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Posterior reversible encephalopathy syndrome in systemic lupus erythematosus: pooled analysis of the literature reviews and report of six new cases

Shaharir SS, Remli R, Marwan AA, Said MS, Kong NCT

Lupus, 2013 Apr;22(5):492-6.
PMID: 23435619 DOI: 10.1177/0961203313478303

INTRODUCTION:Posterior reversible encephalopathy syndrome (PRES) is a rare neurological disorder which is increasingly recognized to occur in systemic lupus erythematosus (SLE).
OBJECTIVE: The purpose of this study was to identify the characteristics of SLE patients with PRES and the associated factors of the poor outcome among them.
METHODS: We investigated SLE patients who developed PRES between 2005-2011 at the Universiti Kebangsaan Malaysia Medical Centre. A comprehensive literature search was done to find all published cases of PRES in SLE. Pooled analysis was conducted to identify the factors associated with poor outcome.
RESULTS: There were 103 cases of PRES in SLE published in the literature but only 87 cases were included in the analysis in view of incomplete individual data in the remaining cases. The majority of the cases were Asians (74.2%), female (95.4%) with mean age of 26.3 ± 8.8 years. PRES was highly associated with active disease (97.5%), hypertension (91.7%) and renal involvement (85.1%). We found that 79 patients had a full recovery (90.8%) with a mean onset of full clinical recovery in 5.6 ± 4.1 days. On univariate analysis and logistic regression analysis the predictors of poor outcome, defined as incomplete clinical recovery or death, were intracranial hemorrhage, odds ratio (OR) 14 (1.1-187.2), p=0.04 and brainstem involvement in PRES, OR 10.9 (1.3-90.6), p=0.003.
CONCLUSION: Intracranial hemorrhage and brainstem involvement were the two important predictors of poor outcome of PRES. Larger prospective studies are needed to further delineate the risk of poor outcome among them.

Matched MeSH terms: Lupus Erythematosus, Systemic/complications*
Tinea faciei mimicking lupus erythematosus

Singh R, Bharu K, Ghazali W, Bharu K, Nor M, Kerian K

Cutis, 1994 Jun;53(6):297-8.
PMID: 8070283

The authors describe a case of tinea faciei occurring in a sixteen-year-old boy. The rash was localized to the face and upper chest and resembled a typical photosensitive disorder, resulting in inappropriate treatment for six months. Results of a potassium hydroxide preparation and culture from the surface scale confirmed the clinical diagnosis.

Matched MeSH terms: Lupus Erythematosus, Systemic/diagnosis*
SLE mortality in an oriental population

Koh ET, Seow A, Leong KH, Chng HH

Lupus, 1997;6(1):27-31.
PMID: 9116715 DOI: 10.1177/096120339700600104

We analysed the causes of 67 deaths, over a 4 y period, in our oriental population with systemic lupus erythematosus (SLE). The median disease duration was 48 +/- 60.5 months (range 1-250 months). The mean age at diagnosis and death were 30 and 35.1 y respectively. SLE alone accounted for death in 30 patients (44.8%), infection in 27 (40.3%), pulmonary embolism in 5 (7.5%), malignancy in 4 (5.9%) and rheumatic heart disease in 1 (1.5%). The major organ involvement in those with active disease at death were SLE related thrombocytopenia (n = 23/44, 52.3%), nephritis (n = 21/44), 47.7%), cerebral lupus (n = 16/44, 36.4%), and pulmonary haemorrhage (n = 12/44, 27.3%). As in other series, SLE and infection were the principal causes of death in our population. During this 4 y period, there was no late death due to atherosclerosis.
Study site: Tan Tock Seng Hospital (TTSH), Singapore

Matched MeSH terms: Lupus Erythematosus, Systemic/mortality*
Fulltext Antiphospholipid antibodies and stroke in the young--a study of three cases

