs1234317 and rs12039904. Association analysis conditioning on the haplotypic background confirmed that these two SNPs explain the entire haplotype effect. This first replication study confirms the association of genetic variation in the upstream region of TNFSF4 with susceptibility to SLE.
Genes and immunity 01/2009; 10(3):248-53. · 4.22 Impact Factor
-
G Cappellano,
E Orilieri,
C Comi,
A Chiocchetti,
S Bocca,
E Boggio,
I S Bernardone,
A Cometa,
R Clementi,
N Barizzone, [......],
F R Guerini,
D Caputo,
D Paolicelli,
M Trojano,
L Figà-Talamanca,
M Salvetti,
F Perla,
M Leone,
F Monaco,
U Dianzani
[show abstract]
[hide abstract]
ABSTRACT: Perforin is involved in cell-mediated cytotoxicity and mutations of its gene (PRF1) cause familial hemophagocytic lymphohistiocytosis (FLH2). PRF1 sequencing in 190 patients with multiple sclerosis and 268 controls detected two FLH2-associated variations (A91V, N252S) in both groups and six novel mutations (C999T, G1065A, G1428A, A1620G, G719A, C1069T) in patients. All together, carriers of these variations were more frequent in patients than in controls (phenotype frequency: 17 vs 9%, P=0.0166; odds ratio (OR)=2.06, 95% confidence interval (CI): 1.13-3.77). Although A91V was the most frequent variation and displayed a trend of association with multiple sclerosis (MS) in the first population of patients and controls (frequency of the 91V allele: 0.076 vs 0.043, P=0.044), we used it as a marker to confirm PRF1 involvement in MS and assessed its frequency in a second population of 966 patients and 1520 controls. Frequency of the 91V allele was significantly higher in patients than in controls also in the second population (0.075 vs 0.058%, P=0.019). In the combined cohorts of 1156 patients and 1788 controls, presence of the 91V allele in single or double dose conferred an OR=1.38 (95% CI=1.10-1.74). These data suggest that A91V and possibly other perforin variations indicate susceptibility to MS.
Genes and immunity 06/2008; 9(5):438-44. · 4.22 Impact Factor
-
S D'Alfonso,
E Bolognesi,
F R Guerini,
N Barizzone,
S Bocca,
D Ferrante,
L Castelli,
L Bergamaschi,
C Agliardi,
P Ferrante,
P Naldi,
M Leone,
D Caputo,
C Ballerini,
M Salvetti,
D Galimberti,
L Massacesi,
M Trojano,
P Momigliano-Richiardi
[show abstract]
[hide abstract]
ABSTRACT: Several studies suggest that the histocompatibility complex (HLA) class I region harbours genes modulating multiple sclerosis (MS) susceptibility independently from the effect of class II alleles. A candidate gene in this region is MOG, encoding the myelin oligodendrocyte glycoprotein. A significant association with the missense variation V142L (rs2857766) was previously reported in a small sample of 50 Italian MS patients. We confirmed this result in two independent Italian sample sets consisting of 878 MS patients and 890 matched controls (P=6.6 x 10(-4)) and 246 trio families (P=1.5 x 10(-3)). The comparison of genotype frequencies suggested a dominant-protective effect of L142. In the combined sample sets L142 conferred an odds ratio (OR)=0.70 (95% confidence interval (CI): 0.60-0.82) that remained similar after accounting for HLA-DRB1(*)15 carrier status. The association with MOG V142L was still significant after conditioning for all DRB1 alleles (P=0.035). Eleven additional single nucleotide polymorphisms in the MOG gene (namely -1077T/C, -910T/C, -875A/G, -93T/C, S5S, Indel L22, V145I, +814C/T, +900A/G, +1024A/T, +1059C/T), two microsatellites in the MOG 5' flanking (MOGCA) and 3' untranslated (MOGTAAA) regions and four microsatellites in the HLA-class I region, from HLA-B to HFE, (namely MIB, D6S265, D6S1683 and D6S2239) were tested by transmission disequilibrium test in 199 trio families. None of these polymorphisms or of their haplotypic combinations showed a significant transmission distortion, in the absence of V142L. In conclusion, MOG V142L, or an untested variant in tight-linkage disequilibrium with it, is an independent MS susceptibility-modulating factor in the HLA class I region.
