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Genetic associations from candidate gene studies to date

Recent reviews of human genetic susceptibility to CD and CCC have catalogued reported associations, in some cases listing associated alleles and significance

levels.18-21 Since it is early in the investigation of susceptibility to CD, few firm conclusions can be drawn, and because of some of the issues outlined above, this chapter merely attempts to summarize available publications.

The tables list studies to date. They may include studies with elements of replication, where results are not repeated, or studies with patient cohorts in common, but reporting some additional information.22,23 Phenotypes listed include “seronega- tives,” where seronegatives are usually presumed to be exposed but not to have had CD, and may also include untested “healthy controls” who would be presumed to be seronegative but from an endemic area, hence exposed. “Asymptomatics” are seropositive and assumed to have had acute infection, and include those categorized as indeterminate. The numbers listed for each of the phenotypes shows the size of the studies and also provides an indication of the questions addressed by the authors, e.g., susceptibility to infection and CD per se through comparison of aysmptomatics with seronegatives, or susceptibility to forms of chronic disease through comparison of these with asymptomatics. It is notable that the most commonly studied chronic form is CCC.

Although more recent investigations often use larger sample sizes, many studies are relatively small and low powered, particularly for considering multiallelic systems or uninformative markers. Associations, whether listed in the tables or described in the text, are as reported by the authors, irrespective of the analytical and statistical methodology employed. The following summaries indicate that investigators have made a good start in the field of human genetic susceptibility to CD.

HLA

There are a number of studies where HLA class I and class II genotyping has been carried out, in several countries, some with ethnically mixed populations, as summarized in Table 27.1. Because of the high diversity in this region of the genome, the majority of recent studies have genotyped using sequence specific oligonucleotide probes (SSO). Problems of sampling and genotyping have led to some minor inconsistencies in the literature, even in serial publications from the same country.23 Both susceptibility to CD per se, by comparison of genotypic distributions in seronega- tives versus asymptomatic individuals, and susceptibility to severe disease, by comparison of genotypic distributions in asymptomatics versus those with manifestations of chronic disease, have been tested. Due to the presence of LD between potentially “causative” loci, examination of haplotypes is useful, but has only been employed in a handful of studies (Tables 27.1 and 27.2).29,48 Some have approximated haplotypic analyses, e.g., a very early study by Llop et al. found HLA- B49 conferred protection against CCC in the presence of HLA-Cw3.26 Similarly, the later study of the class II region by Colorado et al. considered combinations of alleles.35 Detailed analyses are sometimes precluded by small sample sizes, and hampered by lack of adequately matched controls.32

Table 27.1 The major histocompatibilty complex class I, class II, and related loci

Gene

Genotyping

Population

Seronegative

Asymptomatic

CCC (mild/ severe)

Digestive

Mixed

Allele

Association

Refs.

HLA-G

3’UTR

sequencing

Brazil

155

39

52

62

24

Allele/genotype/haplotype

Various with infection and clinical variants

24

HLA-A/HLA-B/HLA-C

Serology

Chile

32

73 ( ± CCC)

B40 Cw3

Increase in seropositives without heart disease

25

HLA-A/HLA-B/HLA-C

Serology

Chile

73

51

B49 in the presence of

Cw3

Conferred protection against CCC

26

HLA-A/HLA-B/HLA-C

By SSO

Venezuela

35

78 (45/33)

C*03 in LD with B* 40 and B* 15

Conferred susceptibility to CCC

22

HLA-A/HLA-B/HLA-C/

KIR

By SSO

Brazil

165

87

44

KIR2DS2 1Z2DL2-/C1 +

Increased frequency in patients, particularly CCC

27

HLA-B/MICA

By SSO

Brazil

159

85

44

MICA*007

MICA*008

B*08 and MICA*008- HLA-B*08

Conferred protection against infection Conferred susceptibility to CCC

Conferred susceptibility to infection

28

HLA-A/HLA-B/MICA/

MICB/HLA-DRB1/

TNF

By sequencing and SSO

Bolivia

133

60

81

17

DRB101 B*1402

DRB101-B* 14- MICA* 011

Conferred protection against CCC and digestive forms of disease

Conferred protection against

CCC and digestive forms of disease Conferred protection against chronic CD

29

HLA-A/HLA-B/HLA-DR

By SSO and SSP

Mexico

127

34

32

B39 and DR4 A68 and B39 DR16

Conferred susceptibility to infection Conferred protection against CCC Conferred susceptibility to CCC