Lee MK, Cheng HM, Ng SC, Menaka N, Tan CT, Wang F

Med J Malaysia, 1993 Sep;48(3):330-5.
PMID: 8183147

Cerebral infarction in the young is likely to be non-atheromatous. While in previous studies no cause has been found in 40% to 50% of patients, an increasing role for haemorheological factors is becoming apparent. Among these, an association between antiphospholipid antibodies (aPLs) and ischaemic cerebrovascular disease is now well-recognised. This entity has not been previously reported in Malaysian patients. In a study of 80 patients with stroke below the age of 50 years who were seen at the University Hospital, Kuala Lumpur, between January 1982 and May 1992, 3 patients with ischaemic cerebral infarction were found to have aPLs. aPLs was detected using ELISA method for anticardiolipin antibodies (aCLs), and presence of lupus anticoagulant (LA) was established by kaolin clotting time, thromboplastin inhibition test and platelet neutralisation procedure. Only 1 patient had active systemic lupus erythematous. Cerebrovascular events were recurrent in one of the 2 non-lupus patients. aPL-related stroke should be considered in young patients who have cerebral ischaemia occurring without obvious cause. More cases are likely to emerge in Malaysia with active screening.

Matched MeSH terms: Lupus Erythematosus, Systemic/immunology
Pneumocystis carinii pneumonia in patients with systemic lupus erythematosus

Liam CK, Wang F

Lupus, 1992 Dec;1(6):379-85.
PMID: 1304406 DOI: 10.1177/096120339200100607

At the University Hospital, Kuala Lumpur, Malaysia, nine patients with systemic lupus erythematosus (SLE) were treated for Pneumocystis carinii pneumonia (PCP) between January 1987 and December 1988. When they developed PCP all the patients' SLE disease course was active and eight of them were on prednisolone. Four of these eight patients were also receiving cyclophosphamide. Patients who were on more intensive immunosuppressive therapy were found to develop more severe PCP. All the patients except one were treated with high-dose cotrimoxazole. Four patients responded to antipneumocystis treatment and survived, while PCP was responsible for the death of the five non-survivors.

Matched MeSH terms: Lupus Erythematosus, Systemic/complications*
Antinuclear antibodies in systemic lupus erythematosus

Fong KY, Boey ML, Howe HS, Feng PH

Med J Malaysia, 1989 Jun;44(2):151-5.
PMID: 2626124

Autoantibodies to the three extractable nuclear antigens (ENA), Anti-SSA (Ro), Anti-Sm, Anti-RNP and antinuclear antibodies were determined in 150 patients with SLE. Seventy patients (46.7%) had Anti-SSA (Ro), 40 (26.7%) Anti-Sm and 25 (16.7%) Anti-RNP antibodies. Ninety four percent patients had a positive Fluorescent anti-nuclear antibody (FANA) test. The commonest FANA pattern is the speckled pattern. Subclinical keratoconjunctivitis sicca (KCS) was present in 60% patients. No correlation could be demonstrated between the presence of ENA autoantibodies and the clinical features of patients.

Matched MeSH terms: Lupus Erythematosus, Systemic/immunology*
Fulltext Transverse myelopathy and hyperphagia in systemic lupus erythematosus: a case report

Chong YH, Cheong I

Med J Malaysia, 1985 Dec;40(4):333-4.
PMID: 3870350

We report a case of systemic lupus erythematosus complicated by transverse myelopathy and hyperphagia. To our knowledge the latter has not been reported before.

Matched MeSH terms: Lupus Erythematosus, Systemic/complications*
Spectrum of nocardiosis in renal patients

