Polymorphisms of Th1–Th2 cytokine genes have previously been implicated in the rate of progression to AIDS in seropositive patients. To evaluate further the impact of these genes in the development of AIDS, we have performed an extensive genetic analysis of IL2, IL4, IL6, IL10, IL12p35 and p40, IL13 and IFNγ. The coding regions and promoters of these genes were sequenced in a Caucasian cohort of 337 HIV-1 seropositive extreme patients (the GRIV cohort) consisting of patients with slow progression and rapid progression, and up to 470 healthy controls. In all, 64 single nucleotide polymorphisms (SNPs) and four deleterious polymorphisms with frequency >1% were identified and evaluated for their association with disease. Statistically significant associations were observed with haplotypes of the IL4 and IL10 genes, but no relation was found with variants of other genes. The catalogue of SNP and haplotypes presented here will facilitate further genetic investigations of Th1–Th2 cytokines in AIDS and other immune-related disorders.
Cytokines have a vital role within the immune system, and cytokine genes have been targeted for studies for association to susceptibility and development of several immune-related diseases.1,2,4,5,6,7,8,9 Such genetic investigations can provide key information on both the function of such genes in the immune system and the molecular etiology of the diseases in question, and they are expected to lead to the development of new therapies and diagnostic tools.3
Th1–Th2 cytokines are of particular interest as targets for genetic studies since they are the fundamental messengers of adaptive immunity and, as such, are likely to be involved in pathogenic mechanisms. In the case of AIDS, although many hypotheses have been presented to explain the molecular mechanisms leading to CD4 cell depletion,10,11,12,13,14,15 the most conclusive and reproducible observations implicate Th1–Th2 cytokines, for example through the so-called Th1/Th2 shift15 and the great fragility of the cells leading to their apoptosis.13 Thus, genetic studies of Th1–Th2 cytokines are of particular relevance in this disease. Although to date, most genetic studies in AIDS have focused on the chemokine/chemokine receptor system and HLA,16,17 promoter polymorphisms in a limited number of Th1–Th2 cytokine genes have been examined for association with the disease,18,19,20 some of which have been correlated to the level of production of cytokine.21 In particular, IL10 and IL4 variants have been reported to be associated with disease progression to AIDS.18,19 These studies underscore the possible involvement of Th1–Th2 cytokines in the development of the disease, and the interest of a complete and systematic exploration of these other Th1–Th2 cytokine genes in AIDS. In regard to the IL10 and IL4 variants that have been implicated in disease progression, an important next step is to seek confirmation in independent cohorts, as such confirmation is a key element in the validation of genetic association.
Studies of the relation between disease progression in AIDS and genetic variants have largely used cohorts of seropositive patients analyzed with respect to their progression to disease.22 In the present study, we have taken an alternative approach based on the comparison between patient groups having extreme patterns of disease progression. We identified a group of 253 seropositive patients with slow progression (SP) of the disease, which represents a 1% subset of patients with extreme phenotypes among a cohort of 25 000 patients at all stages of disease and a group of 84 patients with rapid progression (RP). This cohort, called GRIV (genetics of resistance to immunodeficiency virus), is the largest of its kind in the world and its usefulness has been validated in studies of other genes including CCR5 and HLA.23,24,25 We have performed a systematic genetic study of eight Th1–Th2 cytokine genes, IL2, IL4, IL6, IL10, IL12 p35 and p40, IL13 and IFNγ, by extensive nucleotide sequencing of a group of up to 807 Caucasian individuals, including the 337 members of the GRIV cohort and 470 Caucasian controls of similar ethnic origin. Single nucleotide polymorphisms (SNPs) and other genetic variants identified in through sequencing were evaluated for their association with disease susceptibility and progression.
We sequenced the exons, flanking regions (up to 1000 base pairs) and promoter regions to detect polymorphisms in IL10, IL4 and the six other cytokine genes included in the study in a group of up to 807 Caucasian subjects (Figure 1). Initially, we included DNA from 154 controls for sequencing, but this was extended to 470 control samples for gene regions that contained polymorphisms showing potential association with progression. Of 205 polymorphisms identified, 68 polymorphisms (64 SNPs and four insertion/deletion polymorphisms) have an allele frequency of 1% or greater in the combined cohorts (Table 1). These include promoter polymorphisms in IL10 and IL4 that were reported in other studies to be associated with progression to AIDS.18,19 A cluster of five SNPs in intron 3 of the IL10 gene that exhibit complete linkage disequilibrium (LD) (TGCCT or AAGGA) in our data have been assigned a single SNP designation (IL10_1801) here (see Figure 1 and Table 2). The polymorphism adjacent to exon 7 designated as IL12p35_11861 is an insertion of multiple nucleotides of either 6 bp (I1: GTGGCA) or 14 bp (I2: IndexTermTTGGATAGGGTTATGCCT) in length that are exclusive to each other.
