Single-Nucleotide Polymorphisms in the Interleukin-10 Gene: Differences in Frequencies, Linkage Disequilibrium Patterns, and Haplotypes in Three United States Ethnic Groups

doi:10.1006/geno.2002.6820

Genomics

Volume 80, Issue 2, August 2002, Pages 223-228

https://doi.org/10.1006/geno.2002.6820 Get rights and content

Abstract

Interleukin-10 (IL-10) is a cytokine that seems to function as a downregulator of the innate (nonadaptive) immune system. Approximately three-quarters of interindividual variability in human IL-10 levels has been attributed to genetic variation, and there is evidence suggesting a potential role for IL-10 in a range of human diseases. To provide a basis for haplotype analysis and future disease association studies, we characterized genetic variation in IL10 by sequencing all exons, and 2.5 kb of the 5′- and the 3′-flanking region in a panel of DNA samples from 24 African Americans, 23 European Americans, and 24 Hispanic Americans. The region sequenced was found to contain 28 single-nucleotide polymorphisms (SNPs), 16 with frequency >2% and 14 with frequency >5%. All SNPs with frequency >5% were present in subjects from all three populations. No SNP caused amino acid changes. Differences in pairwise linkage-disequilibrium (LD) patterns and in SNP and haplotype frequency distributions among the three populations may be of potential importance for disease association studies.

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Cited by (66)

