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Genome-wide analysis of single-locus and epistasis single-nucleotide polymorphism effects on anti-cyclic citrullinated peptide as a measure of rheumatoid arthritis.

Ma L, Dvorkin D, Garbe JR, Da Y - BMC Proc (2007)

Bottom Line: Three single-locus effects of two SNPs were significant (p < 10-4).A total of ten epistasis effects of eight pairs of SNPs on 11 autosomes and the X chromosome had significant epistasis effects (p < 10-7).The results indicate that the genetic factors underlying anti-CCP may include single-gene action and gene interactions and that the gene-interaction mechanism underlying anti-CCP could be a complex mechanism involving pairwise epistasis effects and multiple SNPs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Animal Science, University of Minnesota, 1364 Eckles Avenue, St, Paul, Minnesota 55108, USA. maxxx131@umn.edu

ABSTRACT
The goal of this study was to identify single-locus and epistasis effects of SNP markers on anti-cyclic citrullinated peptide (anti-CCP) that is associated with rheumatoid arthritis, using the North American Rheumatoid Arthritis Consortium data. A square root transformation of the phenotypic values of anti-CCP with sex, smoking status, and a selected subset of 20 single-nucleotide polymorphism (SNP) markers in the model achieved residual normality (p > 0.05). Three single-locus effects of two SNPs were significant (p < 10-4). The epistasis analysis tested five effects of each pair of SNPs, the two-locus interaction, additive x additive, additive x dominance, dominance x additive, and dominance x dominance effects. A total of ten epistasis effects of eight pairs of SNPs on 11 autosomes and the X chromosome had significant epistasis effects (p < 10-7). Three of these epistasis effects reached significance levels of p < 10-8, p < 10-9, and p < 10-10, respectively. Two potential SNP epistasis networks were identified. The results indicate that the genetic factors underlying anti-CCP may include single-gene action and gene interactions and that the gene-interaction mechanism underlying anti-CCP could be a complex mechanism involving pairwise epistasis effects and multiple SNPs.

No MeSH data available.


Related in: MedlinePlus

Two potential epistasis networks each centered at an SNP that had one of the most significant epistasis effects and interacted with other loci at lower significance levels. Each type of epistasis effect is represented by the line color: black, I effect; red, A × A; purple, A × D; blue, D × A; green, D × D. A pair of SNPs connected by two lines had two significant epistasis effects. The significance level of each epistasis effect is represented by the node color: red, p < 10-10; cyan, p < 10-7; green, p < 10-6; yellow, p < 10-5. A, Epistasis network centered at rs1009172 of chromosome 11; B, Epistasis network centered at rs1395610 of chromosome 18.
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Figure 2: Two potential epistasis networks each centered at an SNP that had one of the most significant epistasis effects and interacted with other loci at lower significance levels. Each type of epistasis effect is represented by the line color: black, I effect; red, A × A; purple, A × D; blue, D × A; green, D × D. A pair of SNPs connected by two lines had two significant epistasis effects. The significance level of each epistasis effect is represented by the node color: red, p < 10-10; cyan, p < 10-7; green, p < 10-6; yellow, p < 10-5. A, Epistasis network centered at rs1009172 of chromosome 11; B, Epistasis network centered at rs1395610 of chromosome 18.

Mentions: The epistasis results indicate that the gene interaction mechanism underlying anti-CCP could be a complex mechanism involving three types of epistasis effects and multiple SNPs, where 'three types of epistasis' refers to A × A, A × D or D × A, and D × D. The exact content of this complex mechanism can be illustrated using the example of three highly significant pairs of SNPs, rs1009172 (chromosome 11) and rs17410 (chromosome X), rs2056553 (chromosome 7) and rs1328327 (chromosome 10), and rs1400142 (chromosome 12) and rs1959068 (chromosome 14). The exact gene interaction mechanism of these three pairs is (A × A)-(D × A)-(D × D). Close examination of each of the three epistasis effects showed that individuals with 1_1 allele combination of rs1009172 (chromosome 11) and rs17410 (chromosome X) SNP pair, 22_2 genotype-allele combination of rs2056553 (chromosome 7) and rs1328327 (chromosome 10) SNP pair, and 11_12 genotype-genotype combination of rs1400142 (chromosome 12) and rs1959068 (chromosome 14) SNP pair had the lowest square root transformed anti-CCP values. In contrast, individuals with 1_2 allele combination of rs1009172 (chromosome 11) and rs17410 (chromosome X) SNP pair, 12_2 genotype-allele combination of rs2056553 (chromosome 7) and rs1328327 (chromosome 10) SNP pair, and 11_11 genotype-genotype combination of rs1400142 (chromosome 12) and rs1959068 (chromosome 14) SNP pair had the highest square root transformed anti-CCP values. In addition to highly significant epistasis effects, an epistasis network around a locus that has a highly significant epistasis effect with at least one locus and interacted with a large number of other loci at a lower significance level (higher p-value) should be of interest, because many significant epistasis effects involving one locus at a lower significance level are less likely to be random than a single epistasis effect at the same significance level. Figure 2 shows two examples of such epistasis network.


