Fishman et al. (1998) identified a polymorphism in the 5-prime region of the IL6 gene; at position -174, the frequency of an allele carrying C at this position was approximately 40% and the frequency of an allele carrying a G was approximately 60% in healthy individuals. In 92 patients with systemic-onset juvenile rheumatoid arthritis (604302), the statistically lower frequency of the GC genotype was found. Fishman et al. (1998) demonstrated lower expression of a construct containing the -174C change than was found with the 174G construct. Furthermore, expression from the -174C construct did not change after stimulation by LPS or IL1, whereas increases were observed with -174G. A reduced frequency of the potentially protective CC genotype in young patients with systemic onset juvenile rheumatoid arthritis was thought to contribute to its pathogenesis.
Foster et al. (2000) found a strong association between this IL6 promoter polymorphism and susceptibility to Kaposi sarcoma (148000) in HIV-infected men. Homozygotes for IL6 allele G, associated with increased IL6 production, were overrepresented among patients with Kaposi sarcoma, whereas allele C homozygotes were underrepresented.
Fernandez-Real et al. (2000) studied if the IL6 gene polymorphism leads to differences in fasting and postglucose load plasma lipids in healthy subjects. Subjects with G at position -174 of the IL6 gene were similar in age, sex, body mass index (BMI), and waist-to-hip ratio in comparison with carriers of the C allele. However, G carriers showed almost twice plasma triglycerides, very low density lipoprotein (VLDL) triglycerides, higher fasting and postglucose load free fatty acids, slightly lower high density lipoprotein (HDL)-2 cholesterol, and similar cholesterol and LDL cholesterol levels than carriers of the C allele. Serum IL6 levels correlated positively with fasting triglycerides, VLDL triglycerides, and postload free fatty acids and negatively with HDL cholesterol. The authors concluded that subjects with the G allele, associated with higher IL6 secretion, are prone to lipid abnormalities.
To evaluate whether genetic variability in the IL6 gene is associated with hyperandrogenism, Villuendas et al. (2002) studied 4 common polymorphisms in the IL6 promoter, including -597G-A (147620.0002) and -174G-C, in 85 hyperandrogenic patients and 25 healthy women. The -597G-A and -174G-C polymorphisms were in linkage disequilibrium and were associated with patient or control status. The -597G and -174G alleles were more frequent in patients either considering subjects homozygous for G alleles separately, or considering subjects homozygous and heterozygous for G alleles as a whole. In healthy women, G alleles at -597 and -174 were associated with statistically significant higher circulating levels of IL6 and basal cortisol, 11-deoxycortisol, and 17-hydroxyprogesterone, and a tendency for higher total T concentrations compared with -597A and -174C alleles. The authors concluded that the -597G-A and -174G-C polymorphisms in IL6 are involved in the pathogenesis of hyperandrogenic disorders.
Ferrari et al. (2003) studied 2 allelic variants in the IL6 promoter, -572 and -174 G-C, that alone and in combination influence IL6 activity in vitro and in vivo. The association of IL6 -572 genotypes and -572/-174 G-G haplotypes with serum C-reactive protein (CRP; 123260), serum and urinary C-terminal cross-linking of type I collagen (see 120150), a marker of bone resorption, and osteocalcin (112260), a marker of bone formation, was investigated in a cohort of healthy postmenopausal women. Among IL6 -572 genotypes, CRP was 37% higher and urinary C-terminal cross-linking of type I collagen was 20% higher in the presence of the C allele, whereas serum osteocalcin was not different. IL6 -572/-174 haplotypes (G/C, G/G, and C/G) were significantly associated with all biochemical markers, and additive effects of the 2 polymorphic loci were found. In addition, there was a trend for lower age-adjusted bone mineral density at the lumbar spine in subjects with fewer IL6 protective alleles.
