Marina Morellini

DNA multiallelic systems reveal gene/longevity associations not detected by diallelic systems. The APOB locus

Abstract To identify possible genetic factors affecting human longevity we compared allele pools at two candidate loci for longevity between a sample of 143 centenarians (S) and a control sample of 158 individuals (C). The candidate loci were APOB and TPO, which code for apolipoprotein B and thyroid peroxidase, respectively. Both restriction fragment length (RFL) (XbaI2488 and EcoRI4154) and variable number of tandem repeat (VNTR) (3′APOB-VNTR) polymorphisms were analysed at the APOB locus; the TPO-VNTR polymorphism (intron 10) was analysed at the TPO locus. The main result of the investigation was that there is an association between the APOB locus and longevity that is revealed only when multiallelic polymorphisms are considered. In particular: (i) the frequency of 3′APOB-VNTR alleles with fewer than 35 repeats is significantly lower in cases than in controls; (ii) the linkage disequilibrium between the XbaI-RFLP and the EcoRI-RFLP is significantly different from 0 in cases but not in controls; (iii) the EcoRI-RFLP and XbaI-RFLP allele frequencies do not discriminate between cases and controls. The differences observed between case and control allele pools are specific to the APOB locus, since no significant difference was observed at the TPO locus.

p53 Codon 72 Polymorphism and Longevity: Additional Data on Centenarians from Continental Italy and Sardinia

In a previous letter (Bonafe et al. 1999) we tested the hypothesis that polymorphic variants of p53 have an impact on human longevity, by comparing p53 codon 72 allelic and genotypic frequency distributions between young people and centenarians. A nonsignificant difference emerged between the groups, and several explanations were offered. Following the reply letter of Sun et al. (in this issue), we would like to argue with some of their comments and to provide new data regarding centenarians from continental Italy and Sardinia.

Tumor necrosis factor gene polymorphism in migraine

Objective.—To better define the involvement of human leukocyte antigen region (HLA) genes in migraine via an association study of the tumor necrosis factor (TNF) genes, located in the HLA class III region, with migraine with and without aura.

Diabetes-related autoantibodies do appear in children with coeliac disease

Humoral immune factors related to type 1 diabetes have been investigated in children with coeliac disease. Anti‐insulin (IAAb), immunoglobulin (αIgAb), islet cell (ICA) and glucagon autoantibodies were examined in 15 children with coeliac disease at diagnosis (group 1), in 15 children with coeliac disease following a gluten‐free diet (group 2) and in 30 control patients (groups 3 and 4). IAAb were present in 27% of group 1 and in 20% of group 2 patients and αIgAb were significantly increased in group 1 and 2 patients; two patients in group 2 were positive for ICA; none of the coeliac disease patients were positive for anti‐glucagon antibodies. The levels of anti‐gliadin antibodies in group 1 were positively correlated with those of αIgAb. Coeliac disease‐related HLA antigens were not correlated with antibody presence. The presence of diabetes‐related humoral immune factors in coeliac disease raises the question as to whether or not they are predictive of subclinical pancreatic damage or whether they are simply indicators of a more general autoimmune diathesis.

HLA-DR and DQ Antigens and Anticardiolipin Antibodies in Women With Recurrent Spontaneous Abortions

ABSTRACT: IgG anticardiolipin antibodies (ACL) have been shown to occur in a high proportion of women with repeated unexplained miscarriages. Forty‐nine women with unexplained recurrent spontaneous abortions (RSA), previously assayed for the presence of ACL by an enzyme‐linked immunoabsorbent assay, were typed for HLA‐DR and DQ antigens by the classical microlymphocytotoxicity test. Twenty‐five women were positive for ACL and 24 were negative. HLA‐DR7 was found in 24.5% of 49 habitually aborting women vs. 28% of healthy controls; but the DR7 frequency was 40% in ACL positive patients vs. 8.3% in ACL negative patients (P = 0.011). These results show that in the Italian population an association between HLA‐DR7 antigen and ACL is present in women with unexplained RSA, suggesting that HLA‐DR genes might control the susceptibility to specific autoantibody production.

