Rosa Maria Corbo

Combined Effect of Apolipoprotein E Genotype and Past Fertility on Age at Onset of Alzheimer’s Disease in Women

Background: Various risk factors influence the development of Alzheimer’s disease (AD). Apolipoprotein E (APOE) e*4 allele has a major role in AD susceptibility and its presence reduces age at AD onset. APOE is also thought to influence human reproduction, and common APOE genotypes seem to be associated with differential fertility. With this study, we investigated possible relationships between APOE genotype, past fertility, and AD onset age. Methods:APOE genotypes were determined in a sample of 176 women with sporadic AD. The number of children each woman had delivered was recorded. Results: A comparison of APOE genotype distribution in parous and nulliparous AD women confirmed that the e*3/e*3 genotype is associated with higher fertility and the e*4-carrying genotypes with lower fertility. When the combined effects of fertility and APOE genotypes on AD onset age were analyzed, parity was found to be associated with a significantly lower AD onset age (73.8 ± 6.2 years) than nulliparity (80.7 ± 5.0 years; p = 0.0007) among subjects carrying e*3/e*3 and e*3/e*2 genotypes. A similar effect was absent among e*4 carriers. Considering the high frequency of e*3/e*3 plus e*3/e*2 genotypes in Europe (range: 63–87%), past fertility may influence AD onset age in many women. Conclusion: Past fertility may have a relevant effect on AD onset age and this effect is influenced by APOE genotype.

Polymorphisms in the apolipoprotein E gene regulatory region in relation to coronary heart disease and their effect on plasma apolipoprotein E.

Abstract In a previous study which examined the distribution of apolipoprotein E genotypes and plasma levels in a sample of male coronary heart disease (CHD) patients and controls, we found a significant excess of the genotypes carrying APOE*4 allele in CHD men (18.2%) vs. controls (9.6%) and an association between the APOE*4 allele and the lowest concentrations of apoE. In the present investigation, we re-examined in the same samples two recently identified polymorphisms in the promoter region of APOE, −491A/T and −427T/C, which may alter the level of apoE expression. No differences in the distributions of the −491A/T genotypes and alleles were observed between cases and controls (−491*A = 0.760 and 0.757 respectively). Polymorphism −427T/C showed in CHD patients an excess of −427*C allele (patients vs. controls = 0.123 vs. 0.074) and corresponding genotypes that was marginally significant. Stratification of the samples according to the presence/absence of APOE*4 showed that the excess of the −427*C allele concerned only CHD patients not carrying APOE*4 allele (patients vs. controls = 0.133 vs. 0.061; p=0.017). This result suggests that the presence of −427*C allele could represent a risk for developing CHD in subjects with E2/E2, E3/E2, and E3/E3 genotypes. Studies carried out on patients with Alzheimers disease demonstrated that −491A/T and −427T/C polymorphisms affect the level of plasma apoE. In the present study, carried out on CHD patients and controls, the genetic variation at −427 and −491 sites of the APOE regulatory region had no apparent effect on apoE plasma concentration.

Human phosphoglucomutase locus 1: red cell enzymatic activities associated with common isoelectric focusing phenotypes.

Human phosphoglucomutase activity has been determined in red blood cells obtained from 348 unrelated subjects. The mean activities attributed to the four common PGM1 alleles, expressed as micromoles of G6P produced per gram of Hb per hour were 53 for PGMa31, 60 for PGMa11, 61 for PGMa41 and 72 for PGMa21. The relative amount of variation associated with the electrophoretic polymorphism was estimated as 24%.

α2-Macroglobulin deletion polymorphism and plasma levels in late onset Alzheimer's disease

Abstract The acute-phase “panproteinase” inhibitor α2-macroglobulin α2M), a protein involved in inflammatory reactions, has been identified in amyloid plaques in Alzheimers disease (AD). In addition, α2M is involved in AD susceptibility at the genetic level, and a deletion polymorphism at the α2M gene has been found to be associated with sporadic AD. We analyzed the deletion polymorphism and α2M plasma levels in 93 ultraoctuagenarian patients with late-onset sporadic AD and in controls (n=157). α2M allele frequencies did not differ between AD patients α2M*2=0.169) and controls (α2M*2=0.146). The mean plasma concentrations of α2M were similar in patients (271.8±79 mg/dl) and controls (269.5±81.2 mg/dl). No difference was found in the α2M mean plasma levels associated with the three α2M genotypes, indicating that the deletion has no effect on α2M protein level. However, in AD patients α2M mean plasma values differed significantly according to apolipoprotein E genotypes (p=0.03), with E3/E3 homozygotes showing the highest levels. Since in a previous work E3/E3 were found to be associated with the highest plasma levels of α1-antichymotrypsin, another acute-phase protein, the present findings seem to support the hypothesis that inflammation may be a relevant factor in AD pathogenesis peculiar to E3/E3 subjects.

