Human chitotriosidase polymorphism is associated with human longevity in Mediterranean nonagenarians

Malaguarnera1, Luca Nnawuihe Ohazuruike2, Christina Tsianaka2, Tijana Antic2, Michelino Di Rosa1

Lucia Malaguarnera1, Luca Nnawuihe Ohazuruike2, Christina Tsianaka2, Tijana Antic2, Michelino Di Rosa1 and Mariano Malaguarnera2

Human phagocyte-specific chitotriosidase (CHIT-1) is a chitinolytic enzyme associated with several diseases involving macrophage activation. Previous studies have demonstrated that a high activity of Chit could have widespread effects on atherosclerosis, cardiovascular disease and dementia. The 24-bp duplication in the CHIT-1 gene is associated with a deficiency in enzymatic activity. In this study, we attempted to assess whether CHIT-1 could be a plausible candidate gene responsible for human longevity. Therefore, we compared the distribution of the CHIT-1 polymorphism genotype in three different populations of

macrophage activation. Previous studies have demonstrated that a high activity of Chit could have widespread effects on atherosclerosis, cardiovascular disease and dementia. The 24-bp duplication in the CHIT-1 gene is associated with a in enzymatic activity. In this study, we attempted to assess whether CHIT-1 could be a plausible candidate gene responsible human longevity. Therefore, we compared the distribution of the CHIT-1 polymorphism genotype in three different populations the Mediterranean area (Italian, Greek and Tunisian) aged over 90 years. As a control group for each nonagenarian and centenarian, a 60–70-year-old subject was genotyped. We found that the heterozygote frequency for the 24-bp duplication in the CHIT-1 gene was not significantly different among the oldest old subjects of Mediterranean populations, whereas it was significantly different between oldest old subjects and control subjects, being highest among the oldest old subjects and among control groups. In the oldest old group, no subject was observed to be homozygous for CHIT-1 deficiency. Moreover, the mean enzymatic activity in heterozygous oldest subjects was lower than that in the control group. These data indicate that the heterozygosis for a 24-bp duplication in the CHIT-1 gene could have a protective effect in human longevity. Journal of Human Genetics (2010) 55, 8–12; doi:10.1038/jhg.2009.111; published online 30 October 2009

Keywords: chitotriosidase; human longevity; Mediterranean area; polymorphism

INTRODUCTION

family, a group of glycoside hydrolases that cleave chitin. Chitin is a polysaccharide present as a structural component in fungi, nematodes and insects.3–4 The human CHIT-1 gene is localized on chromosome 1q31–q32.5 CHIT-1 is present in normal plasma and is mainly secreted by activated macrophages and to a lesser degree by neutrophils.6 Chit activity has been proposed as a biochemical marker of macrophage accumulation and activity in several lysosomal lipid storage diseases.7–10 Little is known regarding the physiological function of CHIT-1, although its phagocyte-specific expression points to a role of the enzyme in innate immunity.11–12 CHIT-1 mRNA expression is upre- gulated after stimulation by tumor necrosis factor alpha (TNF-a), interferon gamma (IFN-g), prolactin and lipopolysaccharide (LPS).13–15 In vitro studies using recombinant human CHIT-1 have demonstrated that CHIT-1 lyses the hyphal tip of Mucor rouxii and inhibits the growth of hyphae of Candida albicans.6 In vivo, neutropenic mice challenged with lethal doses of C. albicans or with Aspergillosis exhibit increased survival when treated with human recombinant CHIT-1.6 A 24-bp duplication in exon 10 in the CHIT-1 gene activates a cryptic 39 splice site in the same exon, generating an abnormally spliced

Nonagenarians and centenarians comprise a small proportion of the whole population. This group because it survives to an extremely old age, continues to capture the interest of the medical and scientific community. An understandable reason for this interest is the hope to discover the factors allowing certain people to survive and advance greatly in age, whereas others do not. Demographic, clinical, biome- dical and genetic data of centenarians could provide some evidence with regard to the factors related to exceptional longevity.1 Nongenetic factors including diet, physical activity, health habits and psychosocial factors are important. Moreover, a number of studies suggest that about 25% of the variation in human lifespan in average-lived populations can be explained by genetic factors, but in populations with larger numbers of extraordinary survivors, the genetic contribu- tion to lifespan may be higher.2 Substantial interest has developed over past few years in identifying genes that are associated with longevity in humans. Nevertheless, studies on candidate ‘longevity-associated’ genes in humans, referred to as ‘longevity genes,’ have generally been limited.

1Department of Biomedical Science, University of Catania, Catania, Italy and 2Department of Senescence, Urological and Neurological Sciences, University of Catania, Italy Correspondence: Professor L Malaguarnera, Department of Biomedical Science, University of Catania, Via Androne, 83, 95124 Catania, Italy. E-mail: lucmal@mbox.unict.it Received 2 July 2009; revised 2 October 2009; accepted 5 October 2009; published online 30 October 2009

(Attica, Greek Macedonia, Thessalia, Epirus and Peloponnese), at their home. Nonagenarians and centenarians were identified by researching archival records in the City Hall and/or church registries.

mRNA with an in-frame deletion of 87 nucleotides. The spliced mRNA encodes an enzymatically inactive protein that lacks an internal stretch of 29 amino acids.5 The resulting phenotype is an asympto- matic Chit activity deficiency. A mild enzymatic activity has been detected in subjects heterozygous for the duplication.16–17