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Abstract: Genomewide association studies are increasingly being applied to search for novel genes that might underlie cardiovascular diseases. In this article, we briefly review the principles that underlie modern genetic analyses and provide several illustrations from the SardiNIA study of genomewide association studies for cardiovascular risk factor traits. [Copyright &y& Elsevier]

Personality traits are summarized by five broad dimensions with pervasive influences on major life outcomes, strong links to psychiatric disorders and clear heritable components. To identify genetic variants associated with each of the five dimensions of personality we performed a genome-wide association (GWA) scan of 3972 individuals from a genetically isolated population within Sardinia, Italy. On the basis of the analyses of 362 129 single-nucleotide polymorphisms we found several strong signals within or near genes previously implicated in psychiatric disorders. They include the association of neuroticism with SNAP25 (rs362584, P=5 × 10−5), extraversion with BDNF and two cadherin genes (CDH13 and CDH23; Ps<5 × 10−5), openness with CNTNAP2 (rs10251794, P=3 × 10−5), agreeableness with CLOCK (rs6832769, P=9 × 10−6) and conscientiousness with DYRK1A (rs2835731, P=3 × 10−5). Effect sizes were small (less than 1% of variance), and most failed to replicate in the follow-up independent samples (N up to 3903), though the association between agreeableness and CLOCK was supported in two of three replication samples (overall P=2 × 10−5). We infer that a large number of loci may influence personality traits and disorders, requiring larger sample sizes for the GWA approach to confidently identify associated genetic variants. [ABSTRACT FROM AUTHOR]

Potential founder population effects on personality trait means and variances were examined in a large, genetically homogeneous sample ( N = 5,669) from the Ogliastra, an isolated region within Sardinia, Italy. The Italian version of the Revised NEO Personality Inventory showed good psychometric properties: Internal consistency reliabilities ranged from 0.80 to 0.87; the factor structure replicated the American normative structure; and associations with education and gender replicated cross-cultural patterns. The hypothesis that mean trait levels in the Sardinian founder population would differ from mainland Italian values was not supported. Phenotypic variation in this founder population was within the range found in other cultures. However, the hypothesis of restricted phenotypic variation was supported for all five factors and 28 of the 30 facets when a Sardinian subsample matched on age, sex, and education was compared to a mainland Italian sample. The genetic homogeneity effect on the phenotypic expression of complex traits merits further exploration. [ABSTRACT FROM AUTHOR]

A chronically elevated white blood cell (WBC) count is a risk factor for morbidity and mortality. The present research tests whether facets of impulsivity-impulsiveness, excitement-seeking, self-discipline, and deliberation-are associated with chronically elevated WBC counts. Community-dwelling participants ( N = 5,652) from Sardinia, Italy, completed a standard personality questionnaire and provided blood samples concurrently and again 3 years later. Higher scores on impulsivity, in particular impulsiveness and excitement-seeking, were related to higher total WBC counts and higher lymphocyte counts at both time points. Impulsiveness was a predictor of chronic inflammation: for every standard deviation difference in this trait, there was an almost 25% higher risk of elevated WBC counts at both time points (OR = 1.23, 95% CI = 1.10-1.38). These associations were mediated, in part, by smoking and body mass index. The findings demonstrate that links between psychological processes and immunity are not limited to acute stressors; stable personality dispositions are associated with a chronic inflammatory state. [ABSTRACT FROM AUTHOR]