Overall, we found one polymorphism in every 154 bp and one with a frequency higher than 1% in every 464 bp, in agreement with previous genomic studies (Table 1).41,42 Compared to the other cytokines, IL10 appeared to have a greater number of polymorphisms (one polymorphism with more than 1% frequency in every 246 bp). Table 2 summarizes genotype counts and allele frequencies of each polymorphism in the SP, RP and control groups, their associations with AIDS progression (see below), and the relevant information known to date for each polymorphism. The genotype distributions were compatible with Hardy–Weinberg equilibrium in the SP, RP and control subgroups for all polymorphisms.
Ten of the 64 frequent SNPs were located in exons. Three of these introduce nonsynonymous changes, namely, IL6_348 (Asp to Glu at position 162), IL12p40_12076 (Phe to Val at position 298) and IL13_816 (Glu to Arg at position 130). Two other variants with a synonymous change are IL2_12193, IL6_401 and the other five are located either in the 5′-untranslated region (IL4_12200) or the 3′-untranslated region (IL10_393, IL12p40_12080, 12079 and 12064). For the 58 intronic polymorphisms, comparisons of human and mouse sequences around did not show any specific conservation indicating interspecies functional constraints.
Several SNPs located in promoter regions of the gene studies here have previously been reported to affect the production of cytokines. An extensive study of the IL10 promoter showed that IL10_46 and IL10_226 are in the negative regulatory region of transcription, suggesting their functional involvement in IL10 production.43 IL10_38 is located in the ETS-like recognition site.43 Measures of IL10 expression in vitro, however, are still contradictory, probably because of different protocols or the limited number of samples tested.4,27 The T allele of IL4_549 was shown to be associated with higher production of this cytokine in the Japanese population.21 For the other promoter polymorphisms, the degree of evolutionary conservation was higher than in the intron between mouse and human; however, computer searches failed to localize any to motifs that were recognized as related to transcription. These polymorphisms are candidates for experimental evaluation to elucidate their biological significance.
Linkage disequilibrium and haplotypes
Figure 2 shows pairwise LD measured between each pair of polymorphisms using D and D′ statistics as described in Materials and methods. It should be noted that the maximum value of D depends on the allele frequencies of the polymorphisms involved (which is why the D′ values are also shown). As expected, the majority of high LD values occur within genes. In some instance, a high LD measure was observed between polymorphisms in different genes. Mostly these values are related to a relatively rare variant that is detected on few chromosomes, as these may be associated with variants in other genes by chance. For example, IL10_302, which has a frequency of 0.02 (15 heterozygotes observed in the study cohorts), is in LD (as measured by D′) with polymorphisms in most of the other genes examined. In the case of IL4 and IL13, however, the strong LD that is observed between several polymorphisms in these genes can be attributed to their physical proximity on chromosome 5 (12.8 kb apart).
Haplotype frequencies were estimated for each gene based on an EM algorithm. The results are summarized in Figure 2 for those haplotypes with frequency estimates of 1% or more. The average number of haplotypes per gene with frequencies of >1 or >5% in the control population is 6.3 (range: 3–12) and 4.0 (range: 2–5), respectively. Cumulatively, haplotypes with frequencies of greater than 1% (5%) account for 97% (92%) of the total number of chromosomes tested on average per gene.
SNP and haplotype associations with HIV-1
Allele and haplotype frequencies were compared between SP and RP groups, and between SP, RP and controls using contingency table analysis. Nominal P-values (not adjusted for multiple testing) <0.05 were found for eight SNPs (Table 2). While none of the results were significant after adjustment for testing multiple polymorphisms within the same gene using a permutation test (see Methods), it is of interest that five of these SNPs were found in IL10 and one in IL4. Polymorphisms in these genes have previously been implicated in progression to AIDS.18,19
Haplotype analysis provided further insight into the possible relation between SNPs in these genes and disease (Table 3). Two of the 10 IL10 haplotypes (IL10-H4 and IL10-H10) with estimated frequencies >0.01 were found to have nominal P-values <0.05 in the association tests, but only one of these was significant after the P-values were adjusted for the number of tests (IL10-H10). IL10-H4 is a relatively common haplotype with a higher frequency in the RP group compared to others. The frequency of this haplotype is 0.188 in the RP group, compared to 0.126 in the SP group (relative risk (RR)=1.5; nominal P=0.042) and 0.115 in controls (RR=1.7; nominal P=0.011). As shown in Figure 2, IL10-H4 is the only IL10 haplotype that carries a T allele at the IL10_387 site or an A allele at the IL10_307 site. The second of these haplotypes (IL10-H10) is rare overall, but with a lower frequency in the SP group compared to others: 0.002 in the SP group compared to 0.018 in the RP group (RR=9.0; nominal P=0.05) and 0.023 in controls (RR=11.5; nominal P=0.0013). IL10-H10 is distinguished from other IL10 haplotypes by the presence of an A allele at the IL10_46 site in the promoter region.
