Novel IL-6 haplotypes and disease association

Fife, M; Ogilvie, Emma; Kelberman, Daniel; Samuel, JM; Gutiérrez, Ana; Humphries, Steve E.; Woo, Patricia

doi:10.1038/sj.gene.6364186

Cited by 53 publications

(39 citation statements)

References 21 publications

(25 reference statements)

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“…The inconsistency may reflect the disease-specific, tissue-specific and/ or environment-specific regulation of IL-6 expression. In addition, a recent study has suggested that the promoter haplotypes involving two other SNPs, -1363G/T and -1489CTdel affect the risk of systemic onset juvenile arthritis and these two polymorphisms, primarily -1363G/T, may further differentiate the effect of -174C/G although the functionality of these two SNPs remains to be determined (39). However, our data do not support the functional importance of the -1363G/T regarding the association with plasma IL-6 concentrations and lipid parameters.…”

Section: Discussionmentioning

confidence: 99%

The effect of IL6-174C/G polymorphism on postprandial triglyceride metabolism in the GOLDN study*

Shen

Arnett

Pérez-Martínez

et al. 2008

Journal of Lipid Research

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Chronically elevated interleukin-6 (IL-6) affects lipid and lipoprotein metabolism. Individuals genetically predisposed to higher IL-6 secretion may be at risk of dyslipidemia, especially during the postprandial phase. We investigated the effect of genetic variants at the IL6 locus on postprandial lipemia in US Whites participating in the Genetics of Lipid Lowering Drugs and Diet Network study. Subjects were given a single fat load composed of 3% of calories as protein, 14% as carbohydrate, and 83% as fat. Blood was drawn at 0 h, 3.5 h, and 6 h to determine plasma triglyceride (TG), TG-rich lipoprotein (TRL) and lipoprotein particle size. Homozygotes (GG) and heterozygotes (CG) of the -174C/G variant displayed higher plasma IL-6 concentrations compared with major allele homozygotes (CC) (P 5 0.029). GG and CG subjects showed higher fasting plasma TG (P 5 0.025), VLDL (P 5 0.04), and large VLDL (P 5 0.02) concentrations than did CC subjects. Moreover, GG and CG subjects experienced greater postprandial response of TG (P 5 0.006) and TRL, including chylomicrons (P 5 0.005), total VLDL (P 5 0.029), and large VLDL (P 5 0.017) than did CC subjects. These results suggest that the functional polymorphism -174C.G at the IL6 locus determines the difference in both fasting and postprandial TG metabolism. This phenomenon could be responsible for the observed association of this genetic variant with cardiovascular disease

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Section: Discussionmentioning

confidence: 99%

The effect of IL6-174C/G polymorphism on postprandial triglyceride metabolism in the GOLDN study*

Shen

Arnett

Pérez-Martínez

et al. 2008

Journal of Lipid Research

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“…The Ϫ572GϾC SNP has also been associated with the plasma IL-6 concentration, with the rare C allele associated with higher IL-6 concentrations (15 ). A recent study also evaluated 2 other promoter variants, Ϫ1363GϾT and Ϫ1480CTdel, and although these variants were not shown to be functional, they did form a haplotype with the other promoter polymorphisms that showed an increased association with systemic-onset juvenile arthritis (16 ). This finding suggests the presence of functional polymorphisms at this locus that influence IL-6 concentration but that have yet to be identified.…”

confidence: 99%

Association of Serum Interleukin-6 Concentration with a Functional IL6 −6331T>C Polymorphism

et al. 2008

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Background: Interleukin-6 (IL-6) concentrations vary substantially among individuals. This study aimed to identify novel genetic markers to explain these differences. Methods: We sequenced a region 6-kb upstream of the IL6 [interleukin 6 (interferon, beta 2)] transcription start site in a search for functional variants and detected 3 common variants: −6331T>C, −6101A>T, and −5617/−5616C/A>T/G. IL6 −6331T>C (C allele frequency, 0.20; 95% confidence interval, 0.16–0.24) showed strong negative linkage disequilibrium with −174G>C (D′ = −0.97) and was studied further in 309 individuals who underwent coronary artery bypass grafting. Results: Patients with the TT genotype had higher IL-6 concentrations 6 h after surgery than those with the CC genotype (mean, 199.4 ng/L vs 114.9 ng/L; P = 0.02). A similar association was seen in a cohort of 173 patients who underwent intensive periodontal therapy: Individuals with the CC genotype had significantly lower IL-6 concentrations 24 h after therapy than TT patients (mean, 0.78 ng/L vs 5.00 ng/L; P < 0.0001). A similar trend was observed in 203 healthy individuals from northern Europe (1.29 ng/L for the TT genotype vs 0.89 ng/L for the CC genotype; P = 0.07). Reporter assays that used a sequence flanking the −6331 single-nucleotide polymorphism spliced upstream to the IL-6 minimal promoter driving luciferase gene expression demonstrated a 1.3-fold increase in promoter activity (P < 0.01) for constructs containing −6331T. Electrophoretic mobility shift assays revealed enhanced binding of transcription factor Oct-1 to the T allele. Conclusions: IL6 −6331T is associated with increased IL-6 concentrations in an acute inflammatory state via a mechanism involving binding of the Oct-1 transcription factor. This finding may help resolve conflicting studies based on the IL6 −174G>C variant.

