XRCC1 Polymorphism and Systemic Lupus Erythematosus

XRCC1 Arg399Gln and Arg194Try Gene Polymorphisms and the Endanger of Planic Lupus Erythematosus in Iranian population (a manseniority con-over)

  • Saeedeh Salimi, Milad Mohammadoo-khorasani, Ehsan Tabatabai, Mahnaz Sandoughi, Zahra Zakeri

Corresponding Author: Milad Mohammadoo-khorasani

Background & objectives: Planic Lupus Erythematosus (SLE) is an autoimmune multiplan distemper that twain genetic and environmental ingredients are able in predisposing to SLE. DNA mend enzymes ceaselessly checked the chromosomes to redress injured nucleotide executed by methylation, oxidation or oxidative mischief. The civilized XRCC1 gene is weighty restraint DNA mend. XRCC1 is located on chromosome 19q13.2–13.3 with 33 kb in tediousness and 17 exons. In this con-over, we examined couple polymorphisms in XRCC1 gene (Arg399Gln and Arg194Trp).

Methods: 163 SLE patients and 180 vigorous moderates were genotyped restraint the XRCC1 Arg399Gln and Arg194Trp polymorphisms by PCR-exclusion chip tediousness polymorphism rule.

Results: The frequencies of AA and AG genotypes of the XRCC1 Arg399Gln polymorphism were momentously inferior in SLE patients than moderates. No momentous familiarity observed betwixt XRCC1 Arg194Trp polymorphism and increased endanger of SLE in premeditated population. Exaltmore, the haplotype resolution inspired that the rs25484A – rs1799782T are a endanger ingredient restraint SLE.

Interpretation & conclusions: These discoverings hint that XRCC1 Arg399Gln polymorphism may give to SLE pathogenesis save XRCC1 Arg194Trp polymorphism may referable termination in SLE.

Explanation Words: Planic Lupus Erythematosus , XRCC1

 

Introduction

Systemic lupus erythematosus (SLE) is a multiplan guess-work and civilized autoimmune distemper, characterized chiefly by increasing of B-cells vital-force and auto-antibodies product over self-antigens (1, 2). SLE is ten folds past moderation in women (3). The pathogenesis of SLE sweepings deceptive, although the etiology of the distemper is reputed to implicate genetic, hormonal and environmental ingredients (4). Diverse auto-antigens are considered as targets restraint auto-antibodies in SLE (5). Antigenicity may be increased by relocomotive oxygen disposition (ROS) and drugs, accordingly diversifys DNA settlement, which terminations in DNA moderation mischief and smashs (6). DNA mend enzymes ceaselessly checked the chromosomes to redress injured nucleotide executed by methylation, oxidation or oxidative mischief(7). Moderation extirpation mend (BER) and nucleotide extirpation mend (NER) are couple routes that mend most of the DNA mischiefs including ROS(8). The X-ray mend peevish-complementation collection1 (XRCC1) is individual of the most weighty protein that has the role in the BER route(9). XRCC1, a DNA mend protein , which is implicated in separate-shore smashs and BER route , hinted to be binding restraint the able mend of DNA mischief caused by locomotive oxygen, ionization, and alkylating senioritynts.(10) The civilized XRCC1 gene is 33 kb in tediousness, and located on chromosome 19q13.2–13.3 , that has 17 exons.(11). There are past than 300 validated separate nucleotide polymorphisms (SNPs) in the XRCC1 gene reputed in the dbSNP basismoderation (https://www.homeworkessaymarket.com/write-my-paper/ncbi. nlm.nih.gov/SNP), three of which are moderation (12)and manseniority to amino animated reanimation in XRCC1 at codon 194 (exon 6, moderation C to T, amino animated Arg to Trp, dbSNP no. rs1799782), codon 280 (exon 9, moderation G to A, amino animated Arg to His, dbSNP no. rs25489) and codon 399 (exon 10, moderation G to A, amino animated Arg to Gln, dbSNP no.rs25487). Although the authoritative possessions of these polymorphisms in XRCC1 feel referable been implied, it is hinted that amino animated diversifys at preserved regions may alter its character (13). This diversify in protein biochemistry manages to the supposition that contradictory alleles may contract kinetics mend, thereby termination in SLE sensitiveness.(14)

The attend of this con-over was to brave the practicable possessions of XRCC1 polymorphisms on SLE endanger in an Iranian population.

2. Materials and rules

Patients and specimen collection

In this case- moderate con-over, we evaluated 163 patients improbable with SLE who referred to rheumatology clinics in Zahedan city, since 2011 to 2013. They feel been diagnosed with planic lupus erythematosus according to ACR 1998 criteria (American Rheumatology Familiarity). The moderate collection awaited of 180 men-folks. They matched from the viewpoint of seniority, sex and ethnic. Volunteers feel privative ANA experience and no planic distempers and to-boot no race fitness with lupus patients. All participants supposing written cognizant submit according to the Declaration of Helsinki.

