Biomedical subjects

Giuseppina Rose

Publications and source records attributed to Giuseppina Rose.

6 recordsLinked to original sources

PubMed2024

Evidence for a relationship between genetic polymorphisms of the L-DOPA transporter LAT2/4F2hc and risk of hypertension in the context of chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) and hypertension are chronic diseases affecting a large portion of the population frequently coexistent and interdependent. The inability to produce/use adequate renal dopamine may contribute to the development of hypertension and renal dysfunction. The heterodimeric amino acid transporter LAT2/4F2hc (SLC7A8/SLC3A2 genes) promotes the uptake of L-DOPA, the natural precursor of dopamine. We examined the plausibility that SLC7A8/SLC3A2 gene polymorphisms may contribute to hypertensive CKD by affecting the L-DOPA uptake. METHODS: 421 subjects (203 men and 218 women, mean age of 78.9 ± 9.6 years) were recruited and divided in four groups according to presence/absence of CKD, defined as reduced estimated glomerular filtration rate (eGFR < 60 ml/min/m2) calculated using the creatinine-based Berlin Initiative Study-1 (BIS1) equation, and to presence/absence of hypertension (systolic blood pressure ≥ 140 and/or diastolic blood pressure ≥ 90 mmHg). Subjects were analysed for selected SNPs spanning the SLC7A8 and SLC3A2 loci by Sequenom MassARRAY iPLEX platform. RESULTS: The most significant SNP at the SLC3A2 (4F2hc) locus was rs2282477-T/C, with carriers of the C-allele having a lower chance to develop hypertension among CKD affected individuals [OR = 0.33 (CI 0.14-0.82); p = 0.016]. A similar association with hypertensive CKD was found for the SLC7A8 (LAT2) rs3783436-T/C, whose C-allele resulted associated with decreased risk of hypertension among subjects affected by CKD [OR = 0.56 (95% CI 0.35-0.90; p = 0.017]. The two variants were predicted to be potentially functional. CONCLUSIONS: The association between SLC3A2 and SLC7A8 variants to hypertension development in patients with renal failure could be linked to changes in L-DOPA uptake and consequently dopamine synthesis. Although the associations do not survive correction for Bonferroni multiple testing, and additional research is needed, our study opens new avenues for future basic and translational research in the field of hypertensive CKD.

Aged↗

PubMed2006

Mitochondrial DNA involvement in human longevity.

The main message of this review can be summarized as follows: aging and longevity, as complex traits having a significant genetic component, likely depend on a number of nuclear gene variants interacting with mtDNA variability both inherited and somatic. We reviewed the data available in the literature with particular attention to human longevity, and argued that what we hypothesize for aging and longevity could have a more general relevance and be extended to other age-related complex traits such as Alzheimer's and Parkinson's diseases. The genetics which emerges for complex traits, including aging and longevity, is thus even more complicated than previously thought, as epistatic interactions between nuclear gene polymorphisms and mtDNA variability (both somatic and inherited) as well as between mtDNA somatic mutations (tissue specific) and mtDNA inherited variants (haplogroups and sub-haplogroups) must be considered as additional players capable of explaining a part of the aging and longevity phenotype. To test this hypothesis is one of the main challenge in the genetics of aging and longevity in the next future.

Cell Nucleus↗

PubMed2006

Gene expression of cytokines and cytokine receptors is modulated by the common variability of the mitochondrial DNA in cybrid cell lines.

Some lines of evidence indicate that common polymorphisms of mitochondrial DNA (mtDNA) act as susceptibility factors in complex traits, such as age-related common diseases. There is also evidence that the cell capability to compensate ravages caused by intrinsic or extrinsic stress factors could contribute to some of these diseases. The cross-talk between nuclear and mitochondrial genome may link the above observations if we assume that the transcription of stress-responder nuclear genes is modulated according to the mtDNA common variability. Cytokines and cytokine receptors are key molecules in stress response. We could, therefore, check the above hypothesis by analyzing expression patterns of cytokine and cytokine receptor genes in response to stress in cell lines sharing the same nuclear genome but different mtDNA. By using a cybrid model (143B.TK- osteosarcoma cells depleted of their own mtDNA and repopulated with foreign mitochondria) we show that the transcription patterns of some of such genes are specifically modulated by the variability of the mitochondrial genome not only under stress conditions (interleukin-6) but also at basal conditions (interleukin-1beta and tumor necrosis factor receptor 2). These findings provide a first experimental evidence of a relationship between mtDNA common variability and expression pattern of stress responder nuclear genes in human cells.

Cell Fusion↗

PubMed2005

A novel VNTR enhancer within the SIRT3 gene, a human homologue of SIR2, is associated with survival at oldest ages.

SIR2 genes control life span in model organisms, playing a central role in evolutionarily conserved pathways of aging and longevity. We wanted to verify whether similar effects may act in humans too. First, we searched for variability in the human sirtuin 3 gene (SIRT3) and discovered a VNTR polymorphism (72-bp repeat core) in intron 5. The alleles differed both for the number of repeats and for presence/absence of potential regulatory sites. Second, by transient transfection experiments, we demonstrated that the VNTR region has an allele-specific enhancer activity. Third, by analyzing allele frequencies as a function of age in a sample of 945 individuals (20-106 years), we found that the allele completely lacking enhancer activity is virtually absent in males older than 90 years. Thus the underexpression of a human sirtuin gene seems to be detrimental for longevity as it occurs in model organisms.

Adult↗

PubMed2004

Association of the mitochondrial DNA haplogroup J with longevity is population specific.

Evidences are accumulating on the effects of the variability of mitochondrial DNA (mtDNA) on many complex traits. In particular, mtDNA haplogroup J has been reported to increase the individual chance to attain longevity in northern Italians, Northern Irish and Finns. However, since the genetic contribution to longevity may be population specific, we wanted to verify if haplogroup J does affect longevity also in a southern European population having a different genetic and environmental history. We analysed a population sample (883 subjects, 371 males and 521 females; age range 18-108 years) from southern Italy for the presence of haplogroup J. No frequency increase of this mtDNA haplogroup was found in the older cohorts, suggesting that, in this population, haplogroup J does not play a significant role in longevity. This finding shows that, as for other genetic factors, the association of mtDNA inherited variability with longevity is population specific.

Adolescent↗

PubMed2002

An allele of HRAS1 3'variable number of tandem repeats is a frailty allele: implication for an evolutionarily-conserved pathway involved in longevity.

The human HRAS1 belongs to an evolutionarily-conserved family of genes which enrolls among its members the yeast RAS2, a gene which regulates stress response and longevity in the Saccharomyces cerevisiae. In this paper we report that the frequency of the a3 allele of HRAS1 3'variable number tandem repeat (HRAS1 3'VNTR) decreases in centenarians in respect to young people, and we estimate that during aging a3 carriers have a relative mortality risk of 1.126 (95% CI=1.044-1.213). We propose that the germ-line variability at the HRAS1 locus impacts on the individual's capacity to reach the extreme limits of human life-span. Furthermore, we provide suggestive evidence that a3 HRAS1 3'VNTR allele and inherited variants of the mitochondrial genome (mtDNA haplogroups) do not affect independently human longevity, thus recalling the nucleus-mitochondrion interaction which regulates stress response and life-span in the yeast.

Adult↗