Genes and immunity 02/2008; 9(1):7-15. · 4.22 Impact Factor
-
G. Mazzola,
M. Berrino,
M. Bersanti, S. D'Alfonso,
N. Cappello,
A. Bottaro,
E. S. Curtoni,
P. Fusco,
M. Vallati,
S. Bundino,
C. Barbera,
A. Amoroso
[show abstract]
[hide abstract]
ABSTRACT: SUMMARYHLA-DQ genes and gluten diet are the main factors involved in the pathogenesis of Dermatitis Herpetiformis (DH), as well as Coeliac Disease (CD). However other genetic factors are probably relevant, since about 10% of the patients with DH and CD lack the DQA1*0501/B1*0201 heterodimer while the majority of individuals presenting this genotype and also being exposed to gluten diets did not suffer from these diseases. To evaluate the role of other genes, 36 Northern Italian children with DH were analysed for DNA polymorphisms at HLA-DP and immunoglobulin (Ig) heavy chain loci. DPA1*0201 and DPB1*1301 frequencies were higher in patients than in controls (Pc= 0.0357 and Pc= 0.0273). With respect to immunoglobulin heavy chain restriction fragment length polymorphisms (RFLP), the 4.6kb Sad RFLP at the switch α2 gene was more frequent in patients (0.13) than in controls (0.019; Pc= 0.036). Moreover, rare alleles or duplications in the switch regions occurred more frequently in the patients than in the controls. These results support the hypothesis of a multifactorial inheritance of DH, the HLA and Ig constant heavy chain genes being some of the loci contributing to the susceptibility. In accordance with previous CD studies, these data also confirm that DP subregion is probably involved in the pathogenesis of DH.
International Journal of Immunogenetics 04/2007; 19(3):129 - 139. · 1.29 Impact Factor
-
I Ferreiros-Vidal, S D'Alfonso,
C Papasteriades,
F N Skopouli,
M Marchini,
R Scorza,
S Migliaresi,
G D Sebastiani,
E Endreffy,
M Mavromati,
I Kappou-Rigatou,
S Ruzickova,
C Dostal,
R E Schmidt,
T Witte,
J J Gomez-Reino,
A Gonzalez
[show abstract]
[hide abstract]
ABSTRACT: We obtained eight collections of DNA samples from ethnically matched systemic lupus erythematosus (SLE) patients and controls from five European countries totaling 783 patients and 1210 controls. A highly significant cline in the frequency of the PD1.3 A allele was found among controls but not among SLE patients. The frequency of the PD1.3 A allele increased from the Northeast to the Southwest of Europe. The cline was clearly apparent (P=1.2 x 10(-6)) when data from controls of other five SLE susceptibility studies were included in the analysis. This variation has severely biased SLE association studies owing to the lack of parallel changes in SLE patients. As a consequence, the PD1.3 A allele was more common in SLE patients than in controls in the Northeast and Center of Europe, similar to controls in Southeast Europe, and less frequent than in the controls in the Southwest of the Continent. This dissociation in allele frequencies between SLE patients and controls in different subpopulations indicated that programmed cell death 1 variation and disease susceptibility are not independent but the type of relationship is currently unclear. As allele frequency clines are common in other polymorphisms their impact in genetic epidemiology studies should be carefully considered.
Genes and Immunity 04/2007; 8(2):138-46. · 3.87 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Mutations in the SOD1 gene exons and exon/intron boundaries were searched in 66 sporadic and 4 familial Italian ALS cases consecutively referred to our centre from different Italian regions. A mutation was found in three sporadic cases (4.5%): a new nonsense mutation in exon 5 (K136X) in a patient with a rapid and severe disease course and two previously described missense nucleotide substitutions (N65S and A95T) in two patients with a mild disease course. Comparison of the clinical characteristics with previously reported patients carrying the same or similar mutations showed a remarkable genotype-phenotype correlation. No association was found with intronic sequence variations by comparing their frequency in the patients and in 181 matched controls.
Neuromuscular Disorders 12/2006; 16(11):800-4. · 2.80 Impact Factor
-
L Nisticò,
C Fagnani,
I Coto,
S Percopo,
R Cotichini,
M G Limongelli,
F Paparo, S D'Alfonso,
M Giordano,
C Sferlazzas,
G Magazzù,
P Momigliano-Richiardi,
L Greco,
M A Stazi
[show abstract]
[hide abstract]
ABSTRACT: We adopted the twin method to disentangle the genetic and environmental components of susceptibility to coeliac disease (CD). We estimated disease concordance rate by zygosity and HLA genotypes, discordance times, progression rates to disease, and heritability.