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“…A similar result has been shown in the study of Bennermo et al [9] , where healthy individuals homozygous for the G allele had a higher IL-6 response to vaccination with S. typhii as compared to individuals homozygous for the C allele. In addition to the above, there are four recently described SNP-s, -9316 T/C (rs1546762) obtained by searching the HapMap database [10] , -1363 G/T (associated with systemic onset juvenile arthritis [11] ), and +1753 C/G and +2954 G/C (incorporated into haplotypes associated with mortality in critically ill patients [12] ) also in the promoter and coding regions of IL-6. Not only the -174 polymorphism but also haplotypes may associate with the expression of IL-6.…”

Section: Cruited and Genotyped For Il-6 -174(g ] C) -9316(t ] C) -1mentioning

confidence: 99%

Associations between Interleukin-6 Genetic Polymorphisms and Levels of Autoantibodies to 60-kDa Heat-Shock Proteins

Kiszel

Füst²,

Hurme³

et al. 2006

Hum Hered

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Aims: Previously we reported an association between levels of anti-Hsp60 autoantibodies and interleukin-6 (IL-6) –174 SNP in Finnish population. The aim of this study was to investigate the same association in an independent population and to study four recently described SNP in IL-6. Materials and Methods: 313 healthy Hungarian subjects were recruited and genotyped for IL-6 –174(G→C), –9316(T→C), –1363(G→T), +1753(C→G), +2954(G→C). IgG antibodies to Hsp60 were measured by ELISA. LD between SNPs was computed by Haploview 3.2 software. Results: A strong association between IL-6 –174 polymorphism and anti-Hsp60 autoantibody levels was observed. Carriers of –174 CC genotype had significantly lower levels of anti-Hsp60 (p = 0.0052). Eight haplotypes were observed with five SNP-s and autoantibody levels in individuals carrying the most common haplotype (containing allele C of –174) were significantly lower than in all other genotype combinations (p = 0.026). Conclusions: Allele C of –174 promoter polymorphism of the IL-6 gene was repeatedly shown to be associated with low anti-Hsp60 autoantibody levels. Strong linkage in the IL-6 gene was observed and the most frequent haplotype containing the –174 C allele was significantly associated with autoantibody levels. Since the –174 SNP of IL-6 is a functional polymorphism, our results indicate for a direct regulatory effect of IL-6 genotypes in the determination of autoantibody levels.

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Novel IL-6 haplotypes and disease association

Cited by 53 publications

References 21 publications

The effect of IL6-174C/G polymorphism on postprandial triglyceride metabolism in the GOLDN study*

The effect of IL6-174C/G polymorphism on postprandial triglyceride metabolism in the GOLDN study*

Association of Serum Interleukin-6 Concentration with a Functional IL6 −6331T>C Polymorphism

Associations between Interleukin-6 Genetic Polymorphisms and Levels of Autoantibodies to 60-kDa Heat-Shock Proteins

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Novel IL-6 haplotypes and disease association

Cited by 53 publications

References 21 publications

The effect of IL6-174C/G polymorphism on postprandial triglyceride metabolism in the GOLDN study*

The effect of IL6-174C/G polymorphism on postprandial triglyceride metabolism in the GOLDN study*

Association of Serum Interleukin-6 Concentration with a Functional IL6 −6331T&gt;C Polymorphism

Associations between Interleukin-6 Genetic Polymorphisms and Levels of Autoantibodies to 60-kDa Heat-Shock Proteins

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Association of Serum Interleukin-6 Concentration with a Functional IL6 −6331T>C Polymorphism