Association of SLC11A1 (NRAMP1) with persistent oligoarticular and polyarticular rheumatoid factor-negative juvenile idiopathic arthritis in Finnish patients: Haplotype analysis in Finnish families

Jonathan A. Runstadler, Hanna Säilä, Anneli Savolainen, Marjatta Leirisalo-Repo, Kimmo Aho, Eva Tuomilehto-Wolf, Jaakko Tuomilehto, Michael F Seldin

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Abstract

Objective. The SLC11A1 (formerly called NRAMP1) gene is important in natural resistance to a variety of intracellular infections mediated by macrophages and has been proposed as a candidate gene for autoimmune disease susceptibility. The aim of this study was to examine susceptibility in Finnish patients with persistent oligoarticular and polyarticular rheumatoid factor (RF)-negative juvenile idiopathic arthritis (JIA) due to the presence of the SLC11A1 locus on chromosome 2. Methods. A total of 234 Finnish JIA nuclear families and 639 elderly Finnish controls without a history of JIA were evaluated for association with JIA at 3 intragenic single-nucleotide polymorphisms: an intragenie insertion/deletion, a promoter microsatellite (NRAMP1), and a 3′ microsatellite (D2S1471). Results. Analysis of marker haplotypes demonstrated a strong association of Finnish JIA with 6-marker, 4-marker, and 2-marker haplotypes. Most impressively, 1 of the 6-marker haplotypes showed an odds ratio (OR) of 4.0 (95% confidence interval [95% CI] 2.6-6.2) in all JIA patients, 3.5 (95% CI 1.9-6.5) in those with persistent oligoarticular JIA, and 4.1 (95% CI 2.5-6.7) in those with polyarticular RF-negative JIA. Stratification of the haplotype data suggested that susceptibility to JIA in the haplotype spanning the SLC11A1 locus is independent (P < 0.01) of an association with a DRB1 JIA shared epitope (DRB1*JIASE) that includes well-characterized strong susceptibility to DRB1*08 and *11 alleles. This SLC11A1 haplotype also had an additive effect with DRB1*JIASE in those with polyarticular, but not those with persistent oligoarticular, disease (P = 0.06, OR 2.9 [95% CI 0.9-9.2] versus P = 0.5, OR 1.6 [95% CI 0.4-6.0]). Conclusion. Taken together, these data provide support for the existence of a locus at or near SLC11A1 that is a strong susceptibility factor for JIA in Finnish patients.

Original languageEnglish (US)
Pages (from-to)247-256
Number of pages10
JournalArthritis and Rheumatism
Volume52
Issue number1
DOIs
StatePublished - Jan 2005

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Juvenile Arthritis
Rheumatoid Factor
Haplotypes
Confidence Intervals
Odds Ratio
Microsatellite Repeats
Epitopes
Chromosomes, Human, Pair 2
Disease Susceptibility
Nuclear Family
Innate Immunity
Genes
Autoimmune Diseases
Single Nucleotide Polymorphism
Alleles
Macrophages

ASJC Scopus subject areas

  • Immunology
  • Rheumatology

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Association of SLC11A1 (NRAMP1) with persistent oligoarticular and polyarticular rheumatoid factor-negative juvenile idiopathic arthritis in Finnish patients : Haplotype analysis in Finnish families. / Runstadler, Jonathan A.; Säilä, Hanna; Savolainen, Anneli; Leirisalo-Repo, Marjatta; Aho, Kimmo; Tuomilehto-Wolf, Eva; Tuomilehto, Jaakko; Seldin, Michael F.

In: Arthritis and Rheumatism, Vol. 52, No. 1, 01.2005, p. 247-256.

Research output: Contribution to journalArticle

Runstadler, Jonathan A. ; Säilä, Hanna ; Savolainen, Anneli ; Leirisalo-Repo, Marjatta ; Aho, Kimmo ; Tuomilehto-Wolf, Eva ; Tuomilehto, Jaakko ; Seldin, Michael F. / Association of SLC11A1 (NRAMP1) with persistent oligoarticular and polyarticular rheumatoid factor-negative juvenile idiopathic arthritis in Finnish patients : Haplotype analysis in Finnish families. In: Arthritis and Rheumatism. 2005 ; Vol. 52, No. 1. pp. 247-256.
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abstract = "Objective. The SLC11A1 (formerly called NRAMP1) gene is important in natural resistance to a variety of intracellular infections mediated by macrophages and has been proposed as a candidate gene for autoimmune disease susceptibility. The aim of this study was to examine susceptibility in Finnish patients with persistent oligoarticular and polyarticular rheumatoid factor (RF)-negative juvenile idiopathic arthritis (JIA) due to the presence of the SLC11A1 locus on chromosome 2. Methods. A total of 234 Finnish JIA nuclear families and 639 elderly Finnish controls without a history of JIA were evaluated for association with JIA at 3 intragenic single-nucleotide polymorphisms: an intragenie insertion/deletion, a promoter microsatellite (NRAMP1), and a 3′ microsatellite (D2S1471). Results. Analysis of marker haplotypes demonstrated a strong association of Finnish JIA with 6-marker, 4-marker, and 2-marker haplotypes. Most impressively, 1 of the 6-marker haplotypes showed an odds ratio (OR) of 4.0 (95{\%} confidence interval [95{\%} CI] 2.6-6.2) in all JIA patients, 3.5 (95{\%} CI 1.9-6.5) in those with persistent oligoarticular JIA, and 4.1 (95{\%} CI 2.5-6.7) in those with polyarticular RF-negative JIA. Stratification of the haplotype data suggested that susceptibility to JIA in the haplotype spanning the SLC11A1 locus is independent (P < 0.01) of an association with a DRB1 JIA shared epitope (DRB1*JIASE) that includes well-characterized strong susceptibility to DRB1*08 and *11 alleles. This SLC11A1 haplotype also had an additive effect with DRB1*JIASE in those with polyarticular, but not those with persistent oligoarticular, disease (P = 0.06, OR 2.9 [95{\%} CI 0.9-9.2] versus P = 0.5, OR 1.6 [95{\%} CI 0.4-6.0]). Conclusion. Taken together, these data provide support for the existence of a locus at or near SLC11A1 that is a strong susceptibility factor for JIA in Finnish patients.",
author = "Runstadler, {Jonathan A.} and Hanna S{\"a}il{\"a} and Anneli Savolainen and Marjatta Leirisalo-Repo and Kimmo Aho and Eva Tuomilehto-Wolf and Jaakko Tuomilehto and Seldin, {Michael F}",
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T2 - Haplotype analysis in Finnish families