Kong NC, Morad Z, Suleiman AB, Cheong IK, Lajin I

Ann Acad Med Singap, 1990 May;19(3):375-9.
PMID: 2393240

Nocardiosis is an increasingly recognised opportunistic infection in immunologically incompetent hosts but diagnosis is often delayed. Between December 1975 to October 1988, our two Nephrology Units have encountered five cases of nocardiosis occurring in two post-renal transplant patients, two patients with systemic lupus erythematous (SLE) and one patient with mesangiocapillary glomerulo--nephritis. All were on immunosuppressants at the time. The first three patients presented with predominant pulmonary disease and were cured by combined trimethoprim-sulphamethoxazole (cotrimoxazole) and doxycycline therapy. The patient with limited skin involvement responded to cotrimoxazole alone. However, the last patient with lymphocutaneous disease initially responded to cotrimoxazole (+ chloramphenicol) but developed acute-on-chronic renal failure and relapsed with dose reduction of cotrimoxazole. Alternative treatment with amikacin and doxycycline was instituted with good response. We shall review potential clues that may suggest the diagnosis of nocardiosis and discuss other effective antimicrobial agents.

Matched MeSH terms: Lupus Erythematosus, Systemic/complications
Subclinical memory dysfunction in Malaysian systemic lupus erythematosus patients: Association with clinical characteristics and disease activity – A pilot study

Mohd Said MS, Bin Shudim SS, Mohamad K, Shaharir SS, Kong NCT, Ali RA

Egyptian Rheumatologist, 2016;38:189-194.
DOI: 10.1016/j.ejr.2015.12.001

Aim of the work This work aimed to determine the frequency of subclinical memory dysfunction in a group of Malaysian systemic lupus erythematosus (SLE) patients and to study its relation to clinical characteristics, laboratory investigations and disease activity. Patients and methods Fifteen SLE patients attending the Universiti Kebangsaan Malaysia Medical Centre (UKMMC) and not known to have neuropsychiatric lupus were recruited. These patients were assessed using the Wechsler Memory Scale. Disease activity was assessed using the SLE disease activity index 2000 (SLEDAI-2K). Results The median age of the patients was 28 years (25–37 years) and they were 14 females and one male. Their median disease duration was 9.3 years (4.8–10 years). Their median SLEDAI-2K was 4 (0–6). Memory dysfunction was identified in 7/15 (46.7%) SLE patients and was significantly associated with lower serum thyroxine levels (median 12.27; 11.8–13.3 μg/dl) (p = 0.027) compared to those without memory impairment (15.48; 14.39–16.56 μg/dl). Auditory memory impairment was associated with the education level as the auditory memory index was significantly lower in patients with secondary education (n = 7, median 88; 86.5–91.5) compared to those who received tertiary education (n = 8, median 103; 97.5–119.5) (p = 0.025) while visual memory was influenced by disease duration (p = 0.016). There was no association between overall memory dysfunction and disease duration, number of relapses, clinical manifestations and SLEDAI-2K scores. Conclusion There is a high frequency of subclinical memory dysfunction among SLE patients. A remarkable association is present with lower thyroxine. Auditory memory impairment is related to the level of education and visual memory to disease duration. © 2015 The Authors

Matched MeSH terms: Lupus Erythematosus, Systemic*
Systemic lupus erythematosus in a tertiary, east Malaysian hospital: Admission, readmission and death

Teh CL, Chan GYL, Lee J

Int J Rheum Dis, 2008;11(1):24-29.
DOI: 10.1111/j.1756-185X.2008.00325.x

Objective: There are limited data on hospitalization of systemic lupus erythematosus (SLE) patients in Asian countries. Our aim of this study is to describe the characteristics and poor prognostic factors in our patients. Method: We performed a retrospective study of SLE hospitalization during a 1-year period (2006) in our centre. Results: There were 125 episodes of hospitalization of 79 patients with SLE. This is the first report of SLE patients from the native population of east Malaysia. The cause of admission was flare of SLE (80.8%), infection (23.2%), renal biopsy (22.4%) and others (4%). There was only one admission for thromboembolism. Patients with both flare of SLE and infection have the longest median length of stay of 11 days (IQR 5,24) requiring more intensive care therapy (P < 0.01). Readmission occurred in 31.4% and was associated with admission for other reasons during the first admission. Flare of SLE was protective against readmission (P < 0.05, OR = 0.36). There were six deaths (4.8% of admissions). The deaths were due to infection in three patients, active SLE in two and acute myocardial infarction in one. The deaths have a higher cumulative prednisolone dose than the survivals (P < 0.01). In multivariate modelling, the only predictor of death was high Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index score (P < 0.05, OR = 9.61 per increase of 1 score). Conclusion: Active disease and infection remains the main cause of admission, readmission and death in SLE patients. © 2008 Asia Pacific League of Associations for Rheumatology.

