Human leukocyte antigen class I, class II, and tumor necrosis factor-alpha polymorphisms in a healthy elder Mexican Mestizo population

Elena Soto-Vega, Yvonne Richaud-Patin and Luis Llorente*

Address: Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Mexico Mexico Email: Elena Soto-Vega - elenasoto_74@yahoo.com; Yvonne Richaud-Patin - yrichaud@yahoo.com.mx; Luis Llorente* - lllyrp@quetzal.innsz.mx

Address: Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Mexico City,

This article is available from: http://www.immunityageing.com/content/2/1/13

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background: There is strong evidence that an individual's genetic background is an important predisposing factor to longevity. In the present study we analysed the frequency of HLA class I, class α II, as well as the TNF- -308 polymorphism that may be related to an increased life span in Mexican Mestizo healthy elders.

Results: HLA typing was performed by polymerase chain reaction sequence specific α oligonucleotide (PCR SSO) reverse dot blot. The TNF- -308 polymorphism was assessed by PCR restriction fragment length polymorphism. A significant increased frequency of HLA-DRB1*11 was found in elderly women whereas this allele was not present in elderly males. The TNF2 allele was also increased in the elder group when compared to young controls. The frequencies of the remaining alleles tested were not statistically different among groups.

Conclusion: These data suggest an ethnicity independent tendency of HLA-DRB1*11 in elder females to increase life span and a possible role of the TNF2 allele with the successful remodelling of senescent immune system.

Background

class III genes with old age. Thus, longevity has been shown to be related with the selection of HLA alleles or haplotypes being the more frequently associated the A1 B8 Cw7 DR3 in Caucasians [3,4], the increased or decreased frequency of HLA-B40 [5-7], the augmented fre- quency of HLA-DR11 in elder women in Caucasian as well as in Japanese populations [8,9] among other alleles. Immunogenetic studies in aged, healthy Mexican Mestizo population have not been yet performed.

Ageing is associated with a complex remodelling of the immune system often in the direction of apparently decreased immune competence. However, it has been proposed that longevity is related to optimal function of the immune system because some genetic determinants for successful ageing might reside in those polymor- phisms of genes that regulate immune responses e.g. major histocompatibility complex (MHC) [1,2]. The stud- ies of life span in humans have resulted in different, and even controversial, associations of HLA class I, class II and

DRB1*0404 were the more frequent in the young group, being these alleles not statistically significant.

Mexican Mestizo individuals have a proportion of 56% Native American Indian genes, 40% Caucasian genes, and 4% African genes [10]. Mestizo population represents a complex mixture of European and American native inhab- itants, and constitute the core of the Mexican population. This complex genetic process began in the 16th century and has been expanded during the course of time and continues to be a dynamic process, e.g., African popula- tion inhabited the Americas almost 200 years later. On the other hand, aged people in the Mexican population have increased from a life expectancy of 63 years in the 1970's up to 70 years nowadays.

When the differences between aged males and females were analysed, a decreased frequency of HLA-DRB1*11 in males was found when compared to females, for no one in the former group was HLA-DRB1*11 (p = 0.002; OR = 0.18; CI 95% = 0.06–0.53; p = 0.024 by Bonferroni's cor- rection). On the other hand, when elderly males were compared to young males for HLA-DRB1*11, a dimin- ished frequency was found although not statistically sig- nificant when Bonferroni's correction was applied. The high resolution typing showed a decreased frequency of the HLA-DRB1*1101 allele in elderly females when com- pared to the other HLA-DRB1*11 alleles from young women and, again, this difference was not significant by Bonferroni's correction.

Healthy elderly people show a pro-inflammatory pheno- α type with increased levels of cytokines such as TNF- [11]. α The TNF- gene is located within the HLA class III region. This cytokine is involved in tissue remodelling, epithelial cell barrier permeability, macrophage activation, recruit- ment of inflammatory infiltrate, and up-regulation of α adhesion molecules, among other functions. TNF- also determines the strength, effectiveness and duration of local and systemic inflammatory responses [12].

Our data must be balanced against the small number of subjects studied. However, we found that, interestingly, no old man was HLA-DRB1*11, which may suggest that survival being gender-dependent [15,16]. This finding for Mexican Mestizo women is in agreement with previous reports in different populations, which might indicate that the contribution of this allele to an increase in the life span is independent of ethnicity [8].

α TNF- promoter contains numerous polymorphic sites, which are possible targets for transcription factors. The polymorphism at position -308 is defined by de substitu- tion of a G by an A, where the presence of G defines the common allele TNF1 and A defines the TNF2 variant, which is less frequent [13]. Some studies have shown that individuals bearing the TNF2 polymorphism are higher α TNF- producers than those who bear the TNF1 variant [14].