IL10 Promoter Polymorphisms and Automimmune Disease

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Genome wide scans have shown linkage of disease susceptibility to the region on chromosome 1 that encompasses the IL-10 locus. The IL-10 gene has been localized at 1q31-1q32 region, and several genome scans have identified regions ofchromosome 1 (1q21-23, 1q31-32, 1q42-44) which may contain susceptibility loci for SLE and other autoimmune diseases.45-51

Using case-control approaches to look at the distribution of promoter SNP or STRP alleles, several studies have found an association between IL-10 promoter polymorphisms and autoimmune disease susceptibility or disease manifestations (Tables 2 and

Table 1. SNP allele frequencies in different ethnic groups

-3575

-2849

-2776

-2763

-2100

-2013

-1466

-1349

-1082

-819

-592

-429

MT

G/A

A/G

C/A

C/A

G/A

C/T

A/G

A/G

C/T

C/A

G/T

Cauc 0.98A

0.72G

0.95A

0.63C

0.99C

0.97G

1.00C

0.50A

0.49A*

0.79C*

0.79C*

1.00G

0.02T

0.28A

0.05G

0.37A

0.01A

0.03A

0.00T

0.50G

0.51G*

0.21T*

0.21A*

0.00T

Af-Am 0.99A

0.75G

0.88A

0.60C

0.99C

1.00G

0.79C

0.48A

0.46A

0.85G

0.67C

0.77G

0.01T

0.25A

0.12G

0.40A

0.01A

0.00A

0.21T

0.52G

0.54G

0.15T

0.33T

0.13T

Chin -

-

-

-

-

-

-

-

0.94A+

0.33C+

0.33C+

-

-

-

-

-

-

-

-

-

0.06G+

0.67T+

0.67A+

-

Cauc: Caucasians; Af-Am: African Americans; Chin: Chinese. *Data taken from Turner et al, 1997.35 ^ Data taken from Mok et al, 1998.55 All other data taken from Gibson et al, 2001.19

3).19,37,38,41,43,52-65,74 In each autoimmune disease examined, some studies have failed to find associations between promoter polymorphisms and susceptibility or manifestations.37,43,61,63-73 For example, Lazarus et al (1997) have found an association between -1082G, -1082G-containing haplotypes and the presence of anti-Ro autoantibodies and nephritis in Caucasian SLE.53 A study by Crawley et al (1999) also used a Caucasian group, but failed to find a similar association, and Mok et al (1998) have found an association between the ATA haplotype and lupus nephritis in a Chinese population.37,68 Therefore, currently it is not clear which of the 26 identified SNPs, which haplotypes or which STRP alleles are relevant in the disease process. In reviewing these studies several observations are clear: (1) the total number of affecteds that have been studied is small (Table 2); (2) different genetic markers, either SNPs or STRPs, have been screened; (3) different ethnic populations have been used in different studies; and (4) different genotyping techniques have been used, often without delineation of error rates. Since there are clear differences in the allele frequencies in different ethnic and geographic groups, appropriate stratification by ethnicity will be important. In support of this, our group has found an association between the promoter SNP (-2763A/T) in African Americans with SLE 19 but not in a Dutch Caucasian cohort of 98 affecteds compared with 128 controls

Table 2. Association studies of IL-10 polymorphisms and autoimmune disease susceptibility

Disease

Positive Association Reported

No. of Studies (Total Affecteds Studied)

No. Association Identified No. of Studies (Total Affecteds Studied)

SLE

6* (455 Cauc; 200 Af-Am;

3 (180 Cauc; 330 Mex;

230 Mex)19'41'52'53'55'58

88 Chin)37'67'72

RA

1 (251 Cauc; 61 Af-Am) 54

5 (811 Cauc; 138Af-Am) 43'64'66'69'73

MS

2* (463 Cauc) 59'60

2 (366 Cauc)70'71

Psoriasis

2 (352 Cauc)57'62

1 (248 Cau) 63

AS

-

1 (468 Cauc) 61

GBS

1 (87 Cauc) 65

-

*Different IL-10 markers reported as associated with disease susceptibility in each of these studies. Systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), ankylosing spondylitis (AS), Guillian-Barre syndrome (GBS). Cauc: Caucasians; Af-Am: African Americans; Chin: Chinese.