Matched MeSH terms: Lupus Erythematosus, Systemic*
Clinical experience in using CD20 monoclonal antibody in treating severe systemic lupus erythematosus

Mohd Shahrir MS, Abdul Halim AG, Soehardy Z, Kong NCT

APLAR Journal of Rheumatology, 2007;10(2):112-116.
DOI: 10.1111/j.1479-8077.2007.00270.x

Background and method: This clinical experience involved the treatment of resistant systemic lupus erythematosus (SLE) patients with CD20 monoclonal antibody. Five patients failed conventional therapy, two developed complications and one needed rituximab as an emergency measure. Four patients had lupus nephritis, three had autoimmune hemolytic anemia, two had immune thrombocytopenia and one had lupoid hepatitis. The patients were aged 14-49 years, (mean 28.63). Three were Malays, two Chinese, two Indian and one Turkish; six were females. Mean disease duration was 63.25 months and mean total rituximab dose received was 2812.50 mL. Results: Hemoglobin levels improved from 9.3 ± 5.7 to 13.1 ± 8.6 g/dL for two SLE patients with autoimmune hemolytic anemia after 34 weeks (P = 0.180). Platelet counts improved from 25 ± 17 to 198 ± 97 × 10 9/high powered field from 0 to 10 weeks for three SLE patients with immune thrombocytopenia (P = 0.109). In the lupus nephritis patients on rituximab, serum albumin improved from 24.5 ± 23.2 to 37.5 ± 31.8 mmol/L (n = 3) from week 0 to week 17 (P = 0.100). Urine protein creatinine ratio improved from 0.55 ± 0.23 to 0.08 ± 0.03 g/mmol creatinine (P = 0.068) from week 0 to week 13. C3 and C4 improved from 90.8 ± 36.5 to 120.7 ± 37.9 (P = 0.07) and 21.6 ± 10.1-27.3 ± 16.2 mg/dL (P = 0.27), respectively, and Systemic Lupus Erythematosus Activity Disease Index was reduced from 17.9 ± 11.2 to 6.3 ± 6.8 (P = 0.375) after 8 weeks. Two patients developed drug reactions to rituximab. Conclusion: All of the patients responded to rituximab on top of their conventional therapy. © 2007 Asia Pacific League of Associations for Rheumatology and Blackwell Publishing Asia Pty Ltd.

Matched MeSH terms: Lupus Erythematosus, Systemic*
Systemic lupus erythematosus in a malay boy

Wan Mohamad WM, Mohd Ashari NS, Wan AbHamid WZ

International Medical Journal (Tokyo), 2017;24(3):295-296.

Objective: We presented a case report, systemic lupus erythematosus (SLE) in a Malay boy. Interestingly, this case occurs in a boy, which is not so common because autoimmune disease usually occurs in female. Design: Case report. Methods: We highlighted a case of a boy with SLE who presented with clinical symptoms suggestive of SLE and fulfilled the criteria for SLE diagnosis. Results: The patient was successfully managed with antihypertensive, intravenous cyclophosphamide and oral prednisolone and respond well to the therapy. Conclusion: Systemic lupus erythematosus is a chronic autoimmune disease which rarely occurs in male. However we reported one such case which fulfilled the criteria for SLE. © 2017 Japan Health Sciences University & Japan International Cultural Exchange Foundation.

Matched MeSH terms: Lupus Erythematosus, Systemic*
Maternal and perinatal outcomes of pregnancies in systemic lupus erythematosus: A nationwide population-based study

Chen YJ, Chang JC, Lai EL, Liao TL, Chen HH, Hung WT, et al.

