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Increased risk of rheumatoid arthritis among mothers with children who carry DRB1 risk-associated alleles.

ABSTRACT: OBJECTIVE:To investigate whether a child's genotype affects a mother's risk of rheumatoid arthritis (RA) beyond the risk associated with her genotype and to test whether exposure to fetal alleles inherited from the father increases risk of RA among mothers without risk alleles. METHODS:A case-control study was conducted among 1165 mothers (170 cases/995 controls) and their respective 1482 children. We tested the association between having any child with alleles encoding amino acids (AAs) associated with RA including the 'shared epitope' (SE) and DERAA AA sequences at positions 70-74; AA valine, lysine and alanine at positions 11, 71 and 74 of HLA-DRB1; aspartic acid at position 9 of HLA-B and phenylalanine at position 9 of DPB1. We used logistic regression models to estimate OR and 95% CI for each group of alleles, adjusting for maternal genotype and number of live births. RESULTS:We found increased risk of RA among mothers who had any child with SE (OR 3.0; 95%?CI 2.0 to 4.6); DERAA (OR 1.7; 95%?CI 1.1 to 2.6); or valine (OR 2.3; 95%?CI 1.6 to 3.5), lysine (OR 2.3; 95%?CI 1.5 to 3.4) and alanine (OR 2.8; 95%?CI 1.2 to 6.4) at DRB1 positions 11, 71 and 74, respectively. Among non-carrier mothers, increased risk of RA was associated with having children who carried DERAA (OR 1.7; 95%?CI 1.0 to 2.7) and alleles encoding lysine at DRB1 position 71 (OR 2.3; 95%?CI 1.5 to 4.8). CONCLUSION:Findings support the hypothesis that a child's genotype can contribute independently to risk of RA among mothers.

SUBMITTER: Cruz GI

PROVIDER: S-EPMC7450788 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Increased risk of rheumatoid arthritis among mothers with children who carry <i>DRB1</i> risk-associated alleles.

Cruz Giovanna Ibeth GI Shao Xiaorong X Quach Hong H Ho Kimberly A KA Sterba Kirsten K Noble Janelle A JA Patsopoulos Nikolaos A NA Busch Michael P MP Triulzi Darrell J DJ Wong Wendy Sw WS Solomon Benjamin D BD Niederhuber John E JE Criswell Lindsey A LA Barcellos Lisa F LF

Annals of the rheumatic diseases 20170408 8

<h4>Objective</h4>To investigate whether a child's genotype affects a mother's risk of rheumatoid arthritis (RA) beyond the risk associated with her genotype and to test whether exposure to fetal alleles inherited from the father increases risk of RA among mothers without risk alleles.<h4>Methods</h4>A case-control study was conducted among 1165 mothers (170 cases/995 controls) and their respective 1482 children. We tested the association between having any child with alleles encoding amino acid ...[more]

PMID: 28391248

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Project description:INTRODUCTION: The gene MICA encodes the protein major histocompatibility complex class I polypeptide-related sequence A. It is expressed in synovium of patients with rheumatoid arthritis (RA) and its implication in autoimmunity is discussed. We analyzed the association of genetic variants of MICA with susceptibility to RA. METHODS: Initially, 300 French Caucasian individuals belonging to 100 RA trio families were studied. An additional 100 independent RA trio families and a German Caucasian case-control cohort (90/182 individuals) were available for replication. As MICA is situated in proximity to known risk alleles of the HLA-DRB1 locus, our analysis accounted for linkage disequilibrium either by analyzing the subgroup consisting of parents not carrying HLA-DRB1 risk alleles with transmission disequilibrium test (TDT) or by implementing a regression model including all available data. Analysis included a microsatellite polymorphism (GCT)n and single-nucleotide polymorphisms (SNPs) rs3763288 and rs1051794. RESULTS: In contrast to the other investigated polymorphisms, the non-synonymously coding SNP MICA-250 (rs1051794, Lys196Glu) was strongly associated in the first family cohort (TDT: P = 0.014; regression model: odds ratio [OR] 0.46, 95% confidence interval [CI] 0.25 to 0.82, P = 0.007). Although the replication family sample showed only a trend, combined family data remained consistent with the hypothesis of MICA-250 association independent from shared epitope (SE) alleles (TDT: P = 0.027; regression model: OR 0.56, 95% CI 0.38 to 0.83, P = 0.003). We also replicated the protective association of MICA-250A within a German Caucasian cohort (OR 0.31, 95% CI 0.1 to 0.7, P = 0.005; regression model: OR 0.6, 95% CI 0.37 to 0.96, P = 0.032). We showed complete linkage disequilibrium of MICA-250 (D' = 1, r2= 1) with the functional MICA variant rs1051792 (D' = 1, r2= 1). As rs1051792 confers differential allelic affinity of MICA to the receptor NKG2D, this provides a possible functional explanation for the observed association. CONCLUSIONS: We present evidence for linkage and association of MICA-250 (rs1051794) with RA independent of known HLA-DRB1 risk alleles, suggesting MICA as an RA susceptibility gene. However, more studies within other populations are necessary to prove the general relevance of this polymorphism for RA.

Dataset Information

Increased risk of rheumatoid arthritis among mothers with children who carry DRB1 risk-associated alleles.

Publications

Increased risk of rheumatoid arthritis among mothers with children who carry <i>DRB1</i> risk-associated alleles.

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