Dataset Information

Integration of sequence data from a Consanguineous family with genetic data from an outbred population identifies PLB1 as a candidate rheumatoid arthritis risk gene.

ABSTRACT: Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P = 0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF = 0.042] and rs116541814 [MAF = 0.021], combined P = 3.2 × 10(-6)). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P = 0.049 for C-alpha test and P = 0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted.

SUBMITTER: Okada Y

PROVIDER: S-EPMC3919745 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Integration of sequence data from a Consanguineous family with genetic data from an outbred population identifies PLB1 as a candidate rheumatoid arthritis risk gene.

Okada Yukinori Y Diogo Dorothee D Greenberg Jeffrey D JD Mouassess Faten F Achkar Walid A L WA Fulton Robert S RS Denny Joshua C JC Gupta Namrata N Mirel Daniel D Gabriel Stacy S Li Gang G Kremer Joel M JM Pappas Dimitrios A DA Carroll Robert J RJ Eyler Anne E AE Trynka Gosia G Stahl Eli A EA Cui Jing J Saxena Richa R Coenen Marieke J H MJ Guchelaar Henk-Jan HJ Huizinga Tom W J TW Dieudé Philippe P Mariette Xavier X Barton Anne A Canhão Helena H Fonseca João E JE de Vries Niek N Tak Paul P PP Moreland Larry W LW Bridges S Louis SL Miceli-Richard Corinne C Choi Hyon K HK Kamatani Yoichiro Y Galan Pilar P Lathrop Mark M Raj Towfique T De Jager Philip L PL Raychaudhuri Soumya S Worthington Jane J Padyukov Leonid L Klareskog Lars L Siminovitch Katherine A KA Gregersen Peter K PK Mardis Elaine R ER Arayssi Thurayya T Kazkaz Layla A LA Plenge Robert M RM

PloS one 20140210 2

Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrel ...[more]

PMID: 24520335

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Project description:BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disorder affecting approximately 1% of the population. The disease results from the interplay between an individual's genetic background and unknown environmental triggers. Although human leukocyte antigens (HLAs) account for approximately 30% of the heritable risk, the identities of non-HLA genes explaining the remainder of the genetic component are largely unknown. Based on functional data in mice, we hypothesized that the immune-related genes complement component 5 (C5) and/or TNF receptor-associated factor 1 (TRAF1), located on Chromosome 9q33-34, would represent relevant candidate genes for RA. We therefore aimed to investigate whether this locus would play a role in RA.Methods and findingsWe performed a multitiered case-control study using 40 single-nucleotide polymorphisms (SNPs) from the TRAF1 and C5 (TRAF1/C5) region in a set of 290 RA patients and 254 unaffected participants (controls) of Dutch origin. Stepwise replication of significant SNPs was performed in three independent sample sets from the Netherlands (ncases/controls = 454/270), Sweden (ncases/controls = 1,500/1,000) and US (ncases/controls = 475/475). We observed a significant association (p < 0.05) of SNPs located in a haplotype block that encompasses a 65 kb region including the 3' end of C5 as well as TRAF1. A sliding window analysis revealed an association peak at an intergenic region located approximately 10 kb from both C5 and TRAF1. This peak, defined by SNP14/rs10818488, was confirmed in a total of 2,719 RA patients and 1,999 controls (odds ratiocommon = 1.28, 95% confidence interval 1.17-1.39, pcombined = 1.40 x 10(-8)) with a population-attributable risk of 6.1%. The A (minor susceptibility) allele of this SNP also significantly correlates with increased disease progression as determined by radiographic damage over time in RA patients (p = 0.008).ConclusionsUsing a candidate-gene approach we have identified a novel genetic risk factor for RA. Our findings indicate that a polymorphism in the TRAF1/C5 region increases the susceptibility to and severity of RA, possibly by influencing the structure, function, and/or expression levels of TRAF1 and/or C5.

Dataset Information

Integration of sequence data from a Consanguineous family with genetic data from an outbred population identifies PLB1 as a candidate rheumatoid arthritis risk gene.

Publications

Integration of sequence data from a Consanguineous family with genetic data from an outbred population identifies PLB1 as a candidate rheumatoid arthritis risk gene.

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