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Cytokines and their receptors

There are a number of reports that have addressed the role of genetic variation in cytokine genes in relation to susceptibility to CD per se and to CCC (Table 27.4). Some utilize polymorphisms reported to be functionally relevant. Few of these CD studies provide complementary functional information. Perhaps surprising is the lack of studies on cytokine receptor genes. Rare variation in genes, inherited in a Mendelian fashion, including IFNGR1, IFNGRII, IL12B, and IL12RB1, are well known for predisposing to severe mycobacterial infection,72 and there has been a widespread view that common variation in such loci may predispose to more common disease. These genes all are involved in IFN-y related immunity. Single SNPs in IL12B and IFNG have shown some association in Colombian populations, but

more remains to be done.66,70

The IL1A/IL1B/IL1RN gene cluster on chromosome 2, similar to TNF and LTA in the MHC class III region on chromosome 6, has received attention for many diseases since the genes code for the major proinflammatory cytokines. In the first of two studies across IL1A/IL1B/IL1RN, the IL1B + 5810* G allele was overrepresented in CCC, and IL1B haplotypes showed association.60 Notably the second study, across IL1B/IL1RN, used 50 cardiac patients of the 159 seronegative controls in an effort to provide appropriate controls for study of CCC.61 One polymorphism in IL1RN was associated with infection and development of CCC.61 Similarly IL17A has been associated with several pro-inflammatory conditions. A recent substantial Colombian study showed one of five SNPs tested, rs8193036 in the promoter region of IL17A, was associated with protection against infection (P = 0.017) and CCC (P = 0.0065).67 IL-18 is an important cytokine in promotion of Th1 cytokine responses and hence provides a good candidate for investigation. Investigation of these Colombian samples for six SNPs in IL18 showed four to be associated when

Table 27.3 Chemokines and their receptors

Gene

Genotyping

Population

Seronegative

Asymptomatic

CCC

(mild/severe)

Digestive

Mixed

Ref.

CCR5

Д32 and 59029 A/G

Brazil

172

131

109

51

CCR5

Д32 and 59029 A/G

Peru

87

53

32

52

CCR5

Д32 and 59029 A/G

Venezuela

34

73(38/35)

53

CCR2/CCR5

2/7 SNPs

Colombia

206

270(96/174)

54

CCR2/CCR5/ CCL5/CXCL8

1 SNP/7 SNPs 1 Д32/2 SNPs/1 SNP

239

368(111/257)

55

CCR5/CCL2

3/6 SNPs

Brazil

118

315

56

CXCL9/CXCL10/CCR5

1 SNP per gene

Brazil

146

174(79/95)

57

CCL2 (=MCP-1)

1 SNP

Brazil

76

169

58

MIF

1 SNP

Colombia and Peru

199 1 85

115 148

125 1 26

59

Table 27.4 Cytokines and their receptors

Gene

Genotyping

Population

Seronegative

Asymptomatic

CCC (mild/ severe)

Digestive

Mixed

Ref.

IL1A/IL1B/

IL1RN

2/4/3 SNPs

Colombia

130

130

60

IL1B/IL1RN

5 polymorphisms

Mexico

159

28

58

61

IL4

Whole gene sequencing

Bolivia

36

76

62

IL4/IL4RA/

IL10

1/4/3 SNPs

Colombia

130

130

63

IL6

1 SNP

Colombia and Peru

399

113 1 50

117 1 28

64

IL10

1 SNP

Brazil

43

58

97(44/53)

65

IL12B

1 SNP

Colombia

200

130

130

66

IL17A

5 SNPs

Colombia

595

175

401

67

IL18

1 SNP

Brazil

202

849(366/333)

68

IL18

6 SNPs

Colombia

595

175

401

69

IFNG

1 SNP

Colombia

282

116

120

70

TGFB1

5 SNPs

Colombia and

279

175

172

71

Peru

comparing seronegative to seropositive individuals, but not in development of CCC, and further analysis suggested rs360719 was key.69 In contrast, a previous Brazilian study tested only IL18 rs2043055 and had suggested some relevance to progression of CCC.68

IL4 has been examined in two studies, although one of these studies used a single SNP.63 The more detailed Bolivian study, addressing susceptibility to CD per se, illustrates some of the benefits and problems of sequence-based approaches.62 Achieving statistical significance with small sample sizes and large numbers of variants is difficult. Forty-five polymorphic sites were found, 3 of which were in the coding sequence and present in affected only, 16 singleton variants appeared in affected only, and IL4 590* T was a marker of haplotypes conferring protection against infection.62

IL10 and TGFB1 code for “downregulators” of inflammation. Several SNPs in each of these genes have been tested, and analyses of haplotypes carried out, over a number of years for a wide range of other disorders. A small Brazilian study focusing on the potentially functional IL10-1082 polymorphism, where the “A” allele determined low IL-10 production, found weak association.65 However, a Colombian study, using 3 SNPs and haplotypic analyses, failed to show genetic association, but for 10 patients where IL-10 production was correlated with LVEF.63 Susceptibility to CD and/or CCC for other cytokine loci are examined in single studies, in some instances using single SNPs, and further investigation is required (Table 27.4).

 
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