Novel sequence feature variant type analysis of the HLA genetic association in systemic sclerosis

Karp, David R.; Marthandan, Nishanth; Marsh, Steven G.E.; Ahn, Chul; Arnett, Frank C.; DeLuca, David S.; Diehl, Alexander D.; Dunivin, Raymond; Eilbeck, Karen; Feolo, Michael; Guidry, Paula A.; Helmberg, Wolfgang; Lewis, Suzanna; Mayes, Maureen D.; Mungall, Christopher J.; Natale, Darren A.; Peters, Bjoern; Petersdorf, Effie W.; Reveille, John D.; Smith, Barry; Thomson, Glenys; Waller, Matthew J.; Scheuermann, Richard H.

doi:10.1093/hmg/ddp521

Cited by 35 publications

(39 citation statements)

References 33 publications

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“…When evidence of strong balancing selection is seen at a number of AA sites (Salamon et al 1999;Valdes et al 1999;Lancaster 2006), how does one determine which AA sites could potentially show independent evolution vs. correlation due to high LD? Similarly with disease-association studies of individual AAs and biologically relevant sequence features (SFs) and their variant types (VTs) (Karp et al 2010;Thomson et al 2010), how can one distinguish between potentially causal effects vs. those due to LD? These AA-level analyses showed that there are cases with different numbers of "alleles" (AAs or SFVTs) at two loci where W n = 1; nonetheless a stratified analysis could be applied to potentially distinguish disease predisposing variants.…”

Section: Discussionmentioning

confidence: 99%

“…Amino-acid position 13 (AA13) of DRB1 shows the strongest single AA association with JIA-OP. This association is also stronger than other potentially biologically relevant combinations of AAs defined under sequence feature variant-type (SFVT) analysis (Karp et al 2010;Thomson et al 2010). AA13 is also identified as potentially causative in disease using an extension of Salamon's unique combinations algorithm (Salamon et al 1996;Thomson et al 2010).…”

Section: Hla Disease Association Datamentioning

confidence: 91%

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Conditional Asymmetric Linkage Disequilibrium (ALD): Extending the Biallelic r2 Measure

Thomson

Single

2014

Genetics

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For multiallelic loci, standard measures of linkage disequilibrium provide an incomplete description of the correlation of variation at two loci, especially when there are different numbers of alleles at the two loci. We have developed a complementary pair of conditional asymmetric linkage disequilibrium (ALD) measures. Since these measures do not assume symmetry, they more accurately describe the correlation between two loci and can identify heterogeneity in genetic variation not captured by other symmetric measures. For biallelic loci the ALD are symmetric and equivalent to the correlation coefficient r. The ALD measures are particularly relevant for disease-association studies to identify cases in which an analysis can be stratified by one of more loci. A stratified analysis can aid in detecting primary disease-predisposing genes and additional disease genes in a genetic region. The ALD measures are also informative for detecting selection acting independently on loci in high linkage disequilibrium or on specific amino acids within genes. For SNP data, the ALD statistics provide a measure of linkage disequilibrium on the same scale for comparisons among SNPs, among SNPs and more polymorphic loci, among haplotype blocks of SNPs, and for fine mapping of disease genes. The ALD measures, combined with haplotype-specific homozygosity, will be increasingly useful as next-generation sequencing methods identify additional allelic variation throughout the genome.T HE definition of the linkage disequilibrium (LD) parameter D ij of nonrandom association between a pair of alleles A i and B j at two loci (A and B) is straightforward and unequivocal. It is the difference between the observed (or estimated) haplotype (chromosomal or gametic) frequency ( f ij ) and that expected under random association of the two allele frequencies ðp Ai and p Bj Þ : D ij ¼ f ij 2 p Ai p Bj . While this is the base of all other measures of LD, defining the strength of any observed nonrandom association is complicated by the fact that the maximum value D ij can take is a function of the observed allele frequencies. A number of normalized measures to reflect the strength of LD have been proposed; both for bi-and multiallelic data (Hedrick 1987;Lewontin 1988). However, since these are all a single summary of multidimensional data, no proposed measure of the strength of LD can be perfect; although each may have strengths and weaknesses with respect to the question being addressed.The two most common measures of the strength of LD are: (1) the normalized measure of the individual LD values (Lewontin 1964), D ij 9 = D ij /D max (see Supporting Information, File S1 for details) and (2) the correlation coefficient r for biallelic data, which is most often reported as Hedrick (1987) extended the D9 measure for multiallelic data as a weighted average over all alleles at each locus of the individual normalized LD values: D9 = S i S j p Ai p Bj |D ij 9| . The multiallelic extension of the r 2 measure iswhere k A and k B indicate the number of ...