Genome-wide analysis of single-locus and epistasis single-nucleotide polymorphism effects on anti-cyclic citrullinated peptide as a measure of rheumatoid arthritis.

Ma L, Dvorkin D, Garbe JR, Da Y - BMC Proc (2007)

Two potential epistasis networks each centered at an SNP that had one of the most significant epistasis effects and interacted with other loci at lower significance levels. Each type of epistasis effect is represented by the line color: black, I effect; red, A × A; purple, A × D; blue, D × A; green, D × D. A pair of SNPs connected by two lines had two significant epistasis effects. The significance level of each epistasis effect is represented by the node color: red, p < 10-10; cyan, p < 10-7; green, p < 10-6; yellow, p < 10-5. A, Epistasis network centered at rs1009172 of chromosome 11; B, Epistasis network centered at rs1395610 of chromosome 18.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2367477&req=5

Figure 2: Two potential epistasis networks each centered at an SNP that had one of the most significant epistasis effects and interacted with other loci at lower significance levels. Each type of epistasis effect is represented by the line color: black, I effect; red, A × A; purple, A × D; blue, D × A; green, D × D. A pair of SNPs connected by two lines had two significant epistasis effects. The significance level of each epistasis effect is represented by the node color: red, p < 10-10; cyan, p < 10-7; green, p < 10-6; yellow, p < 10-5. A, Epistasis network centered at rs1009172 of chromosome 11; B, Epistasis network centered at rs1395610 of chromosome 18.
Mentions: The epistasis results indicate that the gene interaction mechanism underlying anti-CCP could be a complex mechanism involving three types of epistasis effects and multiple SNPs, where 'three types of epistasis' refers to A × A, A × D or D × A, and D × D. The exact content of this complex mechanism can be illustrated using the example of three highly significant pairs of SNPs, rs1009172 (chromosome 11) and rs17410 (chromosome X), rs2056553 (chromosome 7) and rs1328327 (chromosome 10), and rs1400142 (chromosome 12) and rs1959068 (chromosome 14). The exact gene interaction mechanism of these three pairs is (A × A)-(D × A)-(D × D). Close examination of each of the three epistasis effects showed that individuals with 1_1 allele combination of rs1009172 (chromosome 11) and rs17410 (chromosome X) SNP pair, 22_2 genotype-allele combination of rs2056553 (chromosome 7) and rs1328327 (chromosome 10) SNP pair, and 11_12 genotype-genotype combination of rs1400142 (chromosome 12) and rs1959068 (chromosome 14) SNP pair had the lowest square root transformed anti-CCP values. In contrast, individuals with 1_2 allele combination of rs1009172 (chromosome 11) and rs17410 (chromosome X) SNP pair, 12_2 genotype-allele combination of rs2056553 (chromosome 7) and rs1328327 (chromosome 10) SNP pair, and 11_11 genotype-genotype combination of rs1400142 (chromosome 12) and rs1959068 (chromosome 14) SNP pair had the highest square root transformed anti-CCP values. In addition to highly significant epistasis effects, an epistasis network around a locus that has a highly significant epistasis effect with at least one locus and interacted with a large number of other loci at a lower significance level (higher p-value) should be of interest, because many significant epistasis effects involving one locus at a lower significance level are less likely to be random than a single epistasis effect at the same significance level. Figure 2 shows two examples of such epistasis network.

Bottom Line: Three single-locus effects of two SNPs were significant (p < 10-4).A total of ten epistasis effects of eight pairs of SNPs on 11 autosomes and the X chromosome had significant epistasis effects (p < 10-7).The results indicate that the genetic factors underlying anti-CCP may include single-gene action and gene interactions and that the gene-interaction mechanism underlying anti-CCP could be a complex mechanism involving pairwise epistasis effects and multiple SNPs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Animal Science, University of Minnesota, 1364 Eckles Avenue, St, Paul, Minnesota 55108, USA. maxxx131@umn.edu

ABSTRACT
The goal of this study was to identify single-locus and epistasis effects of SNP markers on anti-cyclic citrullinated peptide (anti-CCP) that is associated with rheumatoid arthritis, using the North American Rheumatoid Arthritis Consortium data. A square root transformation of the phenotypic values of anti-CCP with sex, smoking status, and a selected subset of 20 single-nucleotide polymorphism (SNP) markers in the model achieved residual normality (p > 0.05). Three single-locus effects of two SNPs were significant (p < 10-4). The epistasis analysis tested five effects of each pair of SNPs, the two-locus interaction, additive x additive, additive x dominance, dominance x additive, and dominance x dominance effects. A total of ten epistasis effects of eight pairs of SNPs on 11 autosomes and the X chromosome had significant epistasis effects (p < 10-7). Three of these epistasis effects reached significance levels of p < 10-8, p < 10-9, and p < 10-10, respectively. Two potential SNP epistasis networks were identified. The results indicate that the genetic factors underlying anti-CCP may include single-gene action and gene interactions and that the gene-interaction mechanism underlying anti-CCP could be a complex mechanism involving pairwise epistasis effects and multiple SNPs.

No MeSH data available.


Related in: MedlinePlus