Association of Human Leukocyte Antigen with Interstitial Lung Disease in Rheumatoid Arthritis: A Protective Role for Shared Epitope

INTRODUCTION: Interstitial Lung Disease (ILD) is frequently associated with Rheumatoid Arthritis (RA) as one of extra-articular manifestations. Many studies for Human Leukocyte Antigen (HLA) allelic association with RA have been reported, but few have been validated in an RA subpopulation with ILD. In this study, we investigated the association of HLA class II alleles with ILD in RA. METHODS: An association study was conducted on HLA-DRB1, DQB1, and DPB1 in 450 Japanese RA patients that were or were not diagnosed with ILD, based on the findings of computed tomography images of the chest. RESULTS: Unexpectedly, HLA-DRB1*04 (corrected P [Pc] = 0.0054, odds ratio [OR] 0.57), shared epitope (SE) (P = 0.0055, OR 0.66) and DQB1*04 (Pc = 0.0036, OR 0.57) were associated with significantly decreased risk of ILD. In contrast, DRB1*16 (Pc = 0.0372, OR 15.21), DR2 serological group (DRB1*15 and *16 alleles) (P = 0.0020, OR 1.75) and DQB1*06 (Pc = 0.0333, OR 1.57, respectively) were significantly associated with risk of ILD. CONCLUSION: HLA-DRB1 SE was associated with reduced, while DR2 serological group (DRB1*15 and *16) with increased, risk for ILD in Japanese patients with RA

Interleukin-10 promoter polymorphisms in Southern Chinese patients with systemic lupus erythematosus

Objective. To study the genetic association of interleukin-10 (IL-10) promoter polymorphisms in Southern Chinese patients with systemic lupus erythematosus (SLE), and to investigate possible associations with clinical manifestations of the disease. Methods. DNA was extracted from 88 Chinese patients with SLE and 83 ethnically matched controls. The IL-10 promoter region between positions -533 and -1120 was amplified by polymerase chain reaction, and polymorphisms were detected by restriction-enzyme cleavage. Results. No significant difference in the allele or haplotype frequencies between SLE patients and controls could be demonstrated. The *A and *C alleles at the -597 position were linked to the *T and *C alleles at the - 824 position, respectively. However, when clinical features were examined, the *A allele at the -597 position and the *T allele at the -824 position were significantly associated with lupus nephritis, by chisquare analysis (P < 0.001, odds ratio 4.19, 95% confidence interval 2.02-8.71). Similarly, the haplotype -1087*A/-824*T/-597*A was also associated with renal involvement (P < 0.001, odds ratio 3.62, 95% confidence interval 1.80-7.31). Conclusion. IL- 10 promoter polymorphisms are not strong determinants of susceptibility to the development of SLE, per se, in Southern Chinese individuals. However, IL- 10 genotypes are strongly associated with certain clinical manifestations of SLE and may have a role in predicting disease prognosis.link_to_subscribed_fulltex

Polymorphisms of the vitamin D receptor, infant growth, and adult bone mass.

Family and twin studies have demonstrated a strong genetic component to the development of peak bone mass. Early fetal and infant environment has also been shown to influence bone mass through an effect on skeletal size and mineral content. We report a retrospective study that has examined whether early infant growth is regulated by genetic factors shown to be associated with bone mass. We have determined the vitamin D receptor (VDR) gene alleles for 66 women (mean age 65.5 years) on whom detailed birth records were available. There was a statistically significant trend (P = 0.04) for VDR genotype against weight at the age of 1 year, with the "tt" homozygote group having 7% higher weight. We conclude that early fetal or infant environment may interact with an individual's underlying genotype to program early skeletal growth, and that this may track through later life to influence adult characteristics. Further prospective studies are required, however, to fully clarify the precise environmental and genetic mechanisms underlying these findings

Strong primary selection for the Dw4 subtype of DR4 accounts for the HLA-DQw7 association with Felty's syndrome.