Semin Arthritis Rheum, 2020 06;50(3):451-457.
PMID: 32115237 DOI: 10.1016/j.semarthrit.2020.01.014

OBJECTIVES: Systemic lupus erythematosus (SLE) is an autoimmune disease that develops mainly in women of reproductive age. We aimed to explore the risk of pregnancy complications in Asian patients with SLE.
METHODS: From January 2005 to December 2014, we conducted a nationwide case-control study, using Taiwan's National Health Insurance Research Database. Obstetric complications and perinatal outcomes in SLE patients were compared with those without SLE.
RESULTS: 2059 SLE offspring and 8236 age-matched, maternal healthy controls were enrolled. We found increased obstetric and perinatal complications in SLE population compared with healthy controls. SLE patients exhibited increased risk of preeclampsia/eclampsia (8.98% vs.1.98%, odds ratio [OR]: 3.87, 95% confidence interval [95% CI]: 3.08-4.87, p<0.0001). Their offspring tended to have lower Apgar scores (<7) at both 1 min (10.7% vs. 2.58%, p<0.0001) and 5 min (4.25% vs. 1.17%, p<0.0001), as well as higher rates of intrauterine growth restriction (IUGR, 9.91% vs. 4.12%, OR: 2.24, 95% CI: 1.85-2.71, p<0.0001), preterm birth (23.70% vs 7.56%, OR: 3.00, 95% CI: 2.61-3.45, p<0.0001), and stillbirth (4.23% vs. 0.87%, OR: 3.59, 95% CI: 2.54-5.06, p<0.0001). The risks of preterm birth and stillbirth were markedly increased in SLE patients with concomitant preeclampsia/eclampsia or IUGR. Preterm birth of SLE patients was 1~4 gestational weeks earlier than that of healthy controls and the peak occurrence of stillbirth in SLE population was at 20~30 gestational weeks.
CONCLUSIONS: Asian SLE patients exhibited increased risks of maternal complications and adverse birth outcomes. Frequent antenatal visits before 20 gestational weeks are recommended in high-risk SLE patients.

Matched MeSH terms: Lupus Erythematosus, Systemic/epidemiology*
Multifocal osteoarticular tuberculosis in a systemic lupus erythematosus (SLE) patient: a rarity or an underdiagnosed condition?

Lim SL, Ong PS, Khor CG

Mod Rheumatol Case Rep, 2020 07;4(2):237-242.
PMID: 33086999 DOI: 10.1080/24725625.2020.1754567

Tuberculosis (TB) and its association with rheumatic diseases have been widely recognised. Occurrence of multifocal skeletal involvement constitutes <5% of all skeletal TB cases. We present a Malay patient with multifocal osteoarticular TB (OATB). A 35 year-old SLE woman with background usage of corticosteroid therapy and Azathioprine presented with lupus nephritis flare. Renal biopsy revealed diffuse proliferative lupus nephritis and intravenous (IV) Cyclophosphamide 0.5 g/m2 (850 mg) was initiated. One week later, patient complained dorsum of left hand and right knee swelling. On physical examination, patient was afebrile and the left hand swelling was cystic in consistency while right knee was warm and tender. Erythrocyte Sedimentation Rate (ESR) was 50 mm/hr and C-Reactive Protein (CRP) was 9.4 mg/L. Her Mantoux test was positive with 20 mm induration. Wrist radiograph and chest radiograph was normal. Musculoskeletal ultrasound showed 4th extensor compartment tenosynovitis with Doppler signal and right knee effusion with synovial proliferation. Extensor tenosynovectomy and right knee aspiration was performed. Left hand excised tissue and right knee synovial fluid for acid-fast bacilli (AFB) stain, TB PCR, bacterial and fungal cultures were negative. Urgent histopathological examination of the excised tissue showed necrotising granulomatous inflammation. Patient was empirically started on TB treatment and subsequent mycobacterial culture confirmed the diagnosis of TB. The joints swelling resolved after one month of TB treatment. Multifocal OATB is an infrequent form of extrapulmonary TB and diagnosing OATB requires high index of suspicion particularly in SLE patient on immunosuppression. Prompt investigations are essential to the diagnosis of this rare condition for early initiation of anti-tuberculous therapy.