IL-10 (−1082 G/A) polymorphism in Bataknese with schizophrenia
2024, Journal of Taibah University Medical Sciences
Interleukin-10 polymorphisms and susceptibility to ARV associated hepatotoxicity
2019, Microbial Pathogenesis
Citation Excerpt :
The IL-10 -1082AA genotype associated with the HIV-1 acquisition and cluster differentiation 4+ (CD4+) T helper cells (Th cells) decline the acceleration rates in late stages of HIV disease [18,19]. Three haplotypes have also been reported in the Caucasian population (−1082/-819/-592), GCC, ACC and ATA [15,18,20–22]. IL-10 promoter polymorphism and its association with HIV progression have been described in different populations worldwide [9,18,19,23–29].
Interleukin-10 (IL-10) is an anti-inflammatory cytokine associated with the inhibition of HIV replication. IL-10 polymorphisms were found to be linked to drug-induced hepatotoxicity. Hence we examined the prevalence of IL-10 (-819C/T,-1082A/G) polymorphisms in a total of 165 HIV patients which included 34 patients with hepatotoxicity, 131 without hepatotoxicity and 155 healthy controls by the PCR-RFLP method. In HIV patients with hepatotoxicity, the IL-10-819TT genotype increased the risk of ARV associated hepatotoxicity severity (OR = 1.61, P = 0.35). IL-10-819TT genotype was overrepresented in patients with hepatotoxicity as compared to healthy controls (26.5% vs. 13.5%, OR = 1.61, P = 0.46). IL-10 -819CT genotype was associated with advance HIV disease stage (OR = 0.49, P = 0.045). In HIV patients without hepatotoxicity, the IL-10-819TT genotype was more prevalent in patients consuming tobacco as compared to non-users (OR = 1.60, P = 0.41). In HIV patients without hepatotoxicity using both alcohol + efavirenz along with IL-10 -819CT genotype resulted in increased risk for the acquisition of ARV associated hepatotoxicity (OR = 4.00, P = 0.36). In multivariate logistic regression, taking nevirapine was associated with the risk hepatotoxicity severity (OR = 0.23, P = 0.005). In conclusion, an insignificant association between IL-10 polymorphisms and susceptibility to ARV associated hepatotoxicity.
Association of interleukin-10 polymorphisms with risk factors of Alzheimer's disease and other dementias (SADEM study)
2016, Immunology Letters
Citation Excerpt :
In another study in Seattle, the IL-10 −1082 and IL-10 −592 allele and genotype frequencies were not significantly different between cases and controls [18]. Furthermore, the genotype distribution of IL-10 polymorphisms resulted as different between Caucasians and Asians [9,19–21]. Also, the risk factors of dementia and these polymorphisms have not been studied; therefore, the purpose of this study was to investigate the associations between vascular risk factors of dementia, such as body mass index (BMI), obesity, dyslipidemia heart disease and cigarette smoke, and the promoter region polymorphisms of IL-10 gene (–1082 A/G, −819 T/C and −592 A/C) in elderly Mexican population.
Some studies have reported a genetic association between single nucleotide polymorphisms (SNPs) in the promoter region of Interleukin (IL) 10 and Alzheimer's disease (AD), with conflicting results. To further investigate the proposed association and to clarify the role of cytokines as a potential cause for AD susceptibility, we analyzed genotypes, allele distributions and haplotypes of IL-10 promoter polymorphisms −1082 (rs1800896) and −819 (rs1800871) in a Mexican population: 986 normal controls and 221 cases divided as follows: 122 with Alzheimer disease (AD), 67 with (VaD) and 32 with mixed dementia (AD/VaD). Patients with dementia showed increased frequency of “ATA, CTG, and CTA” haplotypes when compared to controls. We identified two risk haplotypes: ATA (OR = 3.56, 95%CI = 2.84–4.45, p < 0.0001), and CTA (OR = 1.90, 95%CI = 1.38–2.62, p < 0.0001), and four protection haplotypes: ATG (OR = 0.60, 95%CI = 0.45–0.82, p = 0.0012), CTG (OR = 0.38, 95%CI = 0.23–0.62, p < 0.0001), ACG (OR = 0.01, 95%CI = 0.002–1.13, p <0.0001), and CCG (OR = 0.02, 95%CI = 0.004–0.203, p < 0.0001). In summary, this is the first study in Mexican population that considers the analysis of IL-10 in patients with AD, VaD and AD/VaD. Our results showed the relevance of the role that IL-10 plays in the pathological mechanisms that result in the development of dementia. In addition, in our study, it was possible to distinguish two protective and two risk haplotypes for the development of dementia.
Genetic Factors That Affect Risk of Alcoholic and Nonalcoholic Fatty Liver Disease
2016, Gastroenterology
Genome-wide association studies and candidate gene studies have informed our understanding of factors contributing to the well-recognized interindividual variation in the progression and outcomes of alcoholic liver disease and nonalcoholic fatty liver disease. We discuss the mounting evidence for shared modifiers and common pathophysiological processes that contribute to development of both diseases. We discuss the functions of proteins encoded by risk variants of genes including patatin-like phospholipase domain-containing 3 and transmembrane 6 superfamily member 2, as well as epigenetic factors that contribute to the pathogenesis of alcoholic liver disease and nonalcoholic fatty liver disease. We also discuss important areas of future genetic research and their potential to affect clinical management of patients.
Influence of interleukin 10 polymorphisms -592 and -1082 to the HIV, HBV and HCV serostatus among intravenous drug users
2015, Infection, Genetics and Evolution
Citation Excerpt :
IL-10 promoter proximal region possesses three well investigated genetic polymorphisms -592C/A, -819C/T and -1082G/A. The -592 and -819 are in complete linkage disequilibrium forming three haplotypes seen in Caucasian population (-1082/-819/-592): GCC, ACC and ATA (Eskdale et al., 1999; Lazarus et al., 2002; Shin et al., 2000; Turner et al., 1997; Wang et al., 2004). Several studies have linked these polymorphisms with IL-10 production; -1082G has been associated with higher and -592A with lower IL-10 expression (Crawley et al., 1999; Edwards-Smith et al., 1999; Reuss et al., 2002).
Interleukin 10 (IL-10) is a multifunctional cytokine produced by macrophages, monocytes, and T-helper cells. Two polymorphisms at positions -592 and -1082 have been associated with HIV susceptibility. However, their associations with susceptibility to HIV and its co-infections among intravenous drug users (IDUs) are largely unknown.
A total of 345 IDUs were recruited. Of the 173 HIV negative IDUs, 20 were classified as highly exposed HIV seronegative subjects (HESNs). A control group consisted of 496 blood donors; all HIV, HCV, and HBV negative. The IL-10-592C/A and -1082A/G were determined using TaqMan allelic discrimination assay.
Of the IDUs, 50% were HIV positive, 89% HCV positive, 67% HBV positive and 41% had triple infection. IL-10-592C allele and -1082A allele were the most common and the -1082AG/-592CC was the most common genotype pair. All HESNs exhibited -1082A allele as compared to 81.4% of the HIV positive IDUs and 79% of donors (p = 0.029 and p = 0.019, respectively). None of HESNs had GG/CC genotype pair compared with 18.6% of HIV positive IDUs and 21.0% of donors (p = 0.029 and p = 0.019, respectively). The possession of -592AC and genotype pair AG/AC were associated with the decreased odds of HBV infection (OR = 0.28; 95% CI 0.09–0.87; p = 0.028 and OR = 0.19; 95% CI 0.06–0.61; p = 0.052, respectively).
The presence of low producing IL-10-1082A and -592A alleles and their containing genetic variants protect highly exposed IDUs against acquisition of HIV and HBV infections.
Polymorphisms of interleukin 6 and interleukin 10 in Egyptian people with Behcet's disease
2014, Immunobiology
Citation Excerpt :
Since IL-10 has been demonstrated both in active lesions and sera of BD patients (Ben Ahmed et al. 2004), determining the polymorphisms in IL-10 gene may be beneficial for predicting the disease susceptibility. Up to 75% of interindividual variability in human IL-10 production has been attributed to genetic variation (Lazarus et al. 2002). There are contradictory in the studies which link between IL-10 polymorphism and BD.
Cytokines play critical roles in the pathogenesis of Behçet's disease (BD). They mediated many of the effectors and regulatory functions of immune and inflammatory responses. Many studies have linked Interleukin-6 (IL-6) and Interleukin-10 (IL-10) pathologically to BD. Thus, this study aimed to investigate the associations between IL-6 and IL-10 promoter single-nucleotide polymorphisms (SNPs) and the susceptibility to BD and their implication on plasma levels. We genotyped IL-6 −174 G/C (rs1800795) using Mutagenically Separated Polymerase Chain Reaction PCR (MS-PCR) and IL-10 −1082 G/A (rs1800896) and −819 C/T (rs1800871) using Sequence Specific Primer PCR (SSP-PCR) in 87 Egyptian patients and 97 controls. The plasma levels of IL-6 and IL-10 were measured using Enzyme-linked Immunosorbent Assay (ELISA). Significant increase in the frequency of −1082 GG genotype (P < 0.05, OR = 2.25, 95%CI = 1.03–4.91) and significant decrease in the frequency of −1082 GA genotype (P < 0.05, OR = 0.53, 95%CI = 0.29–0.96) was demonstrated in BD patients compare to controls. Patients with genital ulcer had significantly lower frequency of −1082 GG (P < 0.05, OR 0.2, 95% CI = 0.04–0.99) and G allele (P < 0.05, OR = 0.28, 95%CI = 0.08–0.93), while patients with ocular manifestations had significantly higher frequency of −1082 G allele (P < 0.01, OR = 2.28, 95%CI = 1.19–4.36). BD patients had significantly higher level of IL-6 (P < 0.001) and significantly lower level of IL-10 (P < 0.001) compared to controls. The changes in the level of cytokines were independent of any genotype of IL-6 or any genotype/haplotype of IL-10. Patients with active disease state had significantly higher level of IL-6 compared to patients in remission (P < 0.05). In conclusion, our preliminary study indicates that the polymorphism at IL-10 −1082 G/A may play a role in BD susceptibility. The significant increase in IL-6 level and the significant decrease in IL-10 level in BD patients were independent of any particular genotype in IL-6 or any particular genotype/haplotype in IL-10.

