Andrea Galgani

Residual insulin secretion at diagnosis of type 1 diabetes is independently associated with both, age of onset and HLA genotype.

We investigated whether residual insulin secretion and metabolic derangement at diagnosis of type 1 diabetes (T1DM) are influenced by human leukocyte antigens (HLA) class II genes.

Genetic prediction of type 1 diabetes in a population with low frequency of HLA risk genotypes and low incidence of the disease (the DIABFIN study)

To develop a sensitive, specific screening strategy for predicting genetic risk for type 1 diabetes mellitus (T1DM) in the low‐incidence continental Italian population, and to define with this tool, a cohort of high‐to‐moderate risk infants for an immunological follow‐up study aimed at identifying environmental risk factors for T1DM.

Association of β2 adrenergic receptor polymorphisms and related haplotypes with triglyceride and LDL-cholesterol levels

Adrenergic receptors regulate lipid mobilization, energy expenditure and glycogen breakdown. The β2 adrenergic receptor (β2-AR) gene may constitute a potential candidate gene to explain part of the genetic predisposition to human obesity and correlated traits. With regard to the association between β2-AR gene polymorphisms and obesity-related metabolic disorders, published reports give conflicting results. We investigated the role of three polymorphisms, and related haplotypes of the β2-AR in the obesity and related traits in a cohort of overweight/obese subjects. We characterized one single nucleotide polymorphism (SNP) in the promoter region (5′LC-Cys19Arg) and two in the coding region (Gly16Arg and Gln27Glu) of the β2-AR in 642 consecutively recruited overweight/obese subjects in whom extensive clinical and biochemical analysis was performed. The effect of the polymorphisms on quantitative variables was investigated using multiple linear regression analysis. 5′LC-Cys19 homozygous showed higher triglyceride and LDL-cholesterol levels compared to 5′LC-Arg19 homozygous (P=0.03 and P=0.01, respectively). Similar increase in triglyceride and LDL-cholesterol levels was observed for Arg/Arg genotype compared to Gly/Gly genotype of Gly16Arg polymorphism (P=0.02 and P=0.01, respectively) and for Gln/Gln genotype compared to Glu/Glu genotype of the Gln27Glu polymorphism (P=0.01 and P=0.03, respectively). The 5′LC-Cys19Arg16Gln27 haplotype determined a significant increase in triglyceride and LDL-cholesterol levels compared to 5′LC-Arg19Gly16Glu27 haplotype (P=0.05 and P=0.02, respectively). Our findings provide additional weight to previous observations on the influence of these three genetic variants on lipid phenotypes; particularly on the increase of triglycerides and LDL-cholesterol levels in overweight/obese subjects carrying the 5′LC-Cys19Arg16Gln27 haplotype.

Type 1 diabetes risk for human leukocyte antigen (HLA)-DR3 haplotypes depends on genotypic context: association of DPB1 and HLA class I loci among DR3- and DR4-matched Italian patients and controls.

Patients with high-risk human leukocyte antigen (HLA)-DR-DQ genotypes for type 1 diabetes (T1D) were compared with HLA-matched controls to evaluate T1D risk for other HLA loci, including HLA-A, -B, -Cw, and DPB1. Patients (n = 133) with high-risk genotypes (DR3/DR3, DR3/DR4, DR4/DR4) were selected from the Lazio (Rome) region of Italy. Screening of more than 9000 patients from the Lazio region and northern Italy yielded 162 controls with high-T1D-risk haplotypes. Although the overall distributions did not differ significantly, allele frequency differences were discovered between the controls from Lazio and controls from northern Italy for some alleles previously determined to affect T1D risk, such as A*3002, DPB1*0301, and DPB1*0402. Therefore, Lazio patient data were compared both with the Lazio subset of controls (n = 53) and with the entire group of controls for association analyses. Significant allele frequency differences between patients and DR-DQ-matched controls existed for specific alleles at all loci. Data for the DR3/DR3 subset of patients and controls demonstrated an increase of Cw*0702 in patients. Compared with controls, reduced patient frequencies were seen for several alleles, including A*0101, B*0801, and Cw*0701, all on the highly conserved, extended DR3 haplotype known as 8.1 in DR3/DR3, but not DR3/DR4, subgroup. DPB1*0101, often reported on 8.1 haplotypes, was also less frequent in DR3/DR3 patients than controls. Analysis of family-based data from the HBDI repository was consistent with the observed results from the Italian patients, indicating the presence of a T1D-protective locus at or near A*0101 and a second T1D-protective locus at or near DPB1*0101. These data indicate that T1D risk conferred by the 8.1 haplotype is genotype dependent.