Table 3. Association studies of IL-10 polymorphisms and autoimmune disease manifestations

Positive Association Reported No Association Identified

Disease No. of Studies (Total Affecteds Studied) No. of Studies (Total Affecteds Studied)

SLE 4* (224 Cauc; 88 Chin) 37,52,53,56 2 (300 Cauc) 68'72

Psoriasis 1 (248 Cauc) 63

*Different disease manifestations reported as associated with IL-10 polymorphisms in each of these studies. Systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), ankylosing spondylitis (AS), Guillian-Barre syndrome (GBS). Cauc: Caucasians; Af-Am: African Americans; Chin: Chinese.

(-2763AA = 0.37 in affecteds vs 0.36 in controls; Gibson and Huizinga, unpublished results). Others have failed to find a similar association in an Italian SLE group.41

Variable associations between IL-10 STRP alleles and autoimmune disease have also been documented. In different studies, different IL-10G STRP alleles associated with SLE in a UK Caucasian cohort, an Italian Caucasian cohort and in Mexican Americans, while IL-10R alleles associated with RA in two different UK Caucasian cohorts, and in an African American group.41'52'54'55'58 Data from our group did not show an association between the IL-10R STRP and SLE in three ethnic groups (Caucasians, African Americans or Mexican Americans). However, we found significant association between SLE and IL-10.G8 and IL-10.G9 in Cauca-

Table 4. IL-10G allele frequencies in African American, Caucasian and Mexican American SLE populations

Alleles African Am. Mexican Am. Caucasian Am.

Table 4. IL-10G allele frequencies in African American, Caucasian and Mexican American SLE populations

Alleles African Am. Mexican Am. Caucasian Am.

Size

Eksdale

Mehrian

NL

SLE

NL

SLE

NL

SLE

(bp)

(1995)

(1998)

(2n = 192

2n = 184

2n = 88

2n = 144

2n = 206

2n = 132)

192

IL10G-3

11S

0.00S

0.000

0.000

0.000

0.000

0.000

194

IL10G-4

117

0.00S

0.011

0.000

0.000

0.000

0.000

196

IL10G-S

119

0.00S

0.000

0.000

0.000

0.000

0.000

198

IL10G-6

121

0.00S

0.043

0.023

0.017

0.019

0.023

200

IL10G-7

123

0.042

0.022

0.068

0.076

0.034

0.023

202

IL10G-8

125

a 0.177

0.283

0.2S0

0.306 b

0.165

0.311

204

IL10G-9

127

a 0.260

0.152

0.091

0.069 b

0.296

0.083

206

IL10G-10

129

0.1S6

0.239

0.136

0.097

0.073

0.114

208

IL10G-11

131

b0.198

0.082

0.091

0.083

0.073

0.114

210

IL10G-12

133

0.047

0.109

0.2S0

0.174

0.146

0.220

212

IL10G-13

13S

0.063

0.043

0.023

0.132

0.126

0.083

214

IL10G-14

137

0.036

0.016

0.068

0.042

0.068

0.023

216

IL10G-1S

139

0.00S

0.000

0.000

0.014

0.000

0.008

Different allele nomenclatures are shown for comparison. a p < 0.02; b p < 0.002

Different allele nomenclatures are shown for comparison. a p < 0.02; b p < 0.002

sians, and IL-10.G8, IL-10.G9 and IL-10.G11 in African Americans (Table 4). We have not replicated the association in Mexican Americans observed by Mehrian and colleagues, but our cohort numbers were not adequately powered to provide a definitive result (Table 4).

Of particular interest is a recent study that examined distal SNPs in the -8kb promoter region, and extended haplotypes in the 4kb region in an Italian SLE cohort.41 While the authors found no association between SLE and distal SNPs or SNPs in the 3'UTR, a meta-analysis of four IL-10.G STRP association studies found significant association with STRPs containing larger numbers of (CA) repeats. IL-10.G alleles containing 21 (CA) repeats or more (IL-10.G9 and up), and extended SNP-STRP haplotypes that included these longer repeat alleles were associated significantly with SLE.41 This study suggests that the disease association might not be with a particular STRP allele, but with a larger stretch of (CA) repeats. The biologic basis for this observation is not clear at present.

In summary, associations between IL-10 promoter polymorphisms, IL-10 production and autoimmune diseases have been documented. However, while association studies have yielded inconsistent results, the total number of affecteds from each of the various ethnic groups studied has not been large. Additionally, adequate numbers of studies have not been done in all ethnic groups. Recent resequencing efforts have uncovered a more complex promoter structure, and additional SNPs are being discovered in the promoter and in the 3'UTR41,75 (and Gibson, unpublished results). This raises the possibility that other, more complex SNP associations with disease phenotypes might be uncovered in future studies.

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