Abstract: In the context of obesity epidemic, no large population study has extensively investigated the relationships between total and abdominal adiposity and large artery structure and function nor have such relationships been examined by gender, by age, by hypertensive status. We investigated these potential relationships in a large cohort of community dwelling volunteers participating the SardiNIA Study. Methods and results: Total and visceral adiposity and arterial properties were assessed in 6148 subjects, aged 14–102 in a cluster of 4 towns in Sardinia, Italy. Arterial stiffness was measured as aortic pulse wave velocity (PWV), arterial thickness and lumen as common carotid artery (CCA) intima-media thickness (IMT) and diameter, respectively. We reported a nonlinear relationship between total and visceral adiposity and arterial stiffness, thickness, and diameter. The association between adiposity and arterial properties was steeper in women than in men, in younger than in older subjects. Waist correlated with arterial properties better than BMI. Within each BMI quartile, increasing waist circumference was associated with further significant changes in arterial structure and function. Conclusion: The relationship between total or abdominal adiposity and arterial aging (PWV and CCA IMT) is not linear as described in the current study. Therefore, BMI- and/or waist-specific reference values for arterial measurements might need to be defined. [Copyright &y& Elsevier]

Abstract: Objective: Metabolic syndrome (MetS) and its components accelerate age-associated increases in arterial stiffness and thickness. We investigated whether specific proinflammatory cytokines contribute to arterial aging, independent of age, sex, MetS, and other traditional CV risk factors. Research design and methods: MetS components (ATP III criteria) and arterial properties were assessed in 6148 subjects, aged 14–102 in Sardinia, Italy. Common carotid artery (CCA) diameter, intima-media thickness (IMT), and aortic pulse wave velocity (PWV), adiponectin, leptin, high-sensitivity C reactive protein (hsCRP), monocyte chemoattractant protein 1 (MCP1), and interleukin 6 (IL6) were measured. Results: While cytokine levels – except for MCP1 – were significantly higher (lower for adiponectin) in MetS than in control subjects, and the increased PWV and CCA IMT with aging were associated with MetS, this association was independent of cytokine levels (p <0.001 for both PWV and CCA IMT). Specific cytokines, however, were significantly associated with arterial stiffness (higher leptin, p <0.001, and higher hsCRP, p <0.001) or thickness (lower adiponectin, p <0.05, and higher IL6, p <0.001) – independent of age, sex, MetS and other traditional CV risk factors. The co-occurrence of both MetS and higher cytokines levels was associated with greater increases in arterial stiffness and thickness. Conclusion: While MetS and specific cytokine patterns associated with arterial aging, the increases in arterial stiffness and thickness are greater when both MetS and higher cytokine levels are present, suggesting a possible synergistic effect of MetS and inflammation on the arterial wall. [Copyright &y& Elsevier]

Crisponi syndrome is a severe autosomal recessive condition that is phenotypically characterized by abnormal,paroxysmal muscular contractions resembling neonatal tetanus, large face, broad nose, anteverted nares, camptodactyly, hyperthermia, and sudden death in most cases. We performed homozygosity mapping in five Sardinian and three Turkish families with Crisponi syndrome, using high-density single-nucleotide polymorphism arrays, and identified a critical region on chromosome 19p12-13.1. The most prominent candidate gene was CRLF1, recently found to be involved in the pathogenesis of cold-induced sweating syndrome type 1 (CISS1). CISS1 belongs to a group of conditions with overlapping phenotypes, also including cold-induced sweating syndrome type 2 and Stüve-Wiedemann syndrome. All these syndromes are caused by mutations of genes of the ciliary neurotrophic factor (CNTF)-receptor pathway. Here, we describe the identification of four different CRLF1 mutations in eight different Crisponi-affected families, including a missense mutation, a single-nucleotide insertion, and a nonsense and an insertion/deletion (indel) mutation, all segregating with the disease trait in the families. Comparison of the mutation spectra of Crisponi syndrome and CISS1 suggests that neither the type nor the location of the CRLF1 mutations points to a phenotype/genotype correlation that would account for the most severe phenotype in Crisponi syndrome. Other, still-unknown molecular factors may be responsible for the variable phenotypic expression of the CRLF1 mutations.We suggest that the syndromes can comprise a family of ‘CNTF-receptor-related disorders,’ of which Crisponi syndrome would be the newest member and allelic to CISS1. [ABSTRACT FROM AUTHOR]