Matched MeSH terms: Lupus Erythematosus, Systemic/complications*
Treatment of preeclampsia with hydroxychloroquine: a review

Abd Rahman R, DeKoninck P, Murthi P, Wallace EM

J Matern Fetal Neonatal Med, 2018 Feb;31(4):525-529.
PMID: 28142291 DOI: 10.1080/14767058.2017.1289511

In this review, we discuss the potential use of antimalarial drugs as an adjuvant therapy for preeclampsia, focusing on the mechanisms of action of this class of drugs in the context of preeclampsia. In particular, hydroxychloroquine has been shown to have various beneficial effects on patients with systemic lupus erythematosus. There are several pathways targeted by the antimalarial drugs that are similar to the pathophysiology of preeclampsia and hence offering opportunities to develop novel therapies to treat the disease. Given the safety profile of hydroxychloroquine in pregnancy, there is merit in exploring the efficacy of this drug as an adjuvant therapy in women with early onset preeclampsia.

Matched MeSH terms: Lupus Erythematosus, Systemic/drug therapy
Fulltext Myelosclerosis associated with systemic lupus erythematosus in patients in West Malaysia

Lau KS, White JC

J Clin Pathol, 1969 Jul;22(4):433-8.
PMID: 4183835 DOI: 10.1136/jcp.22.4.433

Three cases of myelosclerosis associated with systemic lupus erythematosus are described. The probable role of systemic lupus erythematosus in the initiation of myelonecrosis and subsequent myelosclerosis is discussed.

Matched MeSH terms: Lupus Erythematosus, Systemic/complications*
Systemic lupus erythematosus pregnancies: ten-year data from a single centre in Malaysia

Teh CL, Wan SA, Cheong YK, Ling GR

Lupus, 2017 Feb;26(2):218-223.
PMID: 27522092 DOI: 10.1177/0961203316664996

We performed a retrospective study of all systemic lupus erythematosus (SLE) pregnancies during a 10-year period (2006-2015) to describe the clinical features, maternal and foetal outcomes in our centre. There were 115 pregnancies in 86 women with SLE. Our patients had a mean age of 29.1 years (SD 5.80) and a mean disease duration of 44.63 months (SD 41.17). Fifteen patients had antiphospholipid syndrome (APS). Our patients had complicated pregnancies: 26.1% had SLE flares, 13.9% had pre-eclampsia and 45.1% needed caesarean sections. There were 23.3% foetal losses and 25% preterm deliveries in our patients. There was a higher rate of unplanned pregnancies and lupus flare among pregnancies with active SLE at conception. Pregnancies in lupus nephritis have higher incidence of lupus flares during pregnancy but similar maternal and foetal outcomes compared to those without nephritis. The prognostic indicators for adverse foetal outcome in our patients were flare of SLE (HR 4.08 [CI 95% 1.65-10.13, p

Matched MeSH terms: Lupus Erythematosus, Systemic*
Study of the CTLA-4 gene polymorphisms in systemic lupus erythematosus (SLE) samples from Malaysia

Chua KH, Puah SM, Chew CH, Tan SY, Lian LH

Ann Hum Biol, 2010 Apr;37(2):274-80.
PMID: 19951233 DOI: 10.3109/03014460903325185

In this study, we investigated the polymorphisms of the exon 1 (+49A/G), promoter sites (-1722T/C, -1661A/G, -318C/T), and 3'-untranslated region (3'-UTR) (+6230 A/G) of the CTLA-4 gene in systemic lupus erythematosus (SLE) affected patients. Polymerase chain reaction-restriction fragment length polymorphism was used to determine genotypes of these five markers in 130 SLE patients and 130 healthy controls. Of the five tested polymorphisms, there was no statistical significant difference between the genotypic and allelic frequencies of patients with SLE and controls. Hence, we propose that the CTLA-4 gene does not play a major role in the genetic susceptibility to the development of SLE in the Malaysian population.

