Malgorzata Roszkowska-Gancarz

Functional polymorphisms of the leptin and leptin receptor genes are associated with longevity and with the risk of myocardial infarction and of type 2 diabetes mellitus.

INTRODUCTION Longevity is commonly associated with good health and with delayed onset of age-related diseases with usually benign course. Leptin (LEP) significantly affects metabolism and numerous functions of the organism. To find out if extreme longevity and its phenotype are associated with genetic variants of leptin and leptin receptor (LEPR) genes, we analysed the frequencies of the -2548 G/A and +19 G/A LEP, as well as the K109R, Q223R, and K656N LEPR polymorphisms in centenarians and in control groups. MATERIAL AND METHODS The frequencies of the LEP and LEPR polymorphisms were tested by restriction fragment length polymorphism in 128 centenarians, 414 young controls (Y), 226 myocardial infarction (MI) patients, and 190 type 2 diabetes mellitus (DM2) patients. RESULTS The GG genotype of the -2548 G/A LEP polymorphism was significantly more common in centenarians than in the Y, MI and DM2 groups (p = 0.048, p = 0.003, p = 0.049, respectively). In addition, the AA genotype of the K109R LEPR polymorphism was significantly less frequent in centenarians than in the Y, MI, and DM2 groups (p = 0.026, p = 0.013, and p = 0.001, respectively). CONCLUSIONS We suggest that the leptin pathway plays a role in the regulation of longevity, possibly by modulating the risk of development of MI and of DM2.

The —351A/G polymorphism of ESR1 is associated with risk of myocardial infarction but not with extreme longevity

BACKGROUND Women live longer than men. Some possible reasons for this advantage are the protection provided by high concentrations of 17β-estradiol (E2) during the premenopausal period and polymorphic variants of the estrogen receptors (ERs), which mediate various cardiovascular functions of E2. METHODS We tested whether the -351A/G and -397T/C polymorphisms of the ERα-encoding ESR1 were associated with extreme longevity. The genomic DNA of 148 centenarians (C), 414 young controls (Y), and 208 myocardial infarction patients (MI) was analyzed by RFLP-PCR. RESULTS Both polymorphisms were equally distributed in the Y, C, and in centenarians never diagnosed with MI (HC). In centenarians, none of these polymorphisms was associated with a particular lipid profile. The AA genotype of the -351A/G polymorphism was less frequent in the C, HC and Y groups than in MI patients (p=0.058, p=0.021, and p=0.004, respectively). In MI patients, the GG genotype of the -351A/G polymorphism was associated with significantly lower mean total cholesterol, LDL, and HDL levels compared to the AG (p=0.0194, p=0.0213, and p=0.0367, respectively) and AA genotypes (p=0.0014, p=0.0078, and p=0.0448, respectively). CONCLUSIONS The -351A/G ESR1 polymorphism might be associated with MI, but not with extreme longevity.

Aging is accompanied by a progressive decrease of expression of the WRN gene in human blood mononuclear cells.

The WRN gene encodes DNA helicase participating in genome maintenance. We looked for associations of natural aging with expression and methylation of this gene in blood mononuclear cells and with its common polymorphisms. Analyses were performed in ethnically homogenous Polish Caucasians. The mean level of the WRN messenger RNA was significantly lower in long-living individuals than in young and middle-aged controls (p < .001 and p = .025, respectively). Analysis of the 361 bp WRN promoter CpG island showed that aging might be accompanied by a slight increase of its methylation status; however, it seems to be biologically insignificant. Finally, analysis of the WRN R834C, L1074F, and C1367R polymorphisms showed that the frequencies of the L1074F and C1367R polymorphisms were similar in all age groups tested, whereas the R834C polymorphism was absent from Polish Caucasians. We suggest that age-related decrease of the WRN expression but not its common genetic variants might contribute to human immunosenescence.

Age-related changes of leptin and leptin receptor variants in healthy elderly and long-lived adults

Aging is usually associated with hyperleptinemia and leptin resistance, both increasing the risk of age‐related diseases. It was relevant to establish if healthily aging, non‐obese individuals develop changes in leptin, the soluble leptin receptor (OB‐Re), free leptin index (FLI), in methylation of the leptin receptor gene (LEPR) promoter, and in the expression of long (OB‐Rb) and short (OB‐Ra) leptin receptor isoforms.

ESR2 gene G1730A variant is associated with triglycerides level and myocardial infarction in young men but not in women

OBJECTIVES The aim of the study was to investigate the role of estrogen receptor type 2 gene (ESR2) variant G1730A in myocardial infarction (MI) in young age. METHODS Genotyping was performed with restriction fragments length polymorphism method in 158 patients (79.1% men) with MI aged <50 years (studied group) and in control groups: 150 healthy individuals aged <50 years (63.3% men) and 202 patients (64.3% men) with MI aged ≥50 years. RESULTS The AA genotype of ESR2 G1730A variant was significantly more frequent in men with MI aged <50 comparing to men with MI aged ≥50 (21.6% vs. 8.4%, P = 0.004) and to healthy young men (21.6% vs. 11.6%, P = 0.048). There was statistically significant difference between AA genotype and GA + GG genotypes male carriers with MI aged <50 in median triglyceride (TG) level (2.0 vs. 1.7 mmol/l respectively, p = 0.023). CONCLUSIONS Our findings suggest a possible role of ESR2 G1730A variant as the risk factor of MI in a young age not as an independent but a potential risk factor associated with TG level in men but not in women.

Age-associated increase of thyroid hormone receptor β gene promoter methylation coexists with decreased gene expression

ABSTRACT Purpose: It is not established if healthy aging of the thyroid axis is associated with alterations other than changes in hormone secretion. Methods: The expression of thyroid hormone receptor β gene (THRB) was analyzed in peripheral blood mononuclear cells (PBMC) obtained from young, elderly, and long-lived individuals. The interaction between the 3ʹUTR of TRβ1 mRNA and selected miRNAs was measured using pmirGLO reporter vector. Methylation of the THRB CpG island was analyzed using methylation-sensitive restriction/RT-PCR and bisulfite sequencing methods. Results: Old age was associated with a significantly lower amount of total TRβ mRNA (p = 0.033) and of TRβ1 mRNA (p = 0.02). Older age was also associated with significantly higher methylation of the THRB promoter (restriction/RT-PCR: p = 0.0023, bisulfite sequencing: p = 0.0004). Higher methylation corresponded to a lower expression of the THRB mRNA, but this correlation did not reach the level of significance. miR-26a interacted with two sites in the 3’UTR of the TRβ1 mRNA leading to the decrease of the reporter protein activity (p < 0.0001 and p = 0.0005), and miR-496 interacted with one of the two putative binding sites which also decreased the reporter protein activity (p < 0.0001). Analysis of the expression of miR-21, miR-26a, miR-146a, miR-181a, miR-221, and miR-496 showed that the expression of miR-26a was significantly decreased in old subjects (p = 0.017), while the levels of other miRNAs were unaffected. Conclusions: Age-related decrease of THRB expression in PBMC of elderly and long-lived humans might be, in part, a result of the increased methylation of its promoter, but is unrelated to the activity of the miRNAs analyzed here.