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Background: Nonimmediate (delayed)‐allergic reactions to penicillins are common and some of them can be life‐threatening. The genetic factors influencing these reactions are unknown/poorly known/poorly understood. We assessed the genetic predictors of a delayed penicillin allergy that cover the HLA loci. Methods: Using next‐generation sequencing (NGS), we genotyped the MHC region in 24 patients with delayed hypersensitivity compared with 20 patients with documented immediate hypersensitivity to penicillins recruited in Italy. Subsequently, we analyzed in silico Illumina Immunochip genotyping data that covered the HLA loci in 98 Spanish patients with delayed hypersensitivity and 315 with immediate hypersensitivity compared to 1,308 controls. Results: The two alleles DRB3*02:02:01:02 and DRB3*02:02:01:01 were reported in twenty cases with delayed reactions (83%) and ten cases with immediate reactions (50%), but not in the Allele Frequency Net Database. Bearing at least one of the two alleles increased the risk of delayed reactions compared to immediate reactions, with an OR of 8.88 (95% CI, 3.37–23.32; p <.0001). The haplotype (ACAA) from rs9268835, rs6923504, rs6903608, and rs9268838 genetic variants of the HLA‐DRB3 genomic region was significantly associated with an increased risk of delayed hypersensitivity to penicillins (OR, 1.7; 95% CI: 1.06–1.92; p =.001), but not immediate hypersensitivity. Conclusion: We showed that the HLA‐DRB3 locus is strongly associated with an increased risk of delayed penicillin hypersensitivity, at least in Southwestern Europe. The determination of HLA‐DRB3*02:02 alleles in the risk management of severe delayed hypersensitivity to penicillins should be evaluated further in larger population samples of different origins. [ABSTRACT FROM AUTHOR]

Background: Association of thyroid dysfunction with plasma homocysteine levels and vitamin B12 has previously been reported. We evaluated these associations in the elderly in San Teodoro, a mountainous village of Sicily. Methods: Subjects (n=279) aged 60–85 years (119 males and 160 females) were examined using self-reported signs, clinical examination and laboratory tests. Results: Hypothyroidism and/or goiter were two characteristics that were not associated with a significant change in homocysteine when compared with euthyroidism and the absence of goiter. Vitamin B12 was significantly higher in subjects in the first quartile of the thyroid-stimulating hormone distribution, compared with those in the fourth quartile (371±207 vs. 297±196 pmol/L, p=0.0121). Homocysteine was significantly higher in the first quartile of the free tri-iodothyronine distribution compared to the third quartile (18.0±5.7 vs. 16.0±6.2 μmol/L, p=0.0130) and was correlated with log tri-iodothyronine in euthyroid subjects (p=0.0254). In multivariate analysis, homocysteine was associated with vitamin B12 (p=0.0014), folate (p<0.0001), creatinine (p<0.0001) and age (p<0.0001), but not with either free tri-iodothyronine (p=0.7680), tetra-iodothyronine (p=0.5706) or thyroid-stimulating hormone (p=0.2294). Conclusions: Our results suggest that the influence of thyroid hormones on homocysteine is much weaker in elderly subjects than in selected patients with hypothyroidism. Clin Chem Lab Med 2007;45:143–7. [ABSTRACT FROM AUTHOR]

Background: Homocysteine is associated with age, folate and vitamin B12. Our study investigated the functional and clinical characteristics of the elderly (aged 60–85 years) of San Teodoro, a village in Central Sicily, and evaluated associations with vitamin B12, folate and homocysteine. Methods: Subjects (n=280) were examined after door-to-door recruitment using interview, physician examination and laboratory tests. Results: A total of 19.3% of the population had a low blood level of folate (<7 nmol/L) and 3.2% had low vitamin B12 concentration (<100 pmol/L). The level of dependency, determined by the Barthel index, influenced homocysteine blood levels (p<0.0001), independent of age (p<0.0001), folate (p=0.0028) and vitamin B12 (p=0.0165). Homocysteine was significantly associated with stroke (p=0.0027) and peripheral arterial vascular disease (p=0.0001), but not with myocardial infarction, angina pectoris, venous thrombosis or cancer. Vitamin B12 was lower in myocardial infarction and higher in diabetes and venous thrombosis compared to the other diseases. Conclusions: The prevalence of deficits in folate and vitamin B12 was paradoxically high in the mountainous northeastern area of Sicily. Our study also underlines the association of homocysteine with dependency of the elderly and with stroke and peripheral arteriopathy. Clin Chem Lab Med 2007;45:136–42. [ABSTRACT FROM AUTHOR]

Abstract: The progressive and rapid aging of population is the demographic characteristic in the Western countries. This rapid process of aging is causing an increasing burden on the social and health-care services. In this context, the precise knowledge of the environmental, socio-economical and clinical characteristics of the elderly population is mandatory to find the correct strategies to achieve the successful aging. Our study aimed to investigate the functional and clinical characteristics of the elderly (aged 60 to 85 years) of San Teodoro (1500 inhabitants), a rural village of Central Sicily, in particularly considering the dementia prevalence. In 2005, all the elderly between 60 and 85 years old were invited to participate to the study. The list of the potential participants was obtained from the Registry office of the municipality. The final number of the eligible subjects was 374. Rate of participation was 74.9% (280 subjects, 120 M and 160 F). The study was conducted door-to-door. Dementia prevalence was 7.1% (20 subjects, 8 M and 12 F), with 60% Alzheimer''s disease and 15% vascular dementia, slightly higher than that of the European countries (6%). The high prevalence of hypertension (80.3%) and the low education level, two important risk factors for dementia, could explain in part the difference observed. [Copyright &y& Elsevier]

