Online Mendelian Inheritance in Man (OMIM)

* 142840

MAJOR HISTOCOMPATIBILITY COMPLEX, CLASS I, C; HLA-C

Gene-Phenotype Relationships

TEXT

Cloning and Expression

Sodoyer et al. (1984) isolated genomic clones of HLA-C by screening a genomic library with an HLA class I gene as probe. Mouse L cells transfected with one of the clones expressed a molecule that was serologically characterized as HLA-CW3. The predicted 341-amino acid protein has a putative signal sequence and transmembrane domain.

Cianetti et al. (1989) cloned HLA-C cDNAs, and found that there is alternative splicing of the exon encoding the transmembrane domain. The alternatively spliced mRNA may synthesize a secreted variant of the antigen. Cianetti et al. (1989) stated that class I HLA antigens are heterodimers consisting of a 45-kD polymorphic cell surface glycoprotein noncovalently associated with an invariant 12-kD beta-microglobulin (109700). Class I genes belong to a large multigene family within the major histocompatibility complex (MHC), and include HLA-A (142800), HLA-B (142830), and HLA-C.

Gene Structure

Sodoyer et al. (1984) determined that the HLA-CW3 gene is composed of at least 8 exons spanning approximately 3.5 kb.

Biochemical Features

Crystal Structure

KIR2D receptors are divided into 2 families based on their specificities for different HLA-C allotypes. KIR2DL1 (604936) has specificity for HLA-C alleles with asn77 and lys80, while KIR2DL2 (604937) has specificity for HLA-C alleles with ser77 and asn80. Fan et al. (2001) described the crystal structure of KIR2DL1 and HLA-Cw4 at a resolution of 2.8 angstroms. They determined that met44 of KIR2DL1 is in a pocket that hosts, through both polar and hydrophobic interactions, lys80 of HLA-Cw4.

Molecular Genetics

Kostyu et al. (1997) examined polymorphism in 272 HLA class I alleles and in so doing reported the sequence of many HLA-C alleles.

Carrington et al. (1999) reported that the extended survival of 28 to 40% of HIV-1-infected Caucasian patients who avoided AIDS for 10 or more years (see 609423) could be attributed to their being fully heterozygous at HLA class I loci, to lacking the AIDS-associated alleles B*35 and Cw*04, or to both.

Patients with vascular complications of rheumatoid arthritis (RA; 180300) have an expansion of CD4 (186940)-positive/CD28 (186760)-null T cells that may be involved in endothelial cell damage. By flow cytometric and RT-PCR analyses, Yen et al. (2001) showed that CD4-positive/CD28-null T-cell clones from RA vasculitis patients frequently expressed the stimulatory receptor KIR2DS2 (604953) in the absence of inhibitory receptors such as KIR2DL2 or KIR2DL3 (604938). Yen et al. (2001) noted that KIR genes are variably present in the Caucasian population, with the majority positive for inhibitory KIR. Comparable numbers of normal individuals and RA patients could be typed for either KIR2DS1 (604952) or KIR2DS2, whereas patients with unequivocal vasculitis had a highly significant association with KIR2DS2, suggesting that KIR2DS2 affects not the risk of developing RA but rather the risk of developing vascular complications. HLA-C polymorphisms are recognized by KIR2DS family proteins. HLA-C genotyping revealed that all RA patients had a decreased frequency of HLA-C*04 and an increased frequency of HLA-C*05, but RA vasculitis patients had a frequency of HLA-C*03 nearly double that of normal individuals and much higher than that of other RA patients. Logistic regression analysis determined that both HLA-C*03 and KIR2DS2 are independent, significant risk factors for RA vasculitis. Yen et al. (2001) concluded that MHC class I-recognizing receptors are implicated in the pathogenesis of RA vasculitis and possibly of other acute and chronic diseases characterized by vascular inflammation.

Khakoo et al. (2004) demonstrated that genes encoding the inhibitory natural killer (NK) cell receptor KIR2DL3 and its HLA-C group 1 (HLA-C1) ligand directly influence resolution of hepatitis C virus infection. This effect was observed in Caucasians and African Americans with expected low infectious doses of hepatitis C virus but not in those with high-dose exposure, in whom the innate immune response was likely overwhelmed. The frequency of individuals with 2 copies of HLA-C1 alleles was higher in the group that had resolved infection (37.5%) relative to those with persistent infection (29.9%) (OR = 1.40, p = 0.01). The reciprocal association of 2 HLA-C2 alleles with viral persistence was also observed. Khakoo et al. (2004) concluded that inhibitory NK cell interactions are important in determining antiviral immunity and that diminished inhibitory responses confer protection against hepatitis C virus.