Kristiansen et al. (2003) genotyped 1,129 individuals from 253 Danish families with type 1 dependent diabetes mellitus (T1D, IDDM; 222100) at the IL6 -174G/C SNP. Gender-conditioned transmission disequilibrium test (TDT) analyses revealed that linkage and association with IDDM were present in females exclusively (p = 0.00065 and p = 0.00024, respectively). Heterogeneity analyses (IDDM vs non-IDDM females) excluded preferential meiotic segregation in females and demonstrated differences in the transmission patterns between female and male IDDM offspring. The -174CC genotype was associated with younger age at onset of IDDM in females (p = 0.002). The impact of 17-beta-estradiol (E2) on the -174G/C variants was investigated by reporter studies. The PMA-stimulated activity of the IDDM risk variant (-174C) exceeded that of the IDDM protective variant (-174G) by approximately 70% in the absence of E2, but not with E2 present. The PMA-stimulated activity of the -174G variant was repressed without E2 present, but was derepressed by addition of E2. In contrast, the PMA-stimulated -174C activity was unaffected by E2, as were the constitutive activities of the -174G/C variants. Kristiansen et al. (2003) concluded that higher IL6 promoter activity may confer risk to IDDM in very young females and that this risk may be negated with increasing age, possibly by the increasing E2 levels in puberty.
Mohlig et al. (2004) investigated the -174C-G polymorphism and development of type 2 diabetes mellitus (T2D, NIDDM; 125853). They found that this polymorphism modified the correlation between BMI and IL6 by showing a much stronger increase of IL6 at increased BMI for CC genotypes compared with GG genotypes. The -174C-G polymorphism was found to be an effect modifier for the impact of BMI regarding NIDDM. The authors concluded that obese individuals with BMI greater than or equal to 28 kg/m2 carrying the CC genotype showed a more than 5-fold increased risk of developing NIDDM compared with the remaining genotypes and, hence, might profit most from weight reduction.
Illig et al. (2004) investigated the association of the IL6 SNPs -174C-G and -598a-G on parameters of type 2 diabetes and the metabolic syndrome in 704 elderly participants of the Kooperative Gesundheitsforschung im Raum Augsburg/Cooperative Research in the Region of Augsburg (KORA) Survey 2000. They found no significant associations, although both SNPs exhibited a positive trend towards association with type 2 diabetes. Illig et al. (2004) also found that circulating IL6 levels were not associated with the IL6 polymorphisms; however, significantly elevated levels of the chemokine monocyte chemoattractant protein-1 (MCP1; 158105)/CC chemokine ligand-2 (CKR2; 601267) in carriers of the protective genotypes suggested an indirect effect of these SNPs on the innate immune system.
Obesity represents an expansion of adipose tissue mass and is closely related to insulin resistance and cardiovascular disease. IL6 is one of several hormonal signals that originate from adipose tissue; adipose tissue accounts for one-third of the circulating levels of IL6. Berthier et al. (2003) studied the association between the -174G/C polymorphism of IL6 and indices of obesity in French Canadian men. The -174G/G homozygotes presented the lowest waist circumference (P less than 0.05).
In a study of 2,255 healthy women and 980 healthy men, as well as in a metaanalysis of 26,944 individuals, Qi et al. (2007) did not find evidence of a substantial relation between the -174G-C polymorphism and adiposity.
Crohn disease (see IBD1, 266600) inhibits growth in up to one-third of affected children. Because IL6 is elevated in Crohn disease, Sawczenko et al. (2005) hypothesized that growth failure would vary with IL6 -174 genotype. They found that English and Swedish children with Crohn disease and the -174 GG genotype were more growth retarded at diagnosis and had higher levels of the IL6-induced inflammatory marker C-reactive protein (CRP; 123260) than children with GC or CC genotypes. After corticosteroid or enteral feeding treatment, CRP levels decreased significantly and became comparable to those in children with GC or CC genotypes. Sawczenko et al. (2005) concluded that IL6 -174 genotype mediates growth failure in Crohn disease.
Among 180 patients with brain arteriovenous malformations (BAVM; 108010), Pawlikowska et al. (2004) found an association between homozygosity for the IL6 -174G allele and greater risk of intracranial hemorrhage compared to carriers of the C allele (odds ratio of 2.62). In brain tissue from patients with BAVM, Chen et al. (2006) found that the highest IL6 protein and mRNA levels were associated with the IL6 -174GG genotype compared to the GC and CC genotypes. IL6 protein levels were increased in BAVM tissue from patients with hemorrhagic presentation compared to those without hemorrhage. In vivo studies demonstrated that IL6 enhanced expression and activity of IL1B (147720), TNFA (191160), IL8 (146930), and several matrix metalloproteinases, MMP3 (185250), MMP9 (120361), and MMP12 (601046). IL6 also increased proliferation and migration of cultured human cerebral endothelial cells. Chen et al. (2006) suggested that IL6 expression may modulate downstream inflammatory and angiogenic targets that contribute to intracranial hemorrhage in BAVMs.
