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Haptoglobin (HP) polymorphisms and human longevity: A cross-sectional association study in a Central Italy population

Napolioni a, , Paola Giannì a, Francesco M. Carpi b, Fabio Concetti a,

a Laboratory of Human Genetics, School of Biosciences and Biotechnologies, University of Camerino, Camerino, Italy b Laboratory of Applied Biochemistry, School of Biosciences and Biotechnologies, University of Camerino, Camerino, Italy

Haptoglobin (HP), which scavenges free, cell-toxic hemoglobin and has anti-inflammatory and function in extravascular tissues, may represent an excellent candidate gene to

investigate the life-span expectancy. Methods: HP 1/2 polymorphism has been determined for 1072 (569 females, 503 males) unrelated healthy individuals from Central Italy, 18–106 years old, divided into three gender-specific age classes defined according to demographic information and accounting for the different survivals between sexes. HP*1F/S subtyping was also performed to check the possible existence for a preferential advantage of HP*1F or HP*1S allele.

Results: HP*1/*1 genotype results associated to increased probability of young subjects of attaining longevity (Comparison 1: O.R. 1.709, p=0.0114) with a concomitant advantage of HP*1 allele (Comparison 1: O.R. 1.273, p=0.0194). On the other side, carriers of HP*2 allele displayed an overall significant disadvantage in reaching Age Class 2 (O.R. 0.585, p=0.0092). No significant differences were noticed between age groups either considering total HP*1F and HP*1S allele frequencies or according to HP 1/2 genotypes. Conclusion: The crucial role played by HP in aging process is warranted by its many established functions and its related phenotypes so that it may be considered an important gene involved in the determination of human survival.

© 2010 Elsevier B.V. All rights reserved.

1. Introduction

in small lymphocyte sub-populations [3]. HP has also been shown to bind to the majority of CD4+ and CD8+ T lymphocytes, directly inhibiting their proliferation and modifying the T helper (Th) Th1/Th2 balance [4].

Aging is a complex phenomenon arising from a combination of oxidative, immunological and metabolic factors. In recent years, several candidate genes have been analysed for a possible association with aging and longevity.

HP is an endowed with Hb-binding capacity and is characterized by molecular heterogeneity; this is due to the existence of three major genotypes, i.e. HP*1/*1, HP*2/*1 and HP*2/*2 [5].ThemaindifferencebetweenallelesHP*1andHP*2isthepresenceof a duplicated ~1.7 Kb DNA segment in HP*2, but not HP*1 [6]. Of note, HP*1 has two variants, HP*1F (fast) and HP*1S (slow), which are correlated with the presence of amino acids Asp-Lys (version F) or Asn- Glu (version S) at amino acid positions 52 and 53 in the α1-chain. The HP*2 allele is supposed to originate from a breakage and reunion event at non-homologous positions within the fourth and the second introns (unequal crossing-over) in an individual who was heterozygous for HP*1F and HP*1S [7]. Having exons 3 and 4 in duplicate, HP*2 monomer is bivalent and can associate with 2 different HP monomers. Thus homozygous HP*1/*1 individuals express HP protein as a single α1β homodimer of 86 kDa.HomozygousHP*2/*2individuals expressthe HP 2-2 phenotype, which consists of cyclic HP oligomers containing 3 or more α2β subunits (170–900 kDa). The HP synthesized by HP*2/*1 heterozygous subjects are assembled into linear homodimers and multimers of variable number of α2β subunits flanked ateachterminus

The pleiotropic functions of haptoglobin make HP (Gene map locus 16q22.1, MIM ID*140100) a compelling candidate gene for human longevity. HP is a potent antioxidant playing a scavenging role for the toxic free hemoglobin (Hb) which accumulates during acute-phase inflammatory reaction. HP also exerts a direct angiogenic, anti- inflammatoryandimmunomodulatoryfunctioninextravasculartissues and body fluids. In fact in response to various stimuli, HP is able to migrate through vessel walls and is expressed in different tissues [1]. Furthermore,HPcanbereleasedfromneutrophilgranulocytesatsitesof injury or inflammation and locally dampens tissue damage [2]. HP receptors include CD163 expressed on the monocyte–macrophage system and CD11b(CR3) found on granulocytes, natural killer cells, and

⁎ Corresponding author. Laboratory of Human Genetics, School of Biosciences and Biotechnologies, Via Gentile III da Varano, University of Camerino, 62032 Camerino, Italy. Tel.: +39 0737 403293; fax: +39 0737 403290. E-mail address: valerio.napolioni@unicam.it (V. Napolioni).

0009-8981/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.cca.2010.12.006

by 1α1β subunits (86–300 kDa). Thus, the HP 2-1 phenotype is distinctly different from the phenotypes of the HP*2 or HP*1 homozygotes. Since functional differences in the antioxidant, scaveng- ing, and immune-regulatory properties of HP occur as a function of its polymorphism, the genetics of HP has been associated with predispo- sition to infections, with autoimmune, cardiovascular, and other diseases and disorders [5].

2.3. Statistical analysis