Shin et al18 have implicated the less frequent allele at the IL10_226 (A allele) promoter site in acceleration of progression to AIDS. The IL10-H4 haplotype, which is more frequent in the RP compared to SP groups (ie compatible with acceleration of progression), carries the alternative C allele at this site. Overall, we found no correlation in our data between the presence of the A allele at this site and rapid progression. Similarly, the less frequent allele at the IL10_38 site (G allele) is not associated with rapid progression in our data as found by Shin et al18 in their cohorts.
In the IL4 gene, a single haplotype (IL4-H2) exhibited nominally significant different frequencies in the RP compared to the SP cohorts (RR=1.9; nominal P=0.016); the association remained significant after adjustment for the number of tests. The frequency of IL4-H2 in the SP group was similar to that in controls (0.16 vs 0.15), and lower in the RP group (0.09). The comparison of the RP cohort and control cohort frequency gave an RR=1.7 (nominal P=0.05). IL4-H2 is distinguished from the most common haplotype (IL4-H1; frequency >80% in all the groups we studied) at all four polymorphic sites identified in the gene. IL4-H2 carries the T allele at the IL4_549 site consistent with the results of Nakayama et al19, who reported slower progression to AIDS associated with the IL4_549 T allele.
We have undertaken a systematic investigation of the association of genetic variation in eight Th1–Th2 cytokines to susceptibility and disease progression in AIDS. In all, 68 variants of the eight genes that occurred with frequencies of 1% or greater were detected. Although the majority of these reside outside of exons, promoters or other regions that are known to have biological function, all were considered as possible candidates for association with AIDS, as genetic studies have previously identified polymorphisms with no predicted biological effects. Significant associations were observed only with haplotypes of the IL4 and IL10 genes. Although these associations were weak, we considered them to be of particular interest because polymorphisms of these genes have previously been implicated in progression to AIDS.
Our data were compatible with the reported association of IL4_549 T allele with slower progression to AIDS. The two IL10 promoter variants, IL10_226 and IL10_38, which are reported to be correlated with rate of disease progression elsewhere,18 had statistically similar genotype frequencies in controls and the two disease groups in our study. However, we did find some evidence of possible association of disease progression with other IL10 sites. One of the IL10 haplotypes that we identified as possibly associated with progression (nominally significant P-value < 0.05) is the unique haplotype carrying the IL10_387 T and the IL10_307 A variants. Although neither of these sites is predicted to have a functional effect, it is possible that one or both variants have biological consequences that are as yet unknown. The second IL10 haplotype, for which the association remained significant after adjustment for the number of tests, is the unique haplotype carrying the IL10_46 A variant. This site is in the IL10 5′ promoter region.
The experimental GRIV groups have been voluntarily chosen with extreme patterns of progression in order to unravel differences in their genetic distributions, correlating with their phenotypes. Hence, the study design applied here involves the comparison of two extreme cohorts of patients and controls, whereas previous investigations implicating IL4 and IL10 were based on longitudinal follow-up of patients. In general, variants that affect risk or speed of developing AIDS should be detectable with either study design. For example, the CCR5-delta32 variant, which has a major protective effect on progression to AIDS in longitudinal studies,44 gives an RR of 6.3 and a nominal P-value 0.0001 for comparison of the allele frequencies in the SP and RP groups from GRIV based on data presented elsewhere.23 For a marker such as the IL10_226 A variant, previously reported to be associated with decreased risk of progression as described above, the GRIV study provides a power of 75% to detect an RR of approximately 0.6 in SP compared to controls at a significance level of 0.05, assuming an allele frequency of 0.28 in controls as observed here (implying an allele frequency of 0.19 in SP).
Our data provide some additional evidence for the possible involvement of two Th2 cytokines, IL10 and IL4. IL4 is reported to regulate differentially the expression of CCR5 and CXCR4 and to stimulate the expression of HIV-1, which leads to accelerated disease progression.45 In vitro studies demonstrated the suppressive role of IL10 against HIV production either by direct inhibition of viral replication46 or through suppression of the autocrine production of TNFα and IL6 that enhance HIV replication.47 More importantly, an in vivo study showed the inhibitory effect of IL10 on acute HIV infection.48 In the light of our observations and the previously published reports implicating these genes in progression to AIDS,18,19 further studies in other cohorts to clarify the possible pathogenic role of IL10 and IL4 variants (IL4_H2 and IL10_H10) are now seen to be imperative. The data that we have catalogued on polymorphisms, LD and haplotype patterns in the Th1–Th2 cytokine genes studied here can serve for these investigations in AIDS, and also in other immune-related disorders.