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Regular ArticleSingle-Nucleotide Polymorphisms in the Interleukin-10 Gene: Differences in Frequencies, Linkage Disequilibrium Patterns, and Haplotypes in Three United States Ethnic Groups

Abstract

Section snippets

Supplementary Files

Lancet

Lancet

Am. J. Hum. Genet.

Am. J. Hum. Genet.

Interleukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes

J. Exp. Med.

Mapping of the human IL10 gene and further characterization of the 5′ flanking sequence

Immunogenetics

Interleukin-10 regulation in normal and asthmatic subjects

J. Allergy Clin. Immun.

Interleukin 10. The missing link in asthma regulation?

Am. J. Resp. Cell. Mol. Biol.

Novel single nucleotide polymorphisms in the dstal IL-10 promoter affect IL-10 production and enhance the risk of systemic lupus erythematosus

J. Immunol.

IL10.G microsatellites mark promoter haplotypes associated with protection against the development of reactive arthritis in Finnish patients

Arthritis Rheum.

Linkage disequilibrium in the human genome

Nature

Characterization of single nucleotide polymorphisms in coding regions of human genes

Nat. Genet.

Regular Article
Single-Nucleotide Polymorphisms in the Interleukin-10 Gene: Differences in Frequencies, Linkage Disequilibrium Patterns, and Haplotypes in Three United States Ethnic Groups