C-338A polymorphism of the endothelin-converting enzyme (ECE-1) gene and the susceptibility to sporadic late-onset Alzheimer's disease and coronary artery disease

The human endothelin-converting enzyme (ECE) is involved in β-amyloid synthesis and regulation of the endothelin-1 (ET-1) vasoconstricting peptide. We investigated the distribution of the C-338A polymorphism of the ECE-1b gene in sporadic late-onset Alzheimer’s disease (LOAD) and in coronary artery disease (CAD) to verify its role in the onset of these two complex diseases. Two cohorts of 458 Italian Caucasian LOAD patients and 165 CAD patients were examined for the C-338A polymorphism and compared with respective control samples (260 and 106 subjects, respectively). The A allele was less present in LOAD patients than in controls, but an at limits statistically significant difference was achieved only in subjects aged less than 80 years, where only the AA genotypes appeared to have a protective role against the onset of the sporadic LOAD. For the overall CAD sample the pattern was similar and significant differences were observed only in subjects non carrying the apolipoprotein E (APOE) e*4 allele, where the A allele carrying genotypes had a protective role against the onset of the disease.

Gender-Specific Association Between FSHR and PPARG Common Variants and Human Longevity

Men and women have different life expectancies. Not unexpectedly, several genes involved in life span determination have been found to influence the probability of achieving longevity differently in men and women. This investigation examines the association between longevity and polymorphisms of follicle-stimulating hormone receptor (FSHR, Asn680Ser polymorphism) and peroxisome proliferator-activated receptor gamma (PPARG, Pro12Ala polymorphism), two genes that previous investigations suggested may exert a gender-specific influence on human longevity. A sample of 277 individuals (mean age, 82.9±5.7years) was recruited in 2000. On the basis of mortality data collected in 2009, the sample was divided into two groups of subjects surviving over 90 years (long-lived) or not (controls). The frequency of the FSHR 680 Ser/Ser genotype was significantly higher in the sample of long-lived women compared to controls, indicating that the FSHR 680 Ser/Ser genotype may favor survival to more than 90 years of age only in women (odds ratio [OR]=4.21; 95% confidence interval [CI], 1.10-16.10, p=0.036). In contrast, the frequency of the PPARG Pro/Ala genotype was significantly higher in the sample of male subjects who died before 90 years of age than in the long-lived, suggesting that carrying the PPARG Pro/Ala genotype may prevent the attainment of advanced age only in men (OR=0.13; 95% CI, 0.02-0.79; p=0.03). We then searched the literature for studies reporting a differential role for the genetic component in male and female longevity. To do this, we selected longevity genes with a gender-specific effect. A review of the studies showed that genetic factors tend to have a greater relevance in determining longevity in men than in women. The possible impact of this phenomenon is discussed.

NUCLEOSIDE-PHOSPHORYLASE DEFICIENCY, AUTOIMMUNE HAEMOLYTIC ANAE MIA AND SELECTIVE T-CELL DEFICIENCY

Recently three patients with a severely defective T-cell immunity and no measurable activity of purine nucleoside phosphorylase (NP) were described. We had the occasion to observe a 22 months old girl with NP deficiency who was referred to us because of haemolytic anaemia which proved to be due to IgG and IgM incomplete warm autoantibodies against red cells. A CMV infection was diagnosed and a bilateral infiltration on chest roentgenograra was evident 4 weeks after admission. The NP activity of the red cells and granulocytes was absent. The parents are both heterozygous for the NP deficiency as well as both grandmothers, whose mothers are half-sisters. T-cell deficiency was demonstrated by negative skin tests to PHA, Varidase and Candida, by absence of E-rosette forming cells, total impairment of in vitro mitogenic response and mixed-lymphocyte reaction. The percentage of surface Ig-bearing lymphocytes and all serum immunoglobulin levels were normal. The clinical history will be fully discussed.

Another family with purine nucleoside phosphorylase deficiency

SummaryA brief genetic report is given on a family with a child affected by nucleoside phosphorylase deficiency. Our observations confirm the genetic heterogeneity of this enzyme deficiency which is inherited as a mendelian autosomal trait.