Felty's syndrome (FS) is a rare complication of rheumatoid arthritis (RA) previously shown to be strongly associated with HLA-DR4 and less significantly with HLA-DQw7. To map more precisely the HLA locus responsible for susceptibility to FS, we have examined HLA-DR4 and DQ beta-chain polymorphisms in FS patients and controls using restriction fragment length polymorphism analysis and polymerase chain reaction amplification in conjunction with oligonucleotide probing. The increased frequency of DR4 in FS (93% vs. 32% controls) was due almost entirely to enrichment for the Dw4 subtype (88% vs. 20% controls) with a secondary increase of the Dw14 subtype. Dw10 and Dw13 subtypes of DR4 were absent from the patient group. Increase in DQw7 frequency among DR4 FS patients could be accounted for by linkage disequilibrium between Dw4 and DQw7 alleles. Whereas susceptibility to RA is strongly associated with a conserved HLA-DR beta epitope associated with several DRB1 alleles, it is primarily the Dw4 allele which is associated with progression to Felty's syndrome. The finding that amino acid sequence variation at the DR4B1 locus rather than DQB1 is associated with development of FS will have important implications for the development of novel immunotherapies which are major histocompatibility complex allele-dependent

Genetic analysis of TAP2 in systemic lupus erythematosus patients from two ethnic groups

The aim of this study was to determine whether the TAP2 (Transporter associated with Antigen Processing 2) locus is involved in susceptibility to systemic lupus erythematosus (SLE). We adopted the interethnic approach to overcome problems in the analysis resulting from linkage disequilibrium. The TAP2 gene polymorphisms of the codons corresponding to amino acid positions 379, 565 and 665 were investigated by amplification refractory mutation system polymerase chain reaction (ARMS-PCR) in 186 patients (151 white Europeans, 35 Afrocaribbeans) and 183 controls (79 white Europeans, 104 Afrocaribbeans). In the European SLE patients, the frequency of the TAP2 type V-A-TA was marginally lower compared with the control group (31% vs 42%), with negative linkage disequilibrium between this TAP2 type and DR3 probably accounting for the difference. For the European SLE patients, we confirmed a significant association of DR3 with disease status [odds ratio = 4.16, 95% confidence interval (CI), 2.08-8.39] and in the patients with DR3 there was a significantly high frequency of the TAP2 type V-A-T-. In the Afrocaribbean SLE patients, any associations of disease status with TAP2 phenotype were the inverse of those in the European patients. Thus, in these patients the frequency of V-A-TA was higher than in controls (46% vs 26%, OR = 2.4, 95% CI 1.01-5.74), while the frequency of V-A-T- was lower (26% vs 40%, not significant). Despite possible sampling error, the lack of a difference in TAP2 status between cases and controls within ethnic groups and, if anything, an inverse association across ethnic groups, makes it unlikely that the TAP2 polymorphism studied here is of primary relevance to SLE susceptibility

Corticotropin releasing hormone (CRH) promoter polymorphisms in various ethnic groups of patients with rheumatoid arthritis

The regulatory region of the corticotropin releasing hormone (CRH) is highly conserved and plays a crucial role in the response of the organism to stress. Release of CRH initiates a cascade of events leading to the release of cortisone and the regulation of inflammatory and immune events. Objective: Since it has been postulated that the impaired corticotropin releasing hormone (CRH) response to stress in patients with rheumatoid arthritis (RA) has a genetic basis, we investigated the distribution of CRH alleles in a cohort of UK patients as well as in South African RA patients. Methods: Restriction fragment length polymorphism of PCR amplified DNA products of the CRH promoter. We compared the allele frequencies in the RA patients with the respective healthy control population described previously. Results: As in the control populations we found two biallelic polymorphic sequences (named A1 and A2 and B1 and B2, respectively) in the CRH promoter which could be assigned to compound alleles. The A2B1 compound allele was protective against development of RA in a large group of UK Caucasoid patients (p=0.03; odds ratio 0.43, 95% confidence interval 0.21-0.88). In contrast, A1B1 was positively associated with RA in a cohort of black South African RA patients (p=0.05; odds ratio 1.78, 95% confidence interval 1.01-3.15). Conclusion: Taken together, these findings support the hypothesis that CRH promoter polymorphism represents a new genetic marker for RA susceptibility and may prove useful for the prediction of RA risk in the future when further genetic and environmental risk factors are determined.link_to_subscribed_fulltex