Materials and methods
GRIV patients and control subjects
The GRIV cohort was established in 1995 in France to generate a large collection of DNAs for studies on genetic variations associated with rapid and slow progression of AIDS.25 To avoid the confounding effects associated with racial/ethnic differences in the genetic analyses, only Caucasians of European descent living in France were recruited. This criterion limits the influence of the virogenetic and environmental factors (subjects are all infected by B strains and live in a similar environment) and puts emphasis on the genetic make-up of each individual to determine the various patterns of progression. Patients with SP were defined as asymptomatic individuals seropositive for 8 or more years with a CD4 cell count above 500/mm3 in the absence of antiretroviral therapy. A seropositive test dating more than 8 years was necessary for inclusion in the study. Patients with RP show a drop in their CD4 cell count below 300/mm3 in less than 3 years after the last seronegative test. All patients enrolled in the study signed an informed consent. The DNA was obtained from fresh peripheral blood mononuclear cells or from EBV-transformed cell lines. The control series consisted of 470 French Caucasians from the EGEA study, ascertained without respect to disease status or seropositivity.
For each gene, primers were established in order to amplify by PCR the exon-containing DNA fragments and the promoters. The PCRs were performed in a 15 μl reaction mixture containing 25 ng of DNA. The list of the primers for each gene is available on the web site of the CNG (http://www.cng.fr). Sequencing reactions were performed according to the dye terminator method using an ABI PRISM® 3700 DNA Analyzer (Applied Biosystems, Foster City, CA, USA). Alignment of experimental results, SNP discovery and genotyping were performed with the software Genalys, developed by the CNG.49 Detailed information of all the SNPs including those with a frequency of less than 1% is also available from the CNG web site. The genomic sequences used for the alignment are IL2 (NT_022960.5), IL4 (NT_007072.7), IL6 (NT_025766.6), IL10 (NT_029217.3), IL12p35 (NT_005818.7), IL12p40 (NT_007006.7), IL13 (NT_007072.9) and IFNγ (NT_029419.2).
LD estimates between pairs of polymorphisms within genes were obtained by estimating the two polymorphism haplotype frequencies using the EM algorithm.50 Haplotype frequencies using all polymorphisms for each gene were also estimated with the EM algorithm. Differences in the allele frequencies of individual polymorphisms between the three groups and between the SP and RP groups were examined using a Fisher's exact test on the resulting 2 × 3 and 2 × 2 table of counts. The nominal P-values were adjusted for the number of polymorphisms within each gene by a permutation test preserving the observed LD between the markers. For this, 100 000 replicates were produced by randomly permuting the group labels. Fisher's exact test was performed on all polymorphisms as in the original analysis, and the corrected significance was estimated from the proportion of replicates giving a minimum P-value at one site equal to or lower than the observed P-value. Differences between haplotype frequencies were examined in an analogous way to that used for the individual polymorphisms. For each haplotype (with frequency >1%) in turn, the expected numbers of individuals in each group with and without that haplotype were computed from the estimated marginal haplotype probability distribution for each individual. These numbers were rounded to the nearest integer, and a nominal P-value was computed using Fisher's exact test. Corrected P-values were obtained using a permutation test in the same way as for the individual polymorphism analysis. Computation of D and D′ in Figure 2: let f, p, and q be the frequency of the ab haplotype, the a allele at locus 1, and the b allele at locus 2 respectively. The standard disequilibrium measure D is given by f-q *q. This measure is highly dependent on the allele frequencies, so we also calculated the standardized disequilibrium measure, D′, which ranges from 0 (no disequilibrium) to 1 (the highest amount of disequilibrium given the alleles frequencies).
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We are grateful to all the patients and all the medical staff who have generously collaborated with the GRIV project. We also thank the EGEA cooperative group for having given access to data on the EGEA (Epidemiological study on the Genetics and Environment of Asthma) study, which was partly supported by an INSERM/MSD convention. The GRIV project is supported by grants from ANRS (Agence Nationale de Recherche sur le SIDA) and ACV (AIDS-Cancer Vaccine Development Foundation). The CNG is supported by the Ministere de la Recherche et des Nouvelles Technologies.
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Vasilescu, A., Heath, S., Ivanova, R. et al. Genomic analysis of Th1–Th2 cytokine genes in an AIDS cohort: identification of IL4 and IL10 haplotypes associated with the disease progression. Genes Immun 4, 441–449 (2003) doi:10.1038/sj.gene.6363983
- Th1–Th2 cytokines
- AIDS progression
- single nucleotide polymorphism
- GRIV cohort
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