Matched MeSH terms: Lupus Erythematosus, Systemic/genetics*
Coexistence of antiphospholipid antibodies and cephalalgia

Islam MA, Alam F, Gan SH, Cavestro C, Wong KK

Cephalalgia, 2018 03;38(3):568-580.
PMID: 28952322 DOI: 10.1177/0333102417694881

Background The occurrence of antiphospholipid antibodies (aPLs) and headache comorbidity in the presence or absence of underlying autoimmune diseases remains unclear. Aim The aim of this review was to summarize the relationship between headache and aPLs based on evidences from cohort studies and case reports, in addition to examining the treatment strategies that resolved headache in aPLs-positive individuals.
Methods A comprehensive literature search was conducted through PubMed, ISI Web of Science and Google Scholar. A total of 559 articles were screened and the appropriate articles were selected based on quality and level of evidence.
Results Cohort studies (n = 27) from Europe, North America and Asia demonstrated comorbidity of aPLs and headache in antiphospholipid syndrome, systemic lupus erythematosus (SLE) and neuropsychiatric SLE patients. Significantly higher association between migraine and aPLs was observed (n = 170/779; p

Matched MeSH terms: Lupus Erythematosus, Systemic/epidemiology
Lupus Susceptibility Region Containing CDKN1B rs34330 Mechanistically Influences Expression and Function of Multiple Target Genes, Also Linked to Proliferation and Apoptosis

Singh B, Maiti GP, Zhou X, Fazel-Najafabadi M, Bae SC, Sun C, et al.

Arthritis Rheumatol, 2021 Dec;73(12):2303-2313.
PMID: 33982894 DOI: 10.1002/art.41799

OBJECTIVE: In a recent genome-wide association study, a significant genetic association between rs34330 of CDKN1B and risk of systemic lupus erythematosus (SLE) in Han Chinese was identified. This study was undertaken to validate the reported association and elucidate the biochemical mechanisms underlying the effect of the variant.
METHODS: We performed an allelic association analysis in patients with SLE, followed by a meta-analysis assessing genome-wide association data across 11 independent cohorts (n = 28,872). In silico bioinformatics analysis and experimental validation in SLE-relevant cell lines were applied to determine the functional consequences of rs34330.
RESULTS: We replicated a genetic association between SLE and rs34330 (meta-analysis P = 5.29 × 10-22 , odds ratio 0.84 [95% confidence interval 0.81-0.87]). Follow-up bioinformatics and expression quantitative trait locus analysis suggested that rs34330 is located in active chromatin and potentially regulates several target genes. Using luciferase and chromatin immunoprecipitation-real-time quantitative polymerase chain reaction, we demonstrated substantial allele-specific promoter and enhancer activity, and allele-specific binding of 3 histone marks (H3K27ac, H3K4me3, and H3K4me1), RNA polymerase II (Pol II), CCCTC-binding factor, and a critical immune transcription factor (interferon regulatory factor 1 [IRF-1]). Chromosome conformation capture revealed long-range chromatin interactions between rs34330 and the promoters of neighboring genes APOLD1 and DDX47, and effects on CDKN1B and the other target genes were directly validated by clustered regularly interspaced short palindromic repeat (CRISPR)-based genome editing. Finally, CRISPR/dead CRISPR-associated protein 9-based epigenetic activation/silencing confirmed these results. Gene-edited cell lines also showed higher levels of proliferation and apoptosis.
CONCLUSION: Collectively, these findings suggest a mechanism whereby the rs34330 risk allele (C) influences the presence of histone marks, RNA Pol II, and IRF-1 transcription factor to regulate expression of several target genes linked to proliferation and apoptosis. This process could potentially underlie the association of rs34330 with SLE.

Matched MeSH terms: Lupus Erythematosus, Systemic/genetics*

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