We crosslinked the Italian Twin Registry with the membership lists of the Italian Coeliac Disease Association and recruited 23 monozygotic (MZ) and 50 dizygotic (DZ) twin pairs with at least one affected member. Zygosity was assigned by DNA fingerprinting, and HLA-DQ and DR alleles were genotyped. Disease status was ascertained by antiendomysial, anti-human tissue transglutaminase antibodies, and bowel biopsy.
Concordance was significantly higher in MZ (83.3% probandwise, 71.4% pairwise) than in DZ (16.7% probandwise, 9.1% pairwise) pairs. Concordance was not affected by sex or HLA genotype of the co-twin and being MZ was significantly associated with the occurrence of CD (Cox adjusted hazard ratio 14.3 (95% confidence interval 4.0-50.3)). In 90% of concordant pairs the discordance time was <or=2 years. MZ and DZ co-twins had 70% and 9% cumulative probability of having symptomatic or silent forms of CD, respectively, within five years. Under ACE (additive genetic, common, and unshared environmental factors) models, with CD population prevalences of 1/91 and 1/1000, heritability estimates were 87% and 57%, respectively.
MZ pairs have a high probability of being concordant, regardless of sex or HLA genotype. Most of the affected co-twins receive a diagnosis within two years. A remarkable proportion of phenotypic variance is due to genetic factors.
Gut 06/2006; 55(6):803-8. · 10.11 Impact Factor
-
S D'Alfonso,
N Barizzone,
M Giordano,
A Chiocchetti,
C Magnani,
L Castelli,
M Indelicato,
F Giacopelli,
M Marchini,
R Scorza, [......],
S Migliaresi,
B Bigliardo,
M G Sabbadini,
E Baldissera,
M Galeazzi,
G D Sebastiani,
G Minisola,
R Ravazzolo,
U Dianzani,
P Momigliano-Richiardi
[show abstract]
[hide abstract]
ABSTRACT: To test the association of osteopontin (OPN) polymorphisms with systemic lupus erythematosus (SLE).
The coding 5' and 3' flanking regions of the OPN gene were scanned for polymorphisms by denaturing high-performance liquid chromatography. A case-control association study was performed in 394 Italian SLE patients and 479 matched controls. OPN serum levels were determined by enzyme-linked immunosorbent assay in 40 patients and 124 controls, and the mean levels were compared between the different OPN genotypes.
Among the 13 detected single-nucleotide polymorphisms (SNPs), alleles -156G (frequency 0.714 versus 0.651; P = 0.006, corrected P [P(corr)] = 0.036) and +1239C (0.377 versus 0.297; P = 0.00094, P(corr) = 0.0056) were significantly increased in the SLE patients compared with the controls. The presence of the associated allele in single or double dose conferred an odds ratio (OR) of 2.35 (95% confidence interval [95% CI] 1.38-4.02) for SNP -156 and an OR of 1.57 (95% CI 1.16-2.13) for SNP +1239. These effects were independent of each other, i.e., not a consequence of linkage disequilibrium between the 2 alleles. The risk associated with a double dose of susceptibility alleles at both SNPs was 3.8-fold higher (95% CI 2.0-7.4) relative to the complete absence of susceptibility alleles. With regard to individual clinical and immunologic features, a significant association was seen between lymphadenopathy and -156 genotypes (overall P = 0.0011, P(corr) = 0.046). A significantly increased OPN serum level was detected in healthy individuals carrying +1239C (P = 0.002), which is indicative of an association between the SLE susceptibility allele and OPN levels.
These data suggest the independent effect of a promoter (-156) and a 3'-untranslated region (+1239) SNP in SLE susceptibility. We can speculate that these sequence variants (or others in perfect linkage disequilibrium) create a predisposition to high production of OPN, and that this in turn may confer susceptibility to SLE.
