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1.  A sequence-based approach demonstrates that balancing selection in classical human leukocyte antigen (HLA) loci is asymmetric 
Human Molecular Genetics  2012;22(2):252-261.
Balancing selection has maintained human leukocyte antigen (HLA) allele diversity, but it is unclear whether this selection is symmetric (all heterozygotes are comparable and all homozygotes are comparable in terms of fitness) or asymmetric (distinct heterozygote genotypes display greater fitness than others). We tested the hypothesis that HLA is under asymmetric balancing selection in populations by estimating allelic branch lengths from genetic sequence data encoding peptide-binding domains. Significant deviations indicated changes in the ratio of terminal to internal branch lengths. Such deviations could arise even if no individual alleles present a strikingly altered branch length (e.g. if there is an overall distortion, with all or many terminal branches being longer than expected). DQ and DP loci were also analyzed as haplotypes. Using allele frequencies for 419 distinct populations in 10 geographical regions, we examined population differentiation in alleles within and between regions, and the relationship between allelic branch length and frequency. The strongest evidence for asymmetrical balancing selection was observed for HLA-DRB1, HLA-B and HLA-DPA1, with significant deviation (P ≤ 1.1 × 10−4) in about half of the populations. There were significant results at all loci except HLA-DQB1/DQA1. We observed moderate genetic variation within and between geographic regions, similar to the rest of the genome. Branch length was not correlated with allele frequency. In conclusion, sequence data suggest that balancing selection in HLA is asymmetric (some heterozygotes enjoy greater fitness than others). Because HLA polymorphism is crucial for pathogen resistance, this may manifest as a frequency-dependent selection with fluctuation in the fitness of specific heterozygotes over time.
doi:10.1093/hmg/dds424
PMCID: PMC3526157  PMID: 23065702
2.  CIITA is not associated with risk of developing rheumatoid arthritis 
Genes and immunity  2011;12(3):235-238.
The major histocompatibility complex (MHC) class II transactivator gene (CIITA) encodes an important transcription factor regulating genes required for human leukocyte antigen (HLA) class II MHC-restricted antigen presentation. Major histocompatibility complex (MHC) genes, particularly HLA class II, are strongly associated with risk of developing rheumatoid arthritis (RA). Given the strong biological relationship between CIITA and HLA class II genes, a comprehensive investigation of CIITA variation in RA was conducted. This study tested 31 CIITA SNPs in 2542 RA cases and 3690 controls (N = 6232). All individuals were of European ancestry, as determined by ancestry informative genetic markers. No evidence for association between CIITA variation and RA was observed after a correction for multiple testing was applied. This is the largest study to fully characterize common genetic variation in CIITA, including an assessment of haplotypes. Results exclude even a modest role for common CIITA polymorphisms in susceptibility to RA.
doi:10.1038/gene.2010.67
PMCID: PMC3449225  PMID: 21248776
rheumatoid arthritis; autoimmunity; CIITA; MHC2TA
3.  The rs4774 CIITA missense variant is associated with risk of systemic lupus erythematosus 
Genes and Immunity  2011;12(8):667-671.
The major histocompatibility complex (MHC) class II transactivator gene (CIITA) encodes an important transcription factor required for HLA class II MHC-restricted antigen presentation. MHC genes, including the HLA class II DRB1*03:01 allele, are strongly associated with systemic lupus erythematosus (SLE). Recently the rs4774 CIITA missense variant (+1632G/C) was reported to be associated with susceptibility to multiple sclerosis. In the current study, we investigated CIITA, DRB1*03:01 and risk of SLE using a multi-stage analysis. In stage 1, 9 CIITA variants were tested in 658 cases and 1,363 controls (N = 2,021). In stage 2, rs4774 was tested in 684 cases and 2,938 controls (N = 3,622). We also performed a meta-analysis of the pooled 1,342 cases and 4,301 controls (N = 5,643). In stage 1, rs4774*C was associated with SLE (odds ratio [OR] = 1.24, 95% confidence interval [95% CI] = 1.07–1.44, P = 4.2 × 10−3). Similar results were observed in stage 2 (OR = 1.16, 95% CI = 1.02–1.33, P = 8.5×10−3) and the meta-analysis of the combined dataset (OR = 1.20, 95% CI = 1.09–1.33, Pmeta = 2.5×10−4). In all three analyses, the strongest evidence for association between rs4774*C and SLE was present in individuals who carried at least one copy of DRB1*03:01 (Pmeta= 1.9×10−3). Results support a role for CIITA in SLE, which appears to be stronger in the presence of DRB1*03:01.
doi:10.1038/gene.2011.36
PMCID: PMC3387803  PMID: 21614020
systemic lupus erythematosus; autoimmunity; major histocompatibility complex; HLA; CIITA; MHC2TA
4.  CIITA variation in the presence of HLA-DRB1*1501 increases risk for multiple sclerosis 
Human Molecular Genetics  2010;19(11):2331-2340.
