Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement

The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.


Genome Wide Association Study of Genetic Predictors of Quantitative Anti-CCP Level in RA

Cui1,  Jing, DeStefano2,  Anita, Weinblatt1,  Michael E., Plenge1,  Robert M., Shadick3,  Nancy A., Karlson1,  Elizabeth W.

Brigham and Women's Hospital, Boston, MA
Boston University Schools of Public Health and Medicine, Boston, MA
Brigham and Women's Hospital, Harvard Medical School, Boston, MA

Purpose:

Anti-cyclic citrullinated peptide (anti-CCP) antibody is a marker for progressive erosive rheumatoid arthritis (RA), and a stable quantitative trait. To identify genes that influence quantitative anti-CCP level in RA patients, we carried out a genome wide association study (GWAS) using 909,622 SNPs genotyped in 507 anti-CCP+ RA patients from the Brigham Rheumatoid Arthritis Sequential Study (BRASS).

Method:

Anti-CCP was measured using a second generation ELISA assay (Inova Diagnostics, Inc). Samples were genotyped using Affymetrix 6.0 genotyping platform ("900K array"). To ensure high quality data and to minimize false positive results due to technical artifact, filtering criteria were set as: genotype call rate >=0.95 per SNP and >=0.95 per individual), minor allele frequency (MAF) >=0.01, p-value for Hardy-Weinberg equilibrium test >=0.0001. There were 734,008 SNPs from 491 self-reported Caucasians (81.9% female) that met the criteria. Anti-CCP measures were transformed to a normal distribution by taking the inverse normal of the rank. Association between SNPs and transformed anti-CCP level was tested using general linear model assuming additive model in PLINK. The empirical p value from permutation was utilized to evaluate genome wide significance.

Results:

Mean age was 58.7 and disease duration was 16.7 years. Median anti-CCP titer was 119 (range 20–448). We identified 5 SNPs at p value ~10-6, 46 SNPs at p~10-5, and 721 SNPs at p~10-4. The best SNP within the MHC region has association at p ~10-4. Genome wide permutation testing was pursued to further evaluate the GWAS findings. Under the null, if there is no genetic determinant for anti-CCP level, by chance, we would expect approximately 728 false positive SNPs to be identified at 10-4 significance level, however we observed 775. The excess of observed compared to expected results were significant (p=0.04).

Conclusion:

We carried out an initial genome wide scan on the quantitative trait anti-CCP level. The top 5 SNPs association with anti-CCP level did not reach genome wide significance, however we plan to validate our findings using two independent CCP+ RA cohorts.

Table. Top 20 SNPs associations with Anti-CCP level

ChromosomeSNPgeneBetaP value
7rs4296976FLJ422800.3232.6E–06
2rs2034273HAAO0.3246.4E–06
19rs6966PPP1R13L-0.3747.9E–06
9rs4364717CDKN2B-0.2778.2E–06
1rs1608926-0.7678.8E–06
17rs3744741GEMIN40.3831.2E–05
20rs6064542-0.7631.3E–05
14rs958187FAM14A-0.3631.7E–05
2rs10170593HAAO0.3281.8E–05
9rs12555056FREQ0.3181.9E–05
17rs47935230.2902.1E–05
20rs3787457SLC23A20.3042.2E–05
18rs6507907LAMA3-0.4702.3E–05
12rs12230811SRGAP1-0.7382.4E–05
9rs10123925PAX5-0.3252.5E–05
14rs8021596TXNDC1-0.3532.6E–05
6rs2472867FARS2-0.3452.7E–05
2rs3771686BAZ2B-0.3342.9E–05
20rs17001360CBLN4-0.4303.6E–05
8rs125460540.5253.9E–05

To cite this abstract, please use the following information:
Cui, Jing, DeStefano, Anita, Weinblatt, Michael E., Plenge, Robert M., Shadick, Nancy A., Karlson, Elizabeth W.; Genome Wide Association Study of Genetic Predictors of Quantitative Anti-CCP Level in RA [abstract]. Arthritis Rheum 2009;60 Suppl 10 :747
DOI: 10.1002/art.25827

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