HLA-A, -B and -DRB1 allele frequencies in Cyrenaica population (Libya) and genetic relationships with other populations.

The frequencies of HLA-A, HLA-B and HLA-DRB1 alleles in 118 unrelated Libyans from Benghazi (Cyrenaica) were analysed using high resolution typing and compared with other populations. Their relatedness has been tested by correspondence analyses and principal component analysis. The most frequent HLA-A alleles were A(∗)02:01:01:01 (15.7%), A(∗)01:01:01:01 (11.4%) and A(∗)03:01:01:01 (9.3%). For the HLA-B locus, the commonest allele was HLA-B(∗)50:01:01 (14.4%) followed by B(∗)51:01:01 (9.8%) and B(∗)08:01:01 (6.4%). For the HLA-DRB1 locus, the commonest was HLA-DRB1(∗)07:01:01:01 (16.9%) followed by DRB1(∗)03:01:01:01 (13.6%) and DRB1(∗)13:02:01 (9.3%). The most frequent two-locus haplotypes were HLA-A(∗)02:01:01:01-B(∗)07:02:01 (3.0%) and HLA-B(∗)50:01:01-DRB1(∗)07:01:01:01 (9.6%), and three-locus haplotypes were HLA-A(∗)02:01:01:01-B(∗)50:01:01-DRB1(∗)07:01:01:01 (4.2%) and HLA-A(∗)11:01:01-B(∗)52:01:01:01-DRB1(∗)15:02:01 (2.5%). This study is the first on the HLA status of a Libyan population. The results, when compared to similar HLA data obtained previously from African and Mediterranean populations, indicate genetic influences from several ethnic groups. Moreover, the differences in the HLA allele frequencies between the Libyan population and others reveals that significant admixture has occurred between the original Berber inhabitants and neighbouring and more distant populations, even though a strong genetic Berber substratum remains. These data will be of value to future anthropological and disease association studies involving the Libyan population.

Homozygosity for the Ala Allele of the PPARγ2 Pro12Ala Polymorphism Is Associated with Reduced Risk of Coronary Artery Disease

Several studies suggest that the peroxisome proliferator-activated receptor gamma (PPARγ) is involved in atherogenesis. The Pro12Ala polymorphism in the gene encoding PPARγ (PPARγ2 gene) influences the risk for type 2 diabetes. Two population-based studies have shown that the Ala allele is associated with reduced carotid intimal-medial thickness (IMT). However, studies focusing on acute clinical events have yielded conflicting results. Our aim was to evaluate the role of the Pro12Ala PPARγ2 polymorphism on the risk of coronary artery disease (CAD) in an Italian population with a case-controlled genetic association study in which 478 CAD patients and 218 controls were genotyped for the Pro12Ala polymorphism. CAD was diagnosed by angiography. We found that homozygotes for the Ala12 allele had a significantly reduced risk of CAD after adjusting for diabetes, sex, age, body mass index (BMI), smoking, lipids and hypertension (OR = 0.007; 95% C.I. = 0.00–0.32 p < 0.011). In this casecontrol study, homozygosity for the Ala allele at codon 12 of the PPAR 2 gene resulted in reduced risk of CAD. This is consistent with reports from previous studies focusing on atherosclerosis and myocardial infarction.