30

(Continued)

Table 27.1 (Continued)

Gene

Genotyping

Population

Seronegative

Asymptomatic

CCC (mild/ severe)

Digestive

Mixed

Allele

Association

Refs.

HLA-A/HLA-B/HLA-C/

HLA-DR/HLA-DQ

Cytotoxicity and SSO

Brazil

448

33

78 (18/60)

25

40

A30

DQBP06

Conferred susceptibility to disease

Conferred protection against development of any form of disease

31

HLA-DR/HLA-DQA/HLA-

DQB

SSP and SSO

Brazil

64

142

None

With disease progression

32

HLA-DRB1

By SSO

Argentina

81

71 ( ± CCC)

DRBP0409

DRBP1503

DRBP1103

Conferred susceptibility to infection

Conferred susceptibility to

infection and CCC Conferred protection

33

HLA-DRB1

By SSO

Argentina

41

35

DRBP0409

against infection Conferred susceptibility to disease

34

HLA-DRB1/HLA-DQB1

By SSO

Venezuela

156

67 ( ± CCC)

DRBP14

DQBP0303

DRBP1501

Conferred protection against infection Conferred protection against infection Conferred protection against CCC

23

HLA-DRB1/HLA-DQB1/

HLA-DPB1

By SSO

Venezuela

35

76 (43/33)

DRB1 * 01-DQB1*0501

DPBP0401

DPBP0401

Conferred susceptibility to CCC

Conferred susceptibility to CCC

Conferred protection against CCC

35

HLA-DRB1/HLA-DQB1

PCR-RFLP and SSO

Peru

87

52

33

DRB1 * 14-DQB1*0301 None

Conferred protection against infection With disease progression

36

HLA-A/HLA-B/HLA-C/

HLA-DR

By SSO

Spain

52

B*3505

With moderate to severe cutaneous reaction to benznidazole

37

Table 27.2 The major histocompatibilty complex continued class III

Gene

Genotyping

Population

Seronegative

Asymptomatic

CCC

(mild/severe)

Digestive

Mixed

Ref.

TNF

TNF-308

Brazil

62

84

38

TNFA/

TNFR2

TNF-1031 and -308

Colombia

154

159

39

TNF

TNF-308 and -238

Brazil

132

53

66

40

TNF

TNF-308 and -238

Mexico

169

27

27

41

TNF

TNFa microsatellite and -308

Brazil

42

42

TNF

TNFa microsatellite and -308

Brazil

80

166

43

TNF

TNF microsatellites x5

Brazil

221

33

71 (17/54)

25

33

44

TNF/LTA

TNF-308 and -238/ LTA 1252

Peru

87

52

33

45

LTA

LTA 180 and 1252

Brazil

76

169

46

LTA

LTA 1252

Brazil

161

53

70

47

CYP21A2

1 SNP

Bolivia

133

60

81

17

48

BAT1

2 SNPs

Brazil

76

154

49

IKBL

2 SNPs

Brazil

76

169

50

The less polymorphic HLA-G, MICA, and MICB have also been studied,242829 as have the Killer cell Immunoglobulin-like Receptor (KIR) loci on chromosome 19, together with the genes coding for their HLA ligands on chromosome 6.27 A Spanish study examined HLA associations with cutaneous reactions to benznida- zole, used to treat CD.1,11,37

Although there is no consistent pattern of associations for either class I or class II loci, it seems likely that further investigations will prove useful. Of course bona fide associations with the MHC would carry clear biological implications, e.g., suggest the importance of a key pathogenic epitope triggering autoimmunity, restricted by a single HLA specificity.

 
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