Genome-wide association studies (GWASs) have identified loci contributing to total serum bilirubin level. However, no exome-wide approaches have been performed to address this question. Using exome-wide approach, we assessed the influence of protein-coding variants on unconjugated, conjugated, and total serum bilirubin levels in a well-characterized cohort of 773 ambulatory elderly subjects from Italy. Coding variants were replicated in 227 elderly subjects from the same area. We identified 4 missense rare (minor allele frequency, MAF < 0.5%) and low-frequency (MAF, 0.5%-5%) coding variants located in the first exon of the UGT1A1 gene, which encodes for the substrate-binding domain (rs4148323 [MAF = 0.06%; p.Gly71Arg], rs144398951 [MAF = 0.06%; p.Ile215Val], rs35003977 [MAF = 0.78%; p.Val225Gly], and rs57307513 [MAF = 0.06%; p.Ser250Pro]). These variants were in strong linkage disequilibrium with 3 intronic UGT1A1 variants (rs887829, rs4148325, rs6742078), which were significantly associated with total bilirubin level (P = 2.34 × 10(-34), P = 7.02 × 10(-34), and P = 8.27 × 10(-34)), as well as unconjugated, and conjugated bilirubin levels. We also identified UGT1A6 variants in association with total (rs6759892, p.Ser7Ala, P = 1.98 × 10(-26); rs2070959, p.Thr181Ala, P = 2.87 × 10(-27); and rs1105879, p.Arg184Ser, P = 3.27 × 10(-29)), unconjugated, and conjugated bilirubin levels. All UGT1A1 intronic variants (rs887829, rs6742078, and rs4148325) and UGT1A6 coding variants (rs6759892, rs2070959, and rs1105879) were significantly associated with gallstone-related cholecystectomy risk. The UGT1A6 variant rs2070959 (p.Thr181Ala) was associated with the highest risk of gallstone-related cholecystectomy (OR, 4.58; 95% CI, 1.58-13.28; P = 3.21 × 10(-3)). Using an exome-wide approach we identified coding variants on UGT1A1 and UGT1A6 genes in association with serum bilirubin level and hyperbilirubinemia risk in elderly subjects. UGT1A1 intronic single-nucleotide polymorphisms (SNPs) (rs6742078, rs887829, rs4148324) serve as proxy markers for the low-frequency and rare UGT1A1 variants, thereby providing mechanistic explanation to the relationship between UGT1A1 intronic SNPs and the UGT1A1 enzyme activity. UGT1A1 and UGT1A6 variants might be potentially associated with gallstone-related cholecystectomy risk.

Background: Immediate reactions to β-lactams are the most common causes of anaphylactic reactions and can be life-threatening. The few known genetic factors influencing these reactions suggest a link with atopy and inflammation., Objective: We performed a fine-mapping genome-wide association study of the genetic predictors of β-lactam allergy to better understand the underlying mechanisms., Methods: We studied 387 patients with immediate allergic reactions to β-lactams and 1124 paired control subjects from Spain. We replicated the results in 299 patients and 362 paired control subjects from Italy., Results: We found significant associations with the single nucleotide polymorphisms rs4958427 of ZNF300 (c.64-471G>A, P = 9.9 × 10(-9)), rs17612 of C5 (c.4311A>C [p.Glu1437Asp], P = 7.5 × 10(-7)), rs7754768 and rs9268832 of the HLA-DRA | HLA-DRB5 interregion (P = 1.6 × 10(-6) and 4.9 × 10(-6)), and rs7192 of HLA-DRA (c.724T>G [p.Leu242Val], P = 7.4 × 10(-6)) in an allelic model, with similar results in an additive model. Single nucleotide polymorphisms of HLA-DRA and ZNF300 predicted skin test positivity to amoxicillin and other penicillins but not to cephalosporins. A haplotype block in HLA-DRA and the HLA-DRA | HLA-DRB5 interregion encompassed a motif involved in balanced expression of the α- and β-chains of MHC class II, whereas rs7192 was predicted to influence α-chain conformation. HLA-DRA rs7192 and rs8084 were significantly associated with allergy to penicillins and amoxicillin (P = 6.0 × 10(-4) and P = 4.0 × 10(-4), respectively) but not to cephalosporins in the replication study., Conclusions: Gene variants of HLA-DRA and the HLA-DRA | HLA-DRB5 interregion were significant predictors of allergy to penicillins but not to cephalosporins. These data suggest complex gene-environment interactions in which genetic susceptibility of HLA type 2 antigen presentation plays a central role., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

The genotype of apolipoprotein E was examined in 173 sporadic Alzheimer's disease (AD) patients, 132 with late onset (LOAD) and 41 with early onset (EOAD), and in 174 healthy matched controls from Sicily. Despite a low frequency of the epsilon 4 allele (6.3%, 95% CI: 4.2--9.4) in controls, epsilon 4 allele was a stronger predictor of AD risk (odds ratio: 5.8, 95% CI: 3.5--9.4; p<0.0001) than in most of the studies performed in other regions of Italy, and it has no influence on age at onset. epsilon 4/epsilon 4 and epsilon 4/epsilon 3 genotypes were similar predictors of AD risk. Conversely, a decreased risk was found in epsilon 3 allele carriers (odds ratio: 0.3, 95% CI: 0.2--0.4; p<0.0001), which remained significant when considering EOAD cases only (odds ratio: 0.2, 95% CI: 0.1--0.4, p<0.0001). In conclusion, differences in association strength of epsilon 4 allele with AD between Sicily and other regions of Italy suggest an influence of complex gene-gene and gene-environment interactions.