Arthritis & Rheumatism 03/2005; 52(2):539-47. · 7.87 Impact Factor
-
N Haukim,
J L Bidwell,
A J P Smith,
L J Keen,
G Gallagher,
R Kimberly,
T Huizinga,
M F McDermott,
J Oksenberg,
J McNicholl,
F Pociot,
C Hardt, S D'Alfonso
Genes and Immunity 10/2002; 3(6):313-30. · 3.87 Impact Factor
-
A S Louka,
A Torinsson Naluai, S D'Alfonso,
H Ascher,
I Coto,
J Ek,
M Giordano,
A H Gudjónsdóttir,
M Mellai,
P Momigliano-Richiardi,
S Percopo,
L Samuelsson,
J Wahlström,
L Greco,
L M Sollid
[show abstract]
[hide abstract]
ABSTRACT: Coeliac disease (CD) is a chronic inflammatory disorder where dietary gluten is not tolerated. In the lesion there are gluten reactive T cells predominantly secreting gamma-interferon. Both HLA and non-HLA genes contribute to CD susceptibility. Interleukin-12 (IL-12) regulates gamma-interferon production. The IL12B gene is located in a region (5q31.1-33.1) where there is evidence for linkage with CD. Allele 1 of an IL12B 3'UTR single-nucleotide polymorphism leads to increased expression of IL-12, and was recently implicated in susceptibility for type 1 diabetes (T1D). We found no evidence for association of allele 1 to CD by the transmission/disequilibrium test or case-control approach. No increased frequency was observed in patients belonging to families where the disease was linked to markers on chromosome 5q. Unlike T1D, allele 1 does not appear to confer susceptibility to CD.
Tissue Antigens 02/2002; 59(1):70-2. · 2.59 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The present study is a contribution to the definition of the linkage disequilibrium relationship of MICA and MICB with adjacent loci and to the characterization of extended HLA haplotypes. These issues are of importance for the identification of disease associations and for a better definition of donor–recipient compatibility in bone-marrow grafts through the typing of haplospecific markers. The distribution of the five alleles of MICA and the 13 alleles of MICB microsatellites, located, respectively, in MICA transmembrane exon 5 and in MICB intron 1, was examined in 133 healthy Italian individuals previously typed for HLA class I, class II and complement loci and for the TNFa microsatellite. The MICB microsatellite was also analysed in 49 HTCLs for which MICA typing was already available. Very strong linkage disequilibria with HLA-B and TNFa were detected in the Italian population for both MICA and MICB microsatellite alleles, in spite of the high mutability rate of the larger MICB alleles. Some strong associations were also detected between MICB and DRB1. The strongest associations (P < 0.001, D′ > 0.7) were those of MICA-A4 with HLA-B18, B27 and TNFa1, MICA-A5 with HLA-B35, B61 and B62, MICA-A5.1 with HLA-B7, B8, B13, B63 and MICB-CA24, MICA-A6 with HLA-B51, MICA-A9 with HLA-B39, B57 and TNFa2, MICB-CA14 with HLA-B14, B27 and TNFa1, MICB-CA15 with HLA-B52, TNFa4 and TNFa13, MICB-CA17 with HLA-B7 and TNFa11, MICB-CA18 with HLA-B13 and TNFa7, MICB-CA22 with HLA-B57, and MICB-CA24 with HLA-B8 and TNFa2. From pairwise associations in the random panel and results for the homozygous cell lines it was possible to deduce the MICA and MICB microsatellite alleles present in many of the well-known Caucasoid extended haplotypes.
European Journal of Immunogenetics 09/2001; 28(5):523 - 530.
-
F Coraddu,
S Sawcer, S D'Alfonso,
M Lai,
A Hensiek,
E Solla,
S Broadley,
C Mancosu,
M Pugliatti,
M G Marrosu,
A Compston
[show abstract]
[hide abstract]
ABSTRACT: The prevalence of multiple sclerosis in Sardinia is significantly higher than in neighbouring Mediterranean countries, suggesting that the isolated growth of the population has concentrated genetic factors which increase susceptibility to the disease. The distinct HLA association of multiple sclerosis in Sardinia supports this interpretation. We have performed a whole genome screen for linkage in 49 Sardinian multiplex families using 327 markers. Non parametric linkage analysis of these data reveal suggestive linkage in the region of Chr 1q31, Chr 10q23 and Chr 11p15.
European Journal of HumanGenetics 09/2001; 9(8):621-6. · 4.40 Impact Factor
