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Background

Table 1: VDR, A2M, TNFRII, Fc g RIIIA and ACE genotypes. Frequency. Frequency. Frequency. Frequency. Table 2: Odds Ratio and c 2 values for each genotype. 1986/T.

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Background

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  1. Table 1: VDR, A2M, TNFRII, FcgRIIIA and ACE genotypes Frequency Frequency Frequency Frequency Table 2: Odds Ratio and c2 values for each genotype 1986/T Association Analysis of VDR, a-2-Macroglobulin, TNFRII, FcgRIIIA and ACE gene polymorphism in South Asian Rheumatoid Arthritis patients of the East Midlands, UK. A. Ghelani1, A. Pacynko1, A. Gilmour1, L. Goh2, A. Jones3, A. Samanta2, J.I. Robinson4, A.W. Morgan4, J.D. Isaacs5, S.S. Mastana1. 1) Human Sciences, Loughborough University, Loughborough,UK; 2) Leicester Royal Infirmary, Leicester, UK; 3) City Hospital, Nottingham,UK; 4) St. James' University Hospital, Leeds,UK; 5) University Medical School, Newcastle Upon Tyne, UK. Background Rheumatoid Arthritis (RA) is a polygenic disease characterised by localised joint destruction and osteoporosis. The pathogenesis of RA is not completely understood but genetic factors may play a significant role. The genetic polymorphism in the vitamin D receptor (VDR) gene has been described as a significant determinant of bone turnover and mass1. A number of studies have shown contradictory results, but there are no studies on Asiatic Indian RA patients. Alpha-2-macroglobulin (A2M) is involved in modulation of cytokines. TNFRII is involved in tissue destruction2. FcgRIIIA has an important role in the clearance of immune complexes and polymorphism from low affinity phenylalanine (F) to high affinity valine (V) binding site has been reported to increase susceptibility/severity of RA in UK Caucasian and North Indo-Pakistani groups3. One of the biological roles for the angiotensin-converting enzyme (ACE) is pro-inflammatory4. ACE is expressed in the synovial membranes from patients with RA suggesting pathophysiological role in the joint angiogenesis with a possibility of localised hypertension. The aim of this study is to assess the role of VDR, TNFRII, A2M and ACE genotypes in the development of RA amongst South Asians. This is a part of our ongoing genetic epidemiological studies on South Asian RA patients. Methods The blood samples from 133 South Asians (33 males, 100 females; Age range 29 to 75 years old) with established RA attending Rheumatology referral Clinics in the East Midland hospitals and their siblings (brothers and/or sisters) and random controls from same ethnic groups were collected. Extracted DNA was amplified and analysed for VDR(Bsm1), A2M, TNFRII(196R/M), FcRIIIgA(158V/F) and ACE(I/D) loci. The association analysis was performed by computing Odds Ratios and Chi Square values (P <0.05). Conclusions Our results suggest that the VDR BB and A2M 22 genotypes were associated with RA among South Asians. The mechanism by which the VDR polymorphism is associated with RA is unknown, but they could be related to immuno-regulatory properties of vitamin D. A2M association may be due to cytokine binding affinity which could modulate the progression of RA. TNFRII and FcRIIIgA did not achieve statistical significance. ACE (I/D) polymorphism was also not associated with RA among South Asians. Additional samples are being analysed for these loci and other RA candidate genes to evaluate their role in pathogenesis of RA among Asiatic Indians. Results Our results (Tables 1-Genotypes & 2-Case vs. Controlcomparison, Figures 1 to 4-Genotype Frequency) indicate an increased frequency of BB genotypes of VDR gene in Asian RA patients compared to controls leading to highly significant differences (c2 = 24.61, DF 2, P<0.01). Similarly A2M-22 genotype was prominent in RA patients compared to controls (c2 = 6.75, DF 2, P<0.05). TNFRII loci also showed significant chi-square differences (c2 = 6.72, DF 2, P<0.05) but the Odds Ratios were not significant or high. The ACE I/D polymorphism was not associated in the present sample (c2 = 0.305, DF 2, P>0.05). The BB genotype of VDR locus was associated with RA in Asian patients (Odds ratio = 3.30 (95% CI 1.78 – 6.24), c2 = 16.97, P<0.005). Similarly A2M 22 genotype was associated with RA (Odds ratio = 3.85 (95% CI 1.14 – 136.55), c2 = 4.85, P<0.005). References 1. Morrison et al., Nature 1994; 367: 284-7. 2. Barton et al., Arth & Rheum2001; 44, 61-65. 3. Morgan et al. Arth & Rheum 2000; 43,2328-2334 4. Zapico et al., J Rheumatol 2000; 27, 2308-2311. E-mail Addresses for contact : A.Ghelani2@lboro.ac.uk S.S.Mastana@lboro.ac.uk

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