Accepted Manuscript

Title: Metabolism and Successful Aging: Polymorphic Variation of Syndecan-4 (SDC4) Gene Associated with Longevity and Lipid Profile in Healthy Elderly Italian Subjects.

Author: Giuseppina Rose, Paolina Crocco, Francesco De Rango, Andrea Corsonello, Fabrizia Lattanzio, Maria De Luca, Giuseppe Passarino.

Mechanisms of Ageing and Development

Please cite this article as: Rose, Giuseppina, Crocco, Paolina, Rango, Francesco De, Corsonello, Andrea, Lattanzio, Fabrizia, Luca, Maria De, Passarino, Giuseppe. Metabolism and Successful Aging: Polymorphic variation of syndecan-4 (SDC4) gene associated with longevity and lipid profile in healthy elderly Italian subjects. Mechanisms of Ageing and Development. http://dx.doi.org/10.1016/j.mad.2015.08.003

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Metabolism and Successful Aging: Polymorphic Variation of Syndecan-4 (SDC4) Gene

Rose1*, Paolina Crocco1*, Francesco De Rango1, Andrea Corsonello3, Fabrizia Lattanzio2, Maria De Luca2, Giuseppe Passarino1.

3Italian National Research Centre on Ageing, Cosenza, Italy

4Scientific Direction of the Italian National Research Centre on Ageing, Ancona,

*Giuseppina Rose and Paolina Crocco equally contributed to this study.

Corresponding Author: SDC links longevity and lipid profile. SDC variants rs and rs in SDC are associated with human SDC variants rs and rs in SDC have an effect on the lipid profile.

ABSTRACT

SDC4 alleles affect lipid profile in elderly subjects and may in part mediate the link between aging, longevity, extracellular matrix, metabolism, and syndecans adhesion and behavior (Morgan et al., 2007; Xian et al., 2010). That signaling between cells and the ECM plays a pivotal role in tissue/organ homeostasis. Sdc mutant flies also display less fat and glycogen reserves and lower metabolic activity than invertebrates. Humans contain four SDC genes. Three of them, SDC1, SDC2, and SDC3 (Miller et al., 2011), suggests that this SDC4 genetic variant might molecular link between SDC4 and lipid profile strongly motivate further studies to determine how SDC4 genotypes can affect human health.

Keywords: Aging; Longevity; Extracellular Matrix; Metabolism; Syndecans

2. METHODS

2.1. Study subjects

The study was carried out in a cohort of 624 unrelated subjects (287 males and 337 females, age of Calabria, Italy. A written informed consent was obtained from all participants before enrolling in the study.

2.2. Phenotypic measurements

HbA1c was chosen as a clinical marker of CHD because levels of HbA1c between 6.0 and clothes and without shoes. Blood samples were withdrawn after a 12-h overnight fast and analysis. The selected SNPs are reported in Table and a primer extension reaction using the mass extension primer and the terminator. The 95%; however, genotyping completion rate was lower than 65% for rs6104125.

model]). For each model, a z-score was returned, representing the z-statistics for the analyses, with a pmodel referred to the p value for the most likely genetic model. SNPs influenced gene expression, we explored the Genotype-Tissue Expression (GTEx)

3.1. SCD4 association with longevity

Longevity, however, was not significant after adjusting for multiple testing (Table 2); hence, caution is needed in interpreting this finding. The z-statistics of these models indicated that rs2228384. The haplotype analysis for these two polymorphic sites revealed that, although the Thus, haplotype analysis confirmed association results with the single markers.

with longevity, was correlated with higher levels of LDL-C (positive score; (cid:1868)Recessive Model = 0.022).

3.2. Exploring the functional consequences of SDC4 variants

likely to affect binding (score 2b). of these markers may be the actual causal(G) -0.690 0.328 -0.985 0.490 0.743 0.325 0.545 rs749111 0.16 (T) -0.854 -0.744 -0.712 0.393 0.457 0.477 0.630 rs11697824 0.16 (A) -0.580 -0.073 -0.644 0.562 0.942 0.519 0.769 

1 Z-score represents the z-statistics under the additive, recessive, and dominant models.

2 P-value calculated for each genetic model.

3 Theop refers to the p-value adjusted for multiple comparisons (due to the three different genetic models). In bold, p-value significant after adjusting for multiple comparisons.

Minor Allele Frequency in our control group.

SNPs rs2228384 rs1981429 Freq a Score P-value b T G 0.41452 -2.42697 0.01523 T T 0.18413 0.97116 0.33147 C G 0.01198 1.00192 0.31638 C T 0.38937 1.44286 0.14906 

4 Results of the RobustSNP association test with the hematological variables (total triglyceride, HDL cholesterol, LDL cholesterol, Fasting glucose, and Hemoglobin) in the control group.

SNP Z1.add Z.rec Z.dom P2.add P.rec P.dom Theop3 

Total cholesterol 
rs1981429 -1.496 -0.315 -2.091 0.135 0.753 0.036 bold, p-value significant after adjusting for multiple comparisons.
rs2251252 1.043 1.948 -0.029 0.297 0.051 0.977 
rs6130811 1.148 1.612 0.566 0.251 0.107 0.572 

Triglyceride 
rs1981429 2.251 1.779 2.168 bold, p-value significant after adjusting for multiple comparisons.
0.024 0.075 0.030 
rs2251252 -1.238 -0.716 -1.291 0.216 0.474 0.197 
rs6130811 -1.167 -1.862 -0.659 0.243 0.063 0.510 

HDL cholesterol 
rs1981429 -0.451 0.461 -1.087 0.652 0.645 0.277 
rs2251252 0.479 0.429 0.372 0.632 0.668 0.710 
rs6130811 0.665 0.709 0.463 0.506 0.478 0.643