Preeclampsia (see 189800) is a pregnancy complication in which the fetus receives an inadequate blood supply due to failure of trophoblast invasion. Hiby et al. (2004) noted that the only polymorphic histocompatibility antigens on the trophoblast surface are HLA-C molecules, including the paternal allele, which are recognized by members of the highly polymorphic KIR family of natural killer cell receptors. There are 2 distinct KIR haplotypes, termed A and B. Haplotype A has 1 activating and 6 inhibitory KIRs, whereas haplotype B has 5 activating and 2 inhibitory KIRs. Hiby et al. (2004) found that mothers with an AA KIR genotype and a fetus with HLA-C2 were at greatly increased risk of preeclampsia. KIR2DL5 (605305), a haplotype B gene encoding an inhibitory receptor, was significantly less frequent in preeclampsia mothers. The KIR-HLA-C2 interaction appeared to be physiologic rather than immunologic, in that maternal HLA-C type was of no consequence. Hiby et al. (2004) found that different human populations have reciprocal relationships between KIR AA frequency and HLA-C2 frequency, suggesting that this combination may be selected against and that reproductive success may have influenced the evolution and maintenance of KIR and HLA-C polymorphisms.

Goverdhan et al. (2005) investigated whether HLA genotypes were associated with age-related macular degeneration (ARMD; see 603075). HLA class I-A, -B, -Cw and class II DRB1 (142857) and DQB1 (604305) were genotyped in 200 patients with ARMD, as well as in controls. Allele Cw*0701 correlated positively with ARMD, whereas alleles B*4001 and DRB1*1301 were negatively associated. These HLA associations were independent of any linkage disequilibrium. Goverdhan et al. (2005) concluded that HLA polymorphisms influenced the development of ARMD and proposed modulation of choroidal immune function as a possible mechanism for this effect.

A major genetic determinant of psoriasis, designated psoriasis susceptibility-1 (PSORS1; 177900), resides in the major histocompatibility complex (MHC). There are numerous reports of strong allelic associations with the gene encoding HLA class I antigen (HLA-Cw6; 142840.0001) (Elder et al., 1994). This association is particularly strong in patients with an early age at onset and in patients with a guttate subtype of psoriasis. These findings led many researchers to suggest that HLA-Cw6 is the disease allele at PSORS1. This would be consonant with knowledge that MHC class I molecules play an important role in the function of CD8+ T cells. The major obstacle to confirming or refuting the role of HLA-Cw6 in psoriasis was linkage disequilibrium (LD). The MHC is characterized by extensive and presumably selection-driven variation, as well as the existence of particularly strong extended haplotypes. Overall, the recombination rate for the MHC is lower than the genomewide rate determined by sperm typing, and, in addition, the MHC includes defined subregions of low recombination. One of these regions, characterized by a 2.3-fold reduction in recombination rate relative to the genomic average, resides just telomeric to HLA-C (Walsh et al., 2003). At least 10 genes had been identified within this region. As the allelic variation in these genes was characterized and tested, it became clear that many of them were also associated with psoriasis. However, attempts to stratify associations according to HLA-C status usually failed to identify any association independent of HLA-Cw6. To overcome this challenge, Nair et al. (2006) turned to recombinant ancestral haplotype analysis. By accumulating and analyzing sufficient numbers of subjects, it was possible to identify individuals carrying only portions of the ancestral PSORS1 risk haplotype and to assess the risk conferred by those haplotypes. By sequencing of haplotypes, they found that 7 genes bore no alleles unique to risk haplotypes. Only HLA-C and CDSN (602593) yielded protein alleles unique to risk. The risk alleles of these 2 genes, HLA-Cw6 and CDSN*TTC, were genotyped in 678 families with early-onset psoriasis; 620 of these families were also typed for 34 microsatellite markers spanning the PSORS1 interval. Recombinant haplotypes retaining HLA-Cw6 but lacking CDSN*TTC were significantly associated with psoriasis, whereas recombinants retaining CDSN*TTC but lacking HLA-Cw6 were not associated. These results suggested that HLA-Cw6 is the PSORS1 risk allele that confers susceptibility to early-onset psoriasis.

The International Multiple Sclerosis Genetics Consortium (2007) found evidence that variation in the HLA-C gene influences susceptibility to MS (126200) independent of the HLA-DRB1 gene. Using a combination of microsatellite, SNP, and HLA typing in a family-based and case-control cohort beginning with a sample of 1,201 MS patients, the authors analyzed 264 patients without the common DRB1*1501, DRB1*03, and DRB1*0103 alleles. Significant association was found with the HLA-C locus (p = 5.9 x 10(-5)). Specifically, the HLA-C*05 allele was underrepresented in patients compared to controls (p = 3.3 x 10(-5)), suggesting a protective effect.

