The spectrum of association in HLA region with rheumatoid arthritis in a diverse Asian population: evidence from the MyEIRA case-control study.

BACKGROUND: Fine-mapping of human leukocyte antigen (HLA) region for rheumatoid arthritis (RA) risk factors has identified several HLA alleles and its corresponding amino acid residues as independent signals (i.e., HLA-A, HLA-B, HLA-DPB1, and HLA-DQA1 genes), in addition to the well-established genetic factor in HLA-DRB1 gene. However, this was mainly performed in the Caucasian and East Asian populations, and data from different Asian regions is less represented. We aimed to evaluate whether there are independent RA risk variants in both anti-citrullinated protein antibody (ACPA)-positive and ACPA-negative RA patients from the multi-ethnic Malaysian population, using the fine-mapping of HLA region strategy. METHODS: We imputed the classical HLA alleles, amino acids, and haplotypes using the Immunochip genotyping data of 1260 RA cases (i.e., 530 Malays, 259 Chinese, 412 Indians, and 59 mixed ethnicities) and 1571 controls (i.e., 981 Malays, 205 Chinese, 297 Indians, and 87 mixed ethnicities) from the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA) population-based case-control study. Stepwise logistic regression was performed to identify the independent genetic risk factors for RA within the HLA region. RESULTS: We confirmed that the HLA-DRB1 amino acid at position 11 with valine residue conferred the strongest risk effect for ACPA-positive RA (OR = 4.26, 95% CI = 3.30-5.49, PGWAS = 7.22 × 10-29) in the Malays. Our study also revealed that HLA-DRB1 amino acid at position 96 with histidine residue was negatively associated with the risk of developing ACPA-positive RA in the Indians (OR = 0.48, 95% CI = 0.37-0.62, PGWAS = 2.58 × 10-08). Interestingly, we observed that HLA-DQB1*03:02 allele was inversely related to the risk of developing ACPA-positive RA in the Malays (OR = 0.17, 95% CI = 0.09-0.30, PGWAS = 1.60 × 10-09). No association was observed between the HLA variants and risk of developing ACPA-negative RA in any of the three major ethnic groups in Malaysia. CONCLUSIONS: Our results demonstrate that the RA-associated genetic factors in the multi-ethnic Malaysian population are similar to those in the Caucasian population, despite significant differences in the genetic architecture of HLA region across populations. A novel and distinct independent association between the HLA-DQB1*03:02 allele and ACPA-positive RA was observed in the Malays. In common with the Caucasian population, there is little risk from HLA region for ACPA-negative RA.

HLA-A, -B, -C, -DRB1 and -DQB1 alleles and haplotypes in 271 Southeast Asia Indians from Peninsular Malaysia.

A total of 271 Southeast Asia Indians from Peninsular Malaysia were genotyped for HLA-A, -B, -C, -DRB1, and -DQB1 loci using polymerase chain reaction sequence-specific oligonucleotide probe hybridization methods. In this report, HLA-B and HLA-DQB1 was in Hardy-Weinberg proportions (HWEP) (p > 0.05). We observed significant deviation from the HWEP for HLA-A (p < 0.05), HLA-C (p < 0.01) and HLA-DRB1 (p < 0.01) loci. This genotype data is available in Allele Frequencies Network Database (AFND) Dos Santos et al. (2016).

HLA-A, -B, -C, -DRB1 and -DQB1 alleles and haplotypes in 194 Southeast Asia Chinese from Peninsular Malaysia.

A total of 194 Southeast Asia Chinese from Peninsular Malaysia were genotyped for HLA-A, -B, -C -DRB1, and -DQB1 loci using polymerase chain reaction sequence-specific oligonucleotide probe hybridization methods. In this report, the HLA-B, HLA-DRB1 and HLA-DQB1 were in Hardy-Weinberg proportions (HWEP) (p > 0.05). We observed significant deviation from HWEP in HLA-A (p < 0.05) and HLA-C (p < 0.01) loci. This genotype data was available in Allele Frequencies Network Database (AFND) Dos Santos et al. (2016).

HLA-A, -B, -C, -DRB1 and -DQB1 alleles and haplotypes in 951 Southeast Asia Malays from Peninsular Malaysia.

A total of 951 Southeast Asia Malays from Peninsular Malaysia were genotyped for HLA-A, -B, -C -DRB1, and -DQB1 loci using polymerase chain reaction sequence-specific oligonucleotide probe hybridization methods. In this report, there were significant deviation from Hardy-Weinberg proportions for the HLA-A (p<0.0001), -B (p<0.0001), -DRB1 (p<0.0001) and -DQB1 (p<0.01) loci. Minor deviations from HWEP were detected for HLA-C (p=0.01). This genotype data was available in Allele Frequencies Network Database (AFND) Gonzalez-Galarza et al. (2015).

Thickened carotid intima media thickness and carotid atherosclerosis among lupus nephritis patients: the role of traditional and lupus-specific factors.