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Section: Discussionmentioning

confidence: 99%

Section: Hla Disease Association Datamentioning

confidence: 91%

Conditional Asymmetric Linkage Disequilibrium (ALD): Extending the Biallelic r2 Measure

Thomson

Single

2014

Genetics

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“…In the case of autoimmune diseases, several allelic associations have been established – e.g. HLA-B*2705/2/4/7 with ankylosing spondylitis, HLA-DRB1*0401/*0404/*0405 with rheumatoid arthritis, HLA-DR3, -DQ2 and -C4AQ0 with systemic lupus erythematosus, and HLA-DR3, -DR11 and -DR7 with systemic sclerosis [19,20]. Pericarditis is also associated more or less frequently with autoimmune diseases.…”

Section: Discussionmentioning

confidence: 99%

The Role of the Immunogenetic Background in the Development and Recurrence of Acute Idiopathic Pericarditis

Lazaros

Karavidas²,

Spyropoulou³

et al. 2011

Cardiology

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Objectives: We assessed the role of the immunogenetic background in the development and recurrence of acute idiopathic pericarditis (AIP). Methods: Fifty-five patients with a first episode of AIP were followed for 23.8 ± 6.3 months and recurrences were recorded. The control group consisted of 246 healthy individuals. In all subjects, genomic human leukocyte antigen (HLA) typing was performed. Moreover, circulating lymphocyte subpopulations were studied in 44 randomly selected patients and in 20 controls. Results: An increased frequency of HLA-A*02, -Cw*07 and -DQB1*0202 alleles, and a decreased frequency of the -DQB1*0302 allele was detected in patients with AIP. The recurrence rate was 40% and time to recurrence was 202.8 ± 164.1 days. In patients with idiopathic recurrent pericarditis (RP), increased frequencies of HLA-A*02, -Cw*07 and -DQB1*0202 alleles were found. Notably, no patient with RP exhibited HLA-DRB1*04 and -DQB1*0302 alleles. Patients with RP exhibited lower CD4+/CD45RA+ naïve T cells (p = 0.03) than controls, and higher CD8+DR+ activated T cells (p = 0.01) than patients without recurrence and controls. Conclusions: HLA alleles may confer either susceptibility or resistance to AIP and RP. Circulating T-cell subpopulations may also predict RP. A combination of the above parameters might help to better define patients prone to recurrence.

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“…An exciting and novel approach to the study of associations with the HLA region variables in SSc was described by Karp et al [11]. They subdivided proteins codified by HLA-DRB1 into biologically relevant smaller sequences features (SFs) and their variant types (VTs), and analyzed the combinations of variable amino acid sites shared by several HLA alleles to evaluate which were most likely to describe the causative genetic variants.…”

Section: Hlamentioning

confidence: 99%

The Genetics of Scleroderma

Martín

Fonseca

2010

Curr Rheumatol Rep

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The importance of the genetic component in the pathogenesis of scleroderma, or systemic sclerosis, has been strengthened in the past 2 years with studies on genetic markers-either candidate gene or genome-wide association studies--in large case-control series. Multiple genes have been consistently associated with susceptibility to scleroderma, and interestingly, several of them are involved in immune regulation. Because many of these genes are shared with other autoimmune diseases, a common underlying autoimmune mechanism has been proposed. The challenge that lies ahead is to confirm these associations and to find markers or pathways that are unique to scleroderma and that may define its distinctive phenotype.

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Novel sequence feature variant type analysis of the HLA genetic association in systemic sclerosis

Cited by 35 publications

References 33 publications

Conditional Asymmetric Linkage Disequilibrium (ALD): Extending the Biallelic r2 Measure

Conditional Asymmetric Linkage Disequilibrium (ALD): Extending the Biallelic r2 Measure

The Role of the Immunogenetic Background in the Development and Recurrence of Acute Idiopathic Pericarditis

The Genetics of Scleroderma

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