Using genotyping for an HLA-C promoter variant, -35C-T (142840.0002), and flow cytometric analysis in 1,698 HIV-infected patients of European ancestry, Thomas et al. (2009) found that the -35C allele is a proxy for high HLA-C cell surface expression, and that individuals with high surface expression better control viremia and progress more slowly to AIDS. Thomas et al. (2009) concluded that high HLA-C expression results in more effective control of HIV-1, possibly through better antigen presentation to cytotoxic T lymphocytes.

To define host genetic effects on the outcome of a chronic viral infection, The International HIV Controllers Study (2010) performed genomewide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. The International HIV Controllers Study (2010) identified more than 300 genomewide significant SNPs within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, at positions 62, 63, 67, 70, and 97, as well as an independent HLA-C effect, explained the SNP associations and reconciled both protective and risk HLA alleles. The International HIV Controllers Study (2010) concluded that their results implicated the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection.

Kulkarni et al. (2011) demonstrated that variation within the 3-prime untranslated region of HLA-C regulates binding of the microRNA miR148 (miR148A, 613786 and miR148B, 613787) to its target site, resulting in relatively low surface expression of alleles that bind this microRNA and high expression of HLA-C alleles that escape posttranscriptional regulation. The binding site for miR148A/miR148B contains a single-basepair insertion/deletion at position 263 downstream of the HLA-C stop codon (rs67384697G representing the insertion and rs67384697- representing the deletion).

Although nearly all adults have been exposed to herpes simplex virus (HSV)-1, the clinical course of infection varies remarkably. By analyzing the contribution of gene families on chromosomes 1, 6, 12, and 19 to susceptibility to HSV-1 infection in 302 individuals, Moraru et al. (2012) identified no specific susceptibility locus. However, they found that the risk of suffering clinical HSV-1 infection was modified by MHC class I allotypes, HLA-C1 interaction with KIR2DL2, and the phe/val polymorphism at codon 158 of CD16A (FCGR3A; 146740).

Apps et al. (2013) characterized the differential cell surface expression levels of all common HLA-C allotypes and tested directly for effects of HLA-C expression on outcomes of HIV infection in 5,243 individuals. Increasing HLA-C expression was associated with protection against multiple outcomes independently of individual HLA allelic effects in both African and European Americans, regardless of their distinct HLA-C frequencies and linkage relationships with HLA-B and HLA-A. Higher HLA-C expression was correlated with increased likelihood of cytotoxic T-lymphocyte responses and frequency of viral escape mutation. Apps et al. (2013) found that, in contrast, high HLA-C expression had a deleterious effect in Crohn disease (see 266600), suggesting a broader influence of HLA expression levels in human disease.

Lo Monaco et al. (2013) stated that the monoclonal antibody used by Apps et al. (2013) crossreacts with HLA-E, suggesting that the 2 antigens collaborate to keep the HIV-1 virus at bay. Apps and Carrington (2013) responded that based on the minimal, flat levels of cell surface HLA-E detectable by staining with specific antibodies, evidence remained far stronger that HLA-C is responsible for the HIV control.

Evolution

Using phylogenetic reconstructions and HLA genotyping data from 30 diverse populations, O'hUigin et al. (2011) determined that 3 to 5 million years ago, a genetic exchange occurred between an HLA-C allele and an HLA-B allele belonging to a B*07-like lineage. This exchange necessitated that alleles of the C*02, C*05, C*06, C*08, C*12, C*15, and C*16 lineages, but not those of the C*01, C*03, C*04, C*07, C*14, and C*17 lineages, share a deletion at position 263 in the 3-prime UTR and neighboring substitutions that prevent MIR148A recognition. Members of the former group were termed 'escape alleles,' whereas members of the latter group, which retain an intact MIR148A binding site, were termed 'inhibited alleles.' O'hUigin et al. (2011) proposed that greater understanding of HLA variability may be facilitated by extending the sequence length in databases to include sequences such as the 3-prime UTR.

ALLELIC VARIANTS 2 Selected Examples):

REFERENCES

Contributors:

Paul J. Converse - updated : 8/7/2014
Ada Hamosh - updated : 12/20/2013
Paul J. Converse - updated : 5/6/2013
Ada Hamosh - updated : 5/3/2013
Ada Hamosh - updated : 6/10/2011
Ada Hamosh - updated : 1/19/2011
Paul J. Converse - updated : 12/15/2009
Cassandra L. Kniffin - updated : 10/16/2007
Victor A. McKusick - updated : 4/14/2006
Paul J. Converse - updated : 3/14/2006
Jane Kelly - updated : 11/21/2005
Ada Hamosh - updated : 11/30/2004
Paul J. Converse - updated : 10/9/2001
Paul J. Converse - updated : 5/4/2001
Ada Hamosh - updated : 3/24/1999
Rebekah S. Rasooly - updated : 5/29/1998

Creation Date:

Victor A. McKusick : 6/4/1986

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