AIM: The objectives of this study were to investigate the frequency of thickened carotid intima media thickness (CIMT) and atherosclerosis among lupus nephritis (LN) patients and to study their associated risk factors. METHOD: In this cross-sectional study, carotid ultrasonography was performed on consecutive LN patients to determine CIMT and presence of carotid plaques. CIMT was considered to be abnormally thickened if it was more than the 75th percentile matched for age and sex from the 'Carotid Atherosclerosis Progression Study'. The association between thickened CIMT with traditional cardiovascular risk factors and lupus characteristics were examined. A total of 83 patients with the mean age of 33.6 ± 10 years were recruited. RESULTS: Fourteen patients (16.9%) had thickened CIMT and three (3.6%) had carotid plaques. On univariate analysis, traditional risk factors significantly associated with thickened CIMT (P < 0.05) were patient's current age, diabetes mellitus and waist circumference. Meanwhile, a lower serum C4 levels and higher serum C-reactive protein levels were the lupus-specific factors associated with thickened CIMT (P < 0.05, P < 0.05 and P < 0.01, respectively). In logistic regression analysis, the independent predictors of thickened CIMT were age of diagnosis, lower serum C4 levels and waist circumference (P < 0.05). CONCLUSION: More lupus specific factors were independently associated with thickened CIMT, suggesting that a multi-targeted approach of treatment addressing both the lupus and traditional cardiovascular risks are very important. Larger prospective studies of these special risk factors are indicated.

A cross-sectional study of diastolic dysfunction in rheumatoid arthritis and its association with disease activity.

AIMS: The aim of this study was to evaluate the left ventricular (LV) diastolic dysfunction in rheumatoid arthritis (RA) patients without clinically evident cardiovascular manifestations and to estimate whether there is any correlation between RA disease severity and disability and LV diastolic dysfunction. METHODS: The study was a cross-sectional study involving 53 patients (47 female and 6 male) with RA without clinically evident heart disease and 53 healthy subjects (47 female and 6 male) who served as a control group. Both groups were matched for age and sex. Echocardiographic and Doppler studies were conducted in all patients with RA and control subjects. RESULTS: Of 17 cardiac parameters assessed, only two were abnormal. None of the specific cardiac diastolic dysfunction parameters were significantly different in RA patients compared to the control group. There was no significant correlation between diastolic function values in RA patients and value of Disease Activity Score 28 (DAS-28) and value of Health Assessment Questionnaires Disability Index (HAQDI). Atrial (A) wave velocity was greater in RA patients compared to the control group (0.71 [0.58-0.83] vs. 0.61 [0.51-0.71]; P < 0.04). However, interventricular relaxation time (IVRT) ([73.08 ± 9.92 vs. 70.74 ± 9.02], P = 0.207), lower E/A ratio (1.27 [1.02-1.56] vs. 1.42 [1.20-1.68], P = 0.102), diastolic dysfunction parameters according to Redfield Classification (25 [47.2%] vs. 27 [50.9%] P = 0.56), diastolic dysfunction using E/A (P = 0.321) and tissue doppler imaging (E/E') (P = 0.148) were not different. CONCLUSION: Prevalence of diastolic dysfunction in the rheumatoid arthritis group (47.2%) was not different from controls (50.9%). LV diastolic function had no significant correlation with RA disease severity and duration of disease.

Clinical and high resolution computed tomography characteristics of patients with rheumatoid arthritis lung disease.

INTRODUCTION: Rheumatoid arthritis (RA) is a systemic disease of unknown cause. A variety of pulmonary disorders have been described in association with RA. Among the most common are interstitial lung disease (ILD) and bronchiectasis. OBJECTIVES: This study aims to determine the characteristics of RA patients with lung disease in relation to clinical characteristics, pulmonary function test (PFT) and high resolution computed tomography (HRCT) thorax. METHOD: This is a 6-months cross-sectional study involving 63 consecutive RA patients in an outpatient rheumatology clinic. Patients had a mean disease duration of 5 years and above. Disease activity and severity was assessed by Disease Activity Score 28 (DAS28), Health Assessment Questionnaire (HAQ) and Rheumatoid Arthritis Articular Damage (RAAD) score. Full pulmonary function test (PFT) and HRCT of thorax were performed. CONCLUSIONS: The prevalence of RA-ILD is 44% and 67% of patients are asymptomatic. There was significant higher proportion (68%) in patients of Chinese ethnicity who have ILD. Diffusion capacity of carbon monoxide was abnormal in all patients and forced expiratory flow (FEF)(25-75%) was low in 16%. Restrictive pattern was 66.7% by PFT. The most common HRCT findings were reticulation (46%) followed by ground glass opacities (38.1%) and bronchiectasis (28.6%). There was no association between ILD and male gender, duration of the disease, smoking, rheumatoid factor, extra-articular manifestations, disease activity or severity.