Association of rheumatoid factor production with FcγRIIIa polymorphism in Taiwanese rheumatoid arthritis

Fcγ receptors (FcγR) impact upon the development of inflammatory arthritis through immune complex stimulation and proinflammatory cytokine production. FcγRIIa, FcγRΙΙΙa and FcRγIIIb polymorphisms were genotyped in 212 rheumatoid arthritis (RA) patients and 371 healthy control subjects using an allelic-specific polymerase chain reaction (PCR). No significant skewing in the distribution of FcγRIIa H/R131, FcγRIIIa F/V158 and FcγRIIIb NA1/NA2 was found between RA patients and healthy control subjects. However, a significant skewing distribution of the FcγRIIIa F/V158 polymorphism was observed between rheumatoid factor (RF)-positive versus RF-negative RA patients (P = 0·01). The low-affinity FcγRIIIa F158 allele seems to have a protective role in RF production, in comparison with the FcγRIIIa V158 allele (P = 0·004; OR = 0·485; 95% CI: 0·293–0·803). A high frequency of FcγRIIIa F/F158 was identified in RA patients with negative RF compared with RF-positive patients (for FF158 versus FV158 + VV158; P = 0·002; OR = 0·372; 95% CI: 0·194–0·713). In addition, no association was found between FcγRIIa H/R131, FcγΡIIIa F/V158 and FcγRIIIb NA1/NA2 polymorphisms and other clinical parameters. The results of this study suggest that three activating FcγRs polymorphisms lack association with RA but FcγIIIa F/V158 polymorphism may influence RF production and IgG RF immune complex handling in Taiwanese RA patients

Disease association of two distinct interleukin-18 promoter polymorphisms in Caucasian rheumatoid arthritis patients

Interleukin (IL)-18 is an important mediator of innate and adaptive immunity. We searched for an association of IL-18 promoter single-nucleotide polymorphisms (SNP) with rheumatoid arthritis (RA) in Caucasians. The entire study population was composed of two independent cohorts from Germany (n=200) and Scotland (n=410). Presence of IL-18 SNP at positions -607 and -137 was determined by allele-specific PCR in 327 RA patients and 283 healthy donors (HD). Diplotype distributions of both loci were in Hardy-Weinberg equilibrium (HWE) in the German and Scottish HD cohorts. In contrast, locus -607 was in HW disequilibrium in German, and locus -137 in Scottish RA patients. Diplotypic exact chi(2) tests suggested that -607CC was overrepresented in German, and -137CC in Scottish RA patients, but conservative chi(2) trend analyses could not prove any significant disease association of these single loci. SNP -607 and -137 were in strong linkage disequilibrium. The -607C(*)-137C haplotype was more prevalent in German RA (3.2 vs 1.2%) and in Scottish RA patients (4.1 vs 0.9%) than in the respective HD cohorts. These observations suggest that SNP of both positions contribute to the genetic background of RA pathogenesis

Conserved extended haplotypes of the major histocompatibility complex: further characterization

Since the complete sequencing of a human major histocompatibility complex (MHC) haplotype, interest in non-human leucocyte antigen (HLA) genes encoded in the MHC has been growing. Non-HLA genes, which outnumber the HLA genes, may contribute to or account for HLA and disease associations. Most information on non-HLA genes has been obtained in separate studies of individual loci. To comprehensively address polymorphisms of relevant non-HLA genes in 'conserved extended haplotypes' (CEH), we investigated 101 International Histocompatibility Workshop reference cell lines and nine additional anonymous samples representing all 37 unambiguously characterized CEHs at MICA, NFKBIL1, LTA, NCR3, AIF1, HSPA1A, HSPA1B, BF, NOTCH4 and a single nucleotide polymorphism (SNP) at HLA-DQA1 as well as MICA, NOTCH4, HSPA1B and all five tumour necrosis factor short tandem repeat (STR) polymorphisms. This work (1) provides an extensive catalogue of MHC polymorphisms in all CEHs, (2) unravels interrelationships between HLA and non-HLA haplotypical lineages, (3) resolves reported typing ambiguities and (4) describes haplospecific markers for a number of CEHs. Analysis also identified a DQA1 SNP and segments containing MHC class III polymorphisms that corresponded with class II (DRB3 and DRB4) lineages. These results portray the MHC where lineages containing non-HLA and HLA variants in linkage disequilibrium may operate in concert and can guide more thorough design and interpretation of HLA-disease relationships