title: The functional VNTR of IGH enhancer HS1.2 associates with human longevity and interacts with TNFA promoter diplotype in a population of Central Italy.
abstract: The dysregulation of both immune and inflammatory responses occurring with aging is believed to substantially contribute to morbidity and mortality in humans. We have already reported the association of the functional Variable Number of Tandem Repeat (VNTR) at the Immunoglobulin heavy chain (IGH) enhancer HS1.2 with Immunoglobulin levels and with several autoimmune diseases. Herein we tested the association of the VNTR at the HS1.2 enhancer with human longevity, also evaluating the possible modulatory effect of TNFA promoter diplotype (rs361525/rs1800629). HS1.2 enhancer genotypes have been determined for 193 unrelated healthy individuals from Central Italy divided into two groups: Group 1 (18-84 yrs, mean age 56.8 ± 19.4) and Group 2 (85-100 yrs, mean age 93.0 ± 3.5). Homozygous subjects for 2 allele were significantly disadvantaged in reaching higher life-expectancy (OR=0.457, p=0.021). A significant interaction between TNFA promoter diplotype status, HS1.2 2/2 genotype and the two Groups was found (p=0.014). Of note, TNFA -308A allele seems to exert a protective effect in HS1.2 2/2 carriers. These results support the hypothesis of an important role of HS1.2 VNTR in the puzzle of the immune-system regulation, evidenced also by the potential interaction with TNFA. Moreover, the previous results showing the association of HS1.2 2 allele with inflammatory phenomena are consistent with the hypothesis that this allele is a detrimental factor in reaching advanced age.
authors.affiliation: Innovation Pole for Genomics, Genetics and Biology, Perugia, Italy. Electronic address: napvale@gmail.com.
authors.forename: Valerio
authors.initials: V
authors.lastname: Napolioni
authors.affiliation: Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.
authors.forename: Eliseo
authors.initials: E
authors.lastname: Serone
authors.affiliation: Department of Biology "E Calef", University of Tor Vergata, Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Iacoacci
authors.affiliation: Innovation Pole for Genomics, Genetics and Biology, Perugia, Italy.
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Carpi
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Giambra
authors.affiliation: Department of Biology "E Calef", University of Tor Vergata, Rome, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Frezza
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D004742:Enhancer Elements, Genetic / Q000235:genetics; D004843:Epistasis, Genetic; D005260:Female; D005787:Gene Frequency; D005828:Genetics, Population; D005838:Genotype; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007558:Italy; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats / Q000235:genetics*; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D055815:Young Adult
chemical_list: C530726:HS1,2-A enhancer protein, human; D007143:Immunoglobulin Heavy Chains; D014409:Tumor Necrosis Factor-alpha
keywords: 3′ Regulatory Region; Aging; Enhancer hs1.2; Gene–gene interaction; Immunoglobulin; Longevity; Polymorphism; TNFA