7 research outputs found
Gene-level association analysis of systemic sclerosis: A comparison of African-Americans and White populations
All authors: Olga Y. Gorlova ,
Yafang Li,
Ivan Gorlov,
Jun Ying,
Wei V. Chen,
Shervin Assassi,
John D. Reveille,
Frank C. Arnett,
Xiaodong Zhou,
Lara Bossini-Castillo,
Elena Lopez-Isac,
Marialbert Acosta-Herrera,
Peter K. Gregersen,
Annette T. Lee,
Virginia D. Steen,
Barri J. Fessler,
Dinesh Khanna,
Elena Schiopu,
Richard M. Silver,
Jerry A. Molitor,
Daniel E. Furst,
Suzanne Kafaja,
Robert W. Simms,
Robert A. Lafyatis,
Patricia Carreira,
Carmen Pilar Simeon,
Ivan Castellvi,
Emma Beltran,
Norberto Ortego,
Christopher I. Amos,
Javier Martin,
Maureen D. Mayes.Data Availability Statement: Genetic data is
available from dbGaP repository (https://www.ncbi.
nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_
id=phs000357.v1.p1).Gene-level analysis of ImmunoChip or genome-wide association studies (GWAS) data has not been previously reported for systemic sclerosis (SSc, scleroderma). The objective of this study was to analyze genetic susceptibility loci in SSc at the gene level and to determine if the detected associations were shared in African-American and White populations, using data from ImmunoChip and GWAS genotyping studies. The White sample included 1833 cases and 3466 controls (956 cases and 2741 controls from the US and 877 cases and 725 controls from Spain) and the African American sample, 291 cases and 260 controls. In both Whites and African Americans, we performed a gene-level analysis that integrates association statistics in a gene possibly harboring multiple SNPs with weak effect on disease risk, using Versatile Gene-based Association Study (VEGAS) software. The SNP-level analysis was performed using PLINK v.1.07. We identified 4 novel candidate genes (STAT1, FCGR2C, NIPSNAP3B, and SCT) significantly associated and 4 genes (SERBP1, PINX1, TMEM175 and EXOC2) suggestively associated with SSc in the gene level analysis in White patients. As an exploratory analysis we compared the results on Whites with those from African Americans. Of previously established susceptibility genes identified in Whites, only TNFAIP3 was significant at the nominal level (p = 6.13x10-3) in African Americans in the gene-level analysis of the ImmunoChip data. Among the top suggestive novel genes identified in Whites based on the ImmunoChip data, FCGR2C and PINX1 were only nominally significant in African Americans (p = 0.016 and p = 0.028, respectively), while among the top novel genes identified in the gene-level analysis in African Americans, UNC5C (p = 5.57x10-4) and CLEC16A (p = 0.0463) were also nominally significant in Whites. We also present the gene-level analysis of SSc clinical and autoantibody phenotypes among Whites. Our findings need to be validated by independent studies, particularly due to the limited sample size of African Americans.Funding was provided to MDM by the National Institutes of Health (NIH) the National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS https://www.niams.nih.gov/) Centers of Research Translation (CORT) P50-AR054144, NIH grant N01-AR-02251 and R01-AR-055258, and the Department of Defense (DD) Congressionally Directed Medical Research Program (http://cdmrp.army.mil/) W81XWH-07-1-011 and WX81XWH-13-1-0452 for the collection, analysis and interpretation of the data
Representation of the haplotypes carrying the <i>HLA-DRB1</i> alleles most associated with IgAD.
<p>Reconstructed extended haplotypes using the final set of 49 SNPs spanning the classical HLA region were aligned to the respective extended haplotype. Shown here are the reconstructed haplotypes carrying the HLA-DRB1*03 (a), -DRB1*07 (b), -DRB1*0102 (c) and -DRB1*15 (d) alleles. Recombinant haplotypes represent all haplotypes containing the same <i>HLA-DRB1</i> allele in association with a different <i>HLA-B</i> allele, as compared to the respective extended haplotype. Vertical bars delimit the HLA Class III region. N, Number of haplotypes. Haplotype frequencies in the Swedish/Icelandic, Spanish and Icelandic cohorts are detailed in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002476#pgen-1002476-t001" target="_blank">Table 1</a>.</p
Secondary association signals in the HLA locus.
<p>Combined <i>P</i> values are shown for all SNPs and imputed HLA alleles, following conditioning on the HLA-B*0801-DRB1*0301-DQB1*02 (red diamonds), the HLA-B*0801-DRB1*0301-DQB1*02+HLA-DRB1*0701-DQB1*02 (yellow triangles) and the HLA-B*0801-DRB1*0301-DQB1*02+HLA-DRB1*0701-DQB1*02+HLA-DRB1*0102 (green circles) haplotypes. All association results are represented as the −log<sub>10</sub> of the combined <i>P</i> values (left y-axis). The most associated SNP and HLA allele in each step of the stepwise conditional logistic regression analysis are indicated by squares. Recombination rates from the HapMap CEU are depicted in blue (right y-axis). Genomic positions on the x-axis are based on the NCBI Build 36 (hg 18) assembly. Mb, megabase pairs.</p
Primary association signal of the HLA locus with IgAD.
<p>Allele-based association tests were performed for all 1,686 genotyped SNPs and imputed HLA alleles (represented by yellow diamonds) and for the 9,905 SNPs imputed with high confidence using the HapMap2 reference set (represented by light blue circles). All association results are represented as the −log<sub>10</sub> of the combined <i>P</i> values (left y-axis). The most associated SNP and HLA allele are indicated by yellow squares. Recombination rates from the HapMap CEU are depicted in dark blue (right y-axis). Genomic positions on the x-axis are based on the NCBI Build 36 (hg 18) assembly. CI, confidence interval; Mb, megabase pairs.</p
Genes most significant (at p<10<sup>−3</sup>) in African Americans in the gene-level analysis and the results for these genes in Whites, based on ImmunoChip.
<p>Genes most significant (at p<10<sup>−3</sup>) in African Americans in the gene-level analysis and the results for these genes in Whites, based on ImmunoChip.</p
Comparison of novel candidate genes (at p<4.35x10<sup>-6</sup> indicated in bold) and suggestive genes (4.35x10<sup>-6</sup>−5) detected in Whites to the corresponding statistics in African Americans in the gene level analysis, based on ImmunoChip.
<p>Comparison of novel candidate genes (at p<4.35x10<sup>-6</sup> indicated in bold) and suggestive genes (4.35x10<sup>-6</sup>−5) detected in Whites to the corresponding statistics in African Americans in the gene level analysis, based on ImmunoChip.</p
Results of the gene-level analyses for known genes associated with risk of SSc in Whites and African Americans, based on ImmunoChip.
<p>Results of the gene-level analyses for known genes associated with risk of SSc in Whites and African Americans, based on ImmunoChip.</p