CHROMOSOME 6P-ENCODED HLA-DR2 DETERMINANT DISCRIMINATES MIGRAINE WITHOUT AURA FROM MIGRAINE WITH AURA

Segregation analysis indicates that migraine without aura (MWoA) and migraine with aura (MWA) have multifactorial inheritance, but involved genetic and environmental factors are largely unknown. A controlled study was performed to assess the HLA-driven liability to migraine and to verify if the heterogeneity between MWoA and MWA is HLA-linked. Forty-five migraine patients (31 MWoA, 14 MWA) and 53 healthy blood donors as controls, coming from the same geographic area, were studied. Tissue typing was performed using the standard complement-dependent microlymphocytotoxicity technique for HLA Class I and by PCR-SSP (Sequences Specific Primers) typing for HLA Class II. Data emerging from the present study showed no altered distribution for HLA Class I A, B, C antigen frequency in migraine (MWoA, MWA) if compared to the control group. HLA Class II DR2 antigen showed a decreased frequency in MWA group if compared with both MWoA (p = 0.01) and control group (p = 0.039, RR = 0.21). These results seem to support the hypothesis of a protective role of DR2 antigen in MWA and provide additional basis for the proposed difference within MWoA and MWA.

HLA Antigens and Aging

The major histocompatibility complex is one of the gene systems that influence aging.’ Although it is well known that HLA antigens in man are closely related to autoimmune diseases as well as to immunoresponsiveness, it is not yet clear if a relation exists between HLA antigens and longe~i ty .~ .~ As extreme longevity may be influenced by environmental factors as well as genetic background, we typed for HLA antigens a series of persons over 95 years of age assuming that, although lifestyle, diet, and hygiene can influence life span up to a certain age, genetic factors could predispose to longevity in persons living longer than 95 years.

HLA and Complement Factors Alleles Sharing in Italian Couples with Recurrent Spontaneous Abortions

Recurrent Spontaneous Abortion (RSA) is postulated to be due to several factors including immunogenetic mechanisms. Many studies have been conducted on the effect of the MHC region in the reproductive phenomena suggesting an immunological or genetic involvement in RSA. We studied couples with 3 or more abortions among a larger group of couples in which female partners were anti-cardiolipin antibodies negative, resulting in a population of 43 couples typed for HLA-A, B, C, DR, DQ. In 16 of these 43 couples, complement factors C4A, C4B, and Bf were typed. The data shows a statistically significant increase of C4B*Q0 in RSA patients (N = 32) compared with the control population (N = 44) (pc = .00147) and also a statistically significant increase of C4B*Q0 sharing in aborting couples (43.75%) against the expected sharing rate in the control population (1.86%) (p < .001). Frequency increase of C4B*Q0 allele in aborting population leads to the hypothesis that an imbalance of complement factors expression and activity can have detrimental effects on implantation and embryo survival. Additionally, the significant sharing rate of C4B*Q0 in couples with RSA could indicate the existence of a gene in linked to this allele predisposing to RSA and acting in a recessive manner if present in double copies in the fetus.

Tumor necrosis factor B gene polymorphism contributes to susceptibility to migraine without area

Abstract Migraine without aura (MWOA) and migraine with aura (MWA) are disorders in which multiple factors, including environmental and genetic factors, are involved. In a previous study we hypothesized a protective role of HLA-DR2 antigen, providing additional basis for the proposed genetic heterogeneity between MWOA and MWA. The cytokines TNFA and TNFB are polypeptide effectors of inflammatory reaction and endothelial function. To better define the involvement of HLA region genes in migraine, we performed an association study of the tumor necrosis factor (TNF) genes, located in the HLA class III region, with MWOA and MWA. TNFB alleles 1 and 2 were analyzed by PCR-RFLP in 30 MWOA patients, in 47 MWA patients and in 101 random controls. The frequency of TNFB*2 was significantly increased in MWOA patients as compared with controls (78.72% vs. 61.4%, pc = 0.004), while no significant differences were found between MWA patients and controls. The distribution of TNFB genotypic frequencies showed a significant decrease of TNFB 1,1 homozygotes in MWOA patients (pc = 0.0201). The observed increase of TNFB*2 in MWOA is dustributed in TNFB 2,2 and TNFB 1,2 genotypes, meaning that the susceptibility allele could act as “dominant”: people with TNFB 1,1 genotype are less predisposed to the disease. While more studies are needed in larger migraine samples to reinforce the statistical power of the reported data, the present study supports the hypothesis that TNFB is a susceptibility gene in MWOA.

HLA antigens, epilepsy and cytomegalovirus infection

Thirty-one epileptic patients, selected from among 900 children with previous febrile convulsions and subsequent epilepsy, were typed for HLA antigens. In 16 of the 31 patients CMV was isolated from the urine shortly after the appearance of spontaneous fits; in the remaining 15 patients the virus was never detected. All the examined children were typed for 14 HLA-A, 23 HLA-B, 7 HLA-C and 9 HLA-DR specificities, and compared with a group of healthy subjects. The HLA-A11 antigen was present in 25% of the children with chronic CMV infection and epilepsy, and absent in patients with epilepsy but without CMV infection (p less than 0.02). The possibility that the A11 antigen is a marker of the predisposing genes for CMV infection in children with epilepsy following FC is proposed.