AU - Runstadler, Jonathan A.

AU - Säilä, Hanna

AU - Savolainen, Anneli

AU - Leirisalo-Repo, Marjatta

AU - Aho, Kimmo

AU - Tuomilehto-Wolf, Eva

AU - Tuomilehto, Jaakko

AU - Seldin, Michael F

PY - 2005/1

Y1 - 2005/1

N2 - Objective. The SLC11A1 (formerly called NRAMP1) gene is important in natural resistance to a variety of intracellular infections mediated by macrophages and has been proposed as a candidate gene for autoimmune disease susceptibility. The aim of this study was to examine susceptibility in Finnish patients with persistent oligoarticular and polyarticular rheumatoid factor (RF)-negative juvenile idiopathic arthritis (JIA) due to the presence of the SLC11A1 locus on chromosome 2. Methods. A total of 234 Finnish JIA nuclear families and 639 elderly Finnish controls without a history of JIA were evaluated for association with JIA at 3 intragenic single-nucleotide polymorphisms: an intragenie insertion/deletion, a promoter microsatellite (NRAMP1), and a 3′ microsatellite (D2S1471). Results. Analysis of marker haplotypes demonstrated a strong association of Finnish JIA with 6-marker, 4-marker, and 2-marker haplotypes. Most impressively, 1 of the 6-marker haplotypes showed an odds ratio (OR) of 4.0 (95% confidence interval [95% CI] 2.6-6.2) in all JIA patients, 3.5 (95% CI 1.9-6.5) in those with persistent oligoarticular JIA, and 4.1 (95% CI 2.5-6.7) in those with polyarticular RF-negative JIA. Stratification of the haplotype data suggested that susceptibility to JIA in the haplotype spanning the SLC11A1 locus is independent (P < 0.01) of an association with a DRB1 JIA shared epitope (DRB1*JIASE) that includes well-characterized strong susceptibility to DRB1*08 and *11 alleles. This SLC11A1 haplotype also had an additive effect with DRB1*JIASE in those with polyarticular, but not those with persistent oligoarticular, disease (P = 0.06, OR 2.9 [95% CI 0.9-9.2] versus P = 0.5, OR 1.6 [95% CI 0.4-6.0]). Conclusion. Taken together, these data provide support for the existence of a locus at or near SLC11A1 that is a strong susceptibility factor for JIA in Finnish patients.

AB - Objective. The SLC11A1 (formerly called NRAMP1) gene is important in natural resistance to a variety of intracellular infections mediated by macrophages and has been proposed as a candidate gene for autoimmune disease susceptibility. The aim of this study was to examine susceptibility in Finnish patients with persistent oligoarticular and polyarticular rheumatoid factor (RF)-negative juvenile idiopathic arthritis (JIA) due to the presence of the SLC11A1 locus on chromosome 2. Methods. A total of 234 Finnish JIA nuclear families and 639 elderly Finnish controls without a history of JIA were evaluated for association with JIA at 3 intragenic single-nucleotide polymorphisms: an intragenie insertion/deletion, a promoter microsatellite (NRAMP1), and a 3′ microsatellite (D2S1471). Results. Analysis of marker haplotypes demonstrated a strong association of Finnish JIA with 6-marker, 4-marker, and 2-marker haplotypes. Most impressively, 1 of the 6-marker haplotypes showed an odds ratio (OR) of 4.0 (95% confidence interval [95% CI] 2.6-6.2) in all JIA patients, 3.5 (95% CI 1.9-6.5) in those with persistent oligoarticular JIA, and 4.1 (95% CI 2.5-6.7) in those with polyarticular RF-negative JIA. Stratification of the haplotype data suggested that susceptibility to JIA in the haplotype spanning the SLC11A1 locus is independent (P < 0.01) of an association with a DRB1 JIA shared epitope (DRB1*JIASE) that includes well-characterized strong susceptibility to DRB1*08 and *11 alleles. This SLC11A1 haplotype also had an additive effect with DRB1*JIASE in those with polyarticular, but not those with persistent oligoarticular, disease (P = 0.06, OR 2.9 [95% CI 0.9-9.2] versus P = 0.5, OR 1.6 [95% CI 0.4-6.0]). Conclusion. Taken together, these data provide support for the existence of a locus at or near SLC11A1 that is a strong susceptibility factor for JIA in Finnish patients.

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