Association tests with systemic lupus erythematosus (SLE) of IL10 markers indicate a direct involvement of a CA repeat in the 5′ regulatory region

Abstract

Many lines of evidence suggest that IL10 is a strong candidate gene for systemic lupus erythematosus (SLE) susceptibility. In our previously reported study an allele (IL10.G-140bp) of the microsatellite IL10.G located at position À1100 was significantly increased in Italian SLE patients in comparison with controls. Starting from this observation, we tested if sequence variations in the vicinity of IL10.G were more strongly associated with SLE. We performed a comprehensive association study including 26 SNPs (of which four were newly identified in the present study by DHPLC analysis) spanning 8.5 Kb of the 5 0 flanking and the transcribed region of the IL10 gene. The association study was performed by the DNA pool method on an extended panel of Italian patients (205) and controls (631). Haplotypic associations were studied by individual typing of seven selected markers surrounding IL10.G. Gene, genotype and haplotype frequencies were not significantly different in patients and controls. Thus the IL10.G microsatellite remains to date the only IL10 marker associated with SLE in our population. A meta-analysis of all published results indicates a possible direct role of the IL10.G repeat number in SLE susceptibiliy.

Association of interleukin-10 promoter polymorphisms with systemic lupus erythematosus

“…As described previously, 46 we divided all these 15 alleles into two subgroups: 'long allele' and 'short allele' as defined by long allele with CA repeat number greater than 21 (IL10G.9) and short allele with CA repeat number equal to or smaller than 21 (IL10G.9), because IL10G.9 has the median number of repeats and it is the most dominant allele (around 50% in both SLE patients and controls). In further genetic analysis, the frequency distribution of ht1 genotype together with the short and long alleles was significantly different between patients and controls (overall w 2 test, P ¼ 0.01) ( Table 6).…”

“…27 Although the association of À592CC with SLE susceptibility was clearly stated in this study, no association of À592 allele or genotype were reported previously. 36,37,46,44 This may be due to the difference in allele frequencies of IL-10 promoter SNPs in different ethnic groups. For example, À592C is the rare allele in Hong Kong Chinese (29.4% in our study) but is the common allele in Western population (B70%).…”

“…However, they could only report a marginal association, 36 and association to several clinical features but not directly to the disease; 37,44 only the microsatellite, IL10.G, showed a consistent significant association with SLE in various populations. 46,[47][48][49] As discussed elsewhere, 50,51 a large sample size should be used in association study to maintain statistical power to detect a significant association. Here, we have recruited over 1000 subjects (554 SLE patients and 708 healthy controls) and demonstrated the significant association between SLE and IL-10 promoter genotypes.…”

A sequence variation in the MOG gene is involved in multiple sclerosis susceptibility in Italy

“…51 The temperature required for successful resolution of heteroduplex molecules was determined using a specific program (website http://insertion. stanford.edu/melt.html).…”

Looking back and looking forward

“…These include a manuscript providing the strongest evidence to date for a type I diabetes gene in the IgH region of human chromosome 14, 6 the association of a functional promoter polymorphism in the MIF gene with RA severity, 7 an IL-10 regulatory region dinucleotide repeat with systemic lupus erythematosus (SLE), 8 IL-1B and IL-6 polymorphisms with development of recurrent aphthous stomatitis, 9 IL-11 polymorphism with ulcerative colitis 10 and IL-1ra in both ulcerative colitis and Crohn's disease. 11 Other association studies have examined candidate genes that may modify the host response to infectious agents.…”