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Less functional variants of TLR-1/-6/-10 genes are associated with age.

Hamann L, Kupcinskas J, Berrocal Almanza LC, Almanza B, Skieceviciene J, Franke A, Nöthlings U, Schumann RR - Immun Ageing (2015)

Bottom Line: According to sex we found a positive association of loss-of-function variants of TLR-1 and -6 with healthy aging with odds ratios of 1.54 in males for TLR-6 (249 S/S), and 1.41, 1.66, and 1.64 in females for TLR-1 prom., TLR-1 (248 S/S), and TLR-1 (602 S/S), respectively.Thus, the presence of these variants increases the probability of achieving healthy old age and indicates that a reduced TLR activity may be beneficial in the elderly.While a loss of function of an important immune receptor may be a risk factor for acute infections as has been shown previously, in the setting of healthy ageing it appears to be protective, which may relate to "inflamm-aging".

View Article: PubMed Central - PubMed

Affiliation: Institute of Microbiology and Hygiene, Charité University Medical Center Berlin, Charitéplatz 1, 10117 Berlin, Germany.

ABSTRACT

Background: Determining the prerequisites for healthy aging is a major task in the modern world characterized by a longer lifespan of the individuals. Besides lifestyle and environmental influences genetic factors are involved as shown by several genome-wide association studies. Older individuals are known to have an impaired immune response, a condition recently termed "inflamm-aging". We hypothesize that the induction of this condition in the elderly is influenced by the sensitivity of the innate immune system. Therefore, we investigated genetic variants of the Toll-like receptor (TLR) family, one of the major family of innate immune receptors, for association with age in two cohorts of healthy, disease-free subjects.

Results: According to sex we found a positive association of loss-of-function variants of TLR-1 and -6 with healthy aging with odds ratios of 1.54 in males for TLR-6 (249 S/S), and 1.41, 1.66, and 1.64 in females for TLR-1 prom., TLR-1 (248 S/S), and TLR-1 (602 S/S), respectively. Thus, the presence of these variants increases the probability of achieving healthy old age and indicates that a reduced TLR activity may be beneficial in the elderly.

Conclusions: This is the first report showing an association of TLR variants with age. While a loss of function of an important immune receptor may be a risk factor for acute infections as has been shown previously, in the setting of healthy ageing it appears to be protective, which may relate to "inflamm-aging". These first results should be reproduced in larger trials to confirm this hypothesis.

No MeSH data available.


Related in: MedlinePlus

TLR-6/1/10 region on chromosome 4. Arrangement of TLR-6/1/10 and adjacent genes on chromosome 4 and the localization of investigated SNPs
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Fig1: TLR-6/1/10 region on chromosome 4. Arrangement of TLR-6/1/10 and adjacent genes on chromosome 4 and the localization of investigated SNPs

Mentions: Several SNPs within the TLR-6/1/10 genes located in close proximity to each other have been investigated in case/control studies before [20–25]. We focus here on 5 functionally relevant SNPs that have been extensively analyzed in vitro. Most detailed analyses were carried out for TLR-1 (I602S) indicating that the presence of this SNP inhibits the transport of the receptor to the cell surface resulting in a complete loss of function. TLR-1 (A248S) and TLR-6 (P249S) have been shown to reduce ligand-induced immune responses [26, 27]. The TLR-1 variant rs5743351 leads to a change of sequence within the promoter region and has been suggested to influence transcription leading to a change in cellular TLR-1 expression. The localizations of these SNPs and adjacent genes that may harbour SNPs potentially being in linkage disequilibrium are shown in Fig. 1.Fig. 1


Less functional variants of TLR-1/-6/-10 genes are associated with age.

Hamann L, Kupcinskas J, Berrocal Almanza LC, Almanza B, Skieceviciene J, Franke A, Nöthlings U, Schumann RR - Immun Ageing (2015)

TLR-6/1/10 region on chromosome 4. Arrangement of TLR-6/1/10 and adjacent genes on chromosome 4 and the localization of investigated SNPs
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4495943&req=5

Fig1: TLR-6/1/10 region on chromosome 4. Arrangement of TLR-6/1/10 and adjacent genes on chromosome 4 and the localization of investigated SNPs
Mentions: Several SNPs within the TLR-6/1/10 genes located in close proximity to each other have been investigated in case/control studies before [20–25]. We focus here on 5 functionally relevant SNPs that have been extensively analyzed in vitro. Most detailed analyses were carried out for TLR-1 (I602S) indicating that the presence of this SNP inhibits the transport of the receptor to the cell surface resulting in a complete loss of function. TLR-1 (A248S) and TLR-6 (P249S) have been shown to reduce ligand-induced immune responses [26, 27]. The TLR-1 variant rs5743351 leads to a change of sequence within the promoter region and has been suggested to influence transcription leading to a change in cellular TLR-1 expression. The localizations of these SNPs and adjacent genes that may harbour SNPs potentially being in linkage disequilibrium are shown in Fig. 1.Fig. 1

Bottom Line: According to sex we found a positive association of loss-of-function variants of TLR-1 and -6 with healthy aging with odds ratios of 1.54 in males for TLR-6 (249 S/S), and 1.41, 1.66, and 1.64 in females for TLR-1 prom., TLR-1 (248 S/S), and TLR-1 (602 S/S), respectively.Thus, the presence of these variants increases the probability of achieving healthy old age and indicates that a reduced TLR activity may be beneficial in the elderly.While a loss of function of an important immune receptor may be a risk factor for acute infections as has been shown previously, in the setting of healthy ageing it appears to be protective, which may relate to "inflamm-aging".

View Article: PubMed Central - PubMed

Affiliation: Institute of Microbiology and Hygiene, Charité University Medical Center Berlin, Charitéplatz 1, 10117 Berlin, Germany.

ABSTRACT

Background: Determining the prerequisites for healthy aging is a major task in the modern world characterized by a longer lifespan of the individuals. Besides lifestyle and environmental influences genetic factors are involved as shown by several genome-wide association studies. Older individuals are known to have an impaired immune response, a condition recently termed "inflamm-aging". We hypothesize that the induction of this condition in the elderly is influenced by the sensitivity of the innate immune system. Therefore, we investigated genetic variants of the Toll-like receptor (TLR) family, one of the major family of innate immune receptors, for association with age in two cohorts of healthy, disease-free subjects.

Results: According to sex we found a positive association of loss-of-function variants of TLR-1 and -6 with healthy aging with odds ratios of 1.54 in males for TLR-6 (249 S/S), and 1.41, 1.66, and 1.64 in females for TLR-1 prom., TLR-1 (248 S/S), and TLR-1 (602 S/S), respectively. Thus, the presence of these variants increases the probability of achieving healthy old age and indicates that a reduced TLR activity may be beneficial in the elderly.

Conclusions: This is the first report showing an association of TLR variants with age. While a loss of function of an important immune receptor may be a risk factor for acute infections as has been shown previously, in the setting of healthy ageing it appears to be protective, which may relate to "inflamm-aging". These first results should be reproduced in larger trials to confirm this hypothesis.

No MeSH data available.


Related in: MedlinePlus