Summary

The KIR locus lies at the extreme end of the gene conservation spectrum (the end with least conservation, that is) where genes, especially functionally redundant sets of genes, are allowed to transform at their own free will, relatively speaking. The very fact that they have this privilege suggests that most of the variability observed is not absolutely essential, nor will any new variant have high probability of being outright deadly (though there is a selection bias in this latter measurement); rather the variability represents a means for the innate immune system to remain fluid, delicately contributing to disease outcome as positively as possible. These considerations imply that, for the most part, disease associations with KIR variants are expected to be somewhat weak, as is rather common for most variable genes involved in immune responsiveness. Indeed, the strength of the genetic associations described herein for KIR and their ligand groups is similar to that previously reported for HLA class I alleles and the majority of diseases with which they have been associated, particularly infectious diseases. Given the extent of KIR locus variability and the function of their protein products in both innate and acquired immunity, one might reasonably predict that they may influence the outcomes to most multigenic diseases that directly or indirectly involve the immune response. [Although no involvement of KIR in terms of presence or absence of several KIR genes was observed in celiac disease (Moodie et al. 2002) despite genome-wide linkage studies pointing to 19q13.4 (Zhong et al. 1996), the region in which the KIR gene cluster maps. This study did not rule out the possibility of allelic effects of KIR loci on disease, a possibility that has not been thoroughly explored for any disease to date.] So, in general, the good news for disease gene hunters is that the KIR locus is almost always a strong candidate in the quest for associated genetic variation; the fly in the ointment is the likelihood of small effects conferred by a very complex polymorphic locus, a problem that is only overcome by securing sizeable, clinically well-defined disease cohorts.

Only a handful of diseases have been studied for genetic associations with KIR variability to date (summarized in Table 2), impeding our ability to identify common threads of KIR involvement across diseases that share some etiological characteristics. Nevertheless, parallels may be emerging, such as the consistent observation of activating KIR genotypes with risk of developing autoimmune disease (Yen et al. 2001; van der Slik et al. 2003; Luszczek et al. 2004; Momot et al. 2004; Nelson et al. 2004; Suzuki et al. 2004) and their protection against two infectious diseases (Martin et al. 2002a; Khakoo et al. 2004). Although KIR2DL3 and HLA-C group 1 had the strongest protective effect

Disease

KIR/HLA ligand association Effect

Population

Comments

Reference

Autoimmune

1) Psoriatic Arthritis

2) Psoriasis

3) Rheumatoid vasculitis

4) Scleroderma

5) IDDM

6) Celiac disease

KIR2DS1/KIR2DS2; HLA-Cw group homozygosity KIR2DS1/HLA-Cw*06

KIR2DS1; KIR2DL5; KIR haplotype B

KIR2DS2/HLA-Cw*03

KIR2DS2+/KIR2DL2-

KIR2DS2/HLA-Cw group 1

None

Susceptibility Susceptibility Susceptibility Susceptibility Susceptibility Susceptibility

Caucasian: 366 cases; 299 controls Polish: 116 cases; 123 controls Japanese: 96 cases; 50 controls Caucasian: 30 cases; 76 controls German: 102 cases;

100 controls Dutch:

149 cases; 207 controls UK Caucasian:

101 cases; 133 controls

Small numbers

Martin et al. 2002b; Nelson et al. 2004

Luszczek et al. 2004

Small numbers Suzuki et al. 2004

Small numbers but Yen etal. 2001 corroborated by KIR expression analysis

Small numbers Momot et al. 2004

van der Slik et al. 2003

19q13.4 previously Moodie et al. 2002 identified as a candidate region to o\

Disease

KIR/HLA ligand association Effect

Population

Comments

Reference

Infectious

3) P. falciparum

Cancer 1) Malignant melanoma

2) Leukemia

KIR3DSl/HLA-B-Bw480I

i)KIR2DL3/HLA-Cw group 1 homozygosity ii) KIR3DS1/HLA-Bw4 KIR3DL2*002

KIR2DL2/2DL3; HLA-Cw group 1

i) KIR2DL2

ii) AB1 and AB9 KIR phenotypes

Caucasian: -

N>1000

Caucasian and KIR3DS1/Bw4 African American: effect was weak N = 1023

Slows progression Resolution of infection

Resolution of infection

High response European, Asian, to iRBC African:

Susceptibility Bulgarian: 50 cases; 54 controls Susceptibility Belgian: 96 cases; 148 controls

In vitro study. Response of NK cells from normal blood donors to iRBC

Small numbers

Martin et al. 2002a Khakoo et al. 2004

Artavanis-Tsakonas et al. 2003

Naumova et al. 2004

The AB1 and AB9 Verheyden et al. 2004 phenotypes contain all inhibitory KIR genes

Disease

KIR/HLA ligand association Effect

Population

Comments

Reference

Pregnancy Preeclampsia

Mothers with AA

KIR genotype;

fetus with HLA-Cw group 2

KIR2DL4 polymorphism

Susceptibility

None

200 cases;

201 controls Australian: 45 cases;

48 controls

Hiby et al. 2004

Small numbers Witt et al. 2002

on resolution of HCV, KIR3DS1/HLA-B Bw4 was also protective against HCV just as KIR3DS1/HLA-B Bw4-80I was protective against AIDS progression. These studies pique interest in haplotypes encompassing KIR3DS1, because the expression of KIR3DS1 has been questioned, raising the possibility that another KIR gene or combination of genes on KIR3DS1 positive haplotypes maybe responsible for the protection observed in these diseases. (This would also have to involve Bw4 or alleles in LD with Bw4, because the KIR3DS1 protection noted in both HIV and HCV disease was contingent on the presence of HLA-B Bw4 or a subset of these alleles.) Two genetic epidemiological studies (Hiby et al. 2004; Khakoo et al. 2004) have confirmed the notion that not all inhibitory signals mediated by the various KIR are of equal weight, a property that was recognized through functional studies previously (Winter and Long 1997). Perhaps more intriguing than the similarities in KIR associations among this limited sample of diseases are the differences in KIR/HLA genetic profiles putatively used to attain one of only two outcomes, activation or inhibition of effector cells, a characteristic that is entirely predictable of a multigenic, functionally closely related, highly polymorphic family of genes.

Acknowledgements This project has been funded in whole or part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. N01-C0-12400. We would like to thank Dr. Arman Bashirova for helpful comments and assistance with figures and Teresa Covell for properly formatting the manuscript.

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