The MHC class II transactivator gene (CIITA) is an important transcription factor regulating gene required for HLA class II MHC-restricted antigen presentation. Association with HLA class II variation, particularly HLA-DRB1*1501, has been well-established for multiple sclerosis (MS). In addition, the −168A/G CIITA promoter variant (rs3087456) has been reported to be associated with MS. Thus, a multi-stage investigation of variation within CIITA, DRB1*1501 and MS was undertaken in 6108 individuals. In stage 1, 24 SNPs within CIITA were genotyped in 1320 cases and 1363 controls (n = 2683). Rs4774 (missense +1614G/C; G500A) was associated with MS (P = 4.9 × 10−3), particularly in DRB1*1501 +individuals (P = 1 × 10−4). No association was observed for the −168A/G promoter variant. In stage 2, rs4774 was genotyped in 973 extended families; rs4774*C was also associated with increased risk for MS in DRB1*1501+ families (P = 2.3 × 10−2). In a third analysis, rs4774 was tested in cases and controls (stage 1) combined with one case per family (stage 2) for increased power. Rs4774*C was associated with MS (P = 1 × 10−3), particularly in DRB1*1501+ cases and controls (P = 1 × 10−4). Results obtained from logistic regression analysis showed evidence for interaction between rs4774*C and DRB1*1501 associated with risk for MS (ratio of ORs = 1.72, 95% CI 1.28–2.32, P = 3 × 10−4). Furthermore, rs4774*C was associated with DRB1*1501+ MS when conditioned on the presence (OR = 1.67, 95% CI = 1.19–2.37, P = 1.9 × 10−3) and absence (OR = 1.49, 95% CI = 1.15–1.95, P = 2.3 × 10−3) of CLEC16A rs6498169*G, a putative MS risk allele adjacent to CIITA. Our results provide strong evidence supporting a role for CIITA variation in MS risk, which appears to depend on the presence of DRB1*1501.
doi:10.1093/hmg/ddq101
PMCID: PMC2865376  PMID: 20211854
5.  Analysis of Maternal–Offspring HLA Compatibility, Parent-of-Origin Effects, and Noninherited Maternal Antigen Effects for HLA–DRB1 in Systemic Lupus Erythematosus 
Arthritis and rheumatism  2010;62(6):1712-1717.
Objective
Genetic susceptibility to systemic lupus erythematosus (SLE) is well established, with the HLA class II DRB1 and DQB1 loci demonstrating the strongest association. However, HLA may also influence SLE through novel biologic mechanisms in addition to genetic transmission of risk alleles. Evidence for increased maternal–offspring HLA class II compatibility in SLE and differences in maternal versus paternal transmission rates (parent-of-origin effects) and nontransmission rates (noninherited maternal antigen [NIMA] effects) in other autoimmune diseases have been reported. Thus, we investigated maternal–offspring HLA compatibility, parent-of-origin effects, and NIMA effects at DRB1 in SLE.
Methods
The cohort comprised 707 SLE families and 188 independent healthy maternal–offspring pairs (total of 2,497 individuals). Family-based association tests were conducted to compare transmitted versus nontransmitted alleles (transmission disequilibrium test) and both maternally versus paternally transmitted (parent-of-origin) and nontransmitted alleles (using the chi-square test of heterogeneity). Analyses were stratified according to the sex of the offspring. Maternally affected offspring DRB1 compatibility in SLE families was compared with paternally affected offspring compatibility and with independent control maternal–offspring pairs (using Fisher’s test) and was restricted to male and nulligravid female offspring with SLE.
Results
As expected, DRB1 was associated with SLE (P < 1 × 10−4). However, mothers of children with SLE had similar transmission and nontransmission frequencies for DRB1 alleles when compared with fathers, including those for the known SLE risk alleles HLA–DRB1*0301, *1501, and *0801. No association between maternal–offspring compatibility and SLE was observed.
Conclusion
Maternal–offspring HLA compatibility, parent-of-origin effects, and NIMA effects at DRB1 are unlikely to play a role in SLE.
doi:10.1002/art.27426
PMCID: PMC2948464  PMID: 20191587

Results 1-5 (5)