Genomic DNA origin and genotyping

Blood specimens were unmoved in 2 ml Na-EDTA tubes from patients and vigorous moderates and genomic DNA was extracted by using salting extinguished rule. The nature and muchness of extracted DNA unshaken by spectrophotometer retinue. Genotypes were detected using a polymerase tie reaction-exclusion chip tediousness polymorphism (PCR–RFLP) and tetra-ARMS-PCR techniques. The PCR primer sequences and the pbuoyant of each primer is listed in Board 1

Board 1. The PCR primer sequences

Polymorphisms

Primer sequences(RFLP)

Tm(CËš)

rs1799782

F:5’GCCAGGGCCCCTCCTTCAA- 3′

60

R:5’TACCCTCAGACCCACGAGT- 3′

rs25487

F:5′-GGACTGTCACCGCATGCGTCGG- 3′

60

R: 5′-GGCTGGGACCACC TGTGTT- 3

 

Primer sequences ( tetra-ARMS)

 

rs1799782

outer

F: 5′-CGTCCCAGGTAAGCTGTAC-3

63

R: 5 CACTCCTATCTATGGGACACAG-3

 

inner

F:5- CGGGGGCTCTCTTCTTCATCC-3

R:5- CACCTGGGGATGTCTTGTTGATACA-3

rs25487

outer

F:5-ACCAGCTGTGCCTTTGCCAACACC-3

68

R:5-CTGGAGTACCCCAGCCCCTGCC-3

inner

F: 5-GTCGGCGGCTGCCCTCACA-3

R:5-TGGCGTGTGAGGCCTTACCACC-3

Each PCR products was digested according to its protocol; 10 U/μl of Msp I exclusion enzyme (Fermentas, Lithuania) restraint 12 h at 37ºC. Digested specimens were separated by electrophoresis on a 2.5% agaroz gel and visualized by ethidium bromide staining.

Statistical resolution

Statistical resolution was produced with SPSS-V- 18. Student t experience was used to assimilate immanent variables and χ 2experience was used to assimilate non-immanent variables. Logistic retirement resolution was used to assess the refractory property of each endanger polymorphism on PE. Linkseniority dismakeweight (LD) was analyzed using Cube X software (15). Values of p<0.05 were considered statistically momentous.

Result

Demographic basis of SLE patients and moderate collection are pretextn in board2. There were no momentous dissimilitudes in genders and ethnics betwixt SLE patients and moderates. Pastover, there was no large dissimilitude betwixt the moderation seniority betwixt moderate collection (32.1±11.7) and SLE patients (32.6±8.6, p=0.4).

Board 2. Demographic characteristics of SLE patients and moderates

Parameter

SLE

N=163

Controls

N=180

p-Value

χ2

Seniority (yr)

32.6±8.6

32.1±11.7

0.68

0.04

Sex (male/female)

13/150

14/166

0.6

0.04

Race N (%)

Persian

Balouch

82 (50)

81 (50)

86 (48)

94 (52)

0.36

0.27

According to our discoverings dermomucus manifestations open in 85% of SLE patients (54% with malar thoughtless). Arthritis was institute in 84% of patients, seeing neuropsychiatric manifestations were observed in 17% of patients. Lupus nephritis was open with exalted serum creatinine in 27% of patients.

The allele and genotype frequencies of patients with SLE and moderates are pretextn in Board 3. All loci were in Hardy–Weinberg makeweight. The rs1799782and rs25484 did referable feel momentous LD (D=0.708, r2 =0.162 and P < 0.05) as unshaken by pair-wise LD tone.

The genotype and allele frequencies of XRCC1 Arg194Trp (rs1799782) polymorphism was referable momentously unanalogous betwixt SLE patients and moderate collection. However, the genotypic and allelic frequencies of XRCC1 Arg399Gln (rs25484) polymorphism was statistically unanalogous betwixt couple collections. The endanger of SLE was inferior in men-folks with AG and AA genotype in assimilate to those with GG genotype. (OR, 0.43 [95% CI, 0.26 to 0.71]; P=0.001 and 0.53[95% CI, 0.027 to 1.03). In conjunction, the reckon of G allele was momentously upper in SLE pateints p=0.011.

Table3. Genotypes and alleles reckon of XRCC1 polymorphisms in SLE patients and moderates

genotype

case

N=163(%)

control

N=180(%)

p value

OR

Arg399Gln

       

GG

64 (39.3%)

41 (22/8%)

   

AG

75 (46%)

110 (61/2%)

0.001

0.436(0.267-0.712)

AA

24 (14.7%)

29 (16%)

0.044

0.530(0.271-1.034)

allele

       

A

123 (37.7%)

168 (46.7%)

   

G

203 (62.2%)

192 (53.3%)

0.011

1.445(1.064-1.96)

Arg194Trp

       

CC

106 (65%)

112 (62.2%)

   

CT

52 (32%)

65 (36.1%)

0.269

0.845(0.538-1.328)

TT

5 (3%)

3 (1.7%)

0.341

1.76(0.41-7.575)

allele

       

C

264 (81%)

289 (80.3%)

   

T

62 (19%)

71 (19.7)

0.446

0.939(0.654-1.396)

Four haplotypes of the XRCC1 await of couple-alleles of each polymorphism office is pretextn in board 4.we institute a agitate in AT haplotype reckon in patients improbable with SLE that can be guarded as endanger ingredient restraint this distemper.

Board 4.observed haplotype of rs1799782 and rs25484

haplotype

rs25484 – rs1799782

case

control

p value

OR

AC

0.578

0.544

0.109

1.28 (0.946 – 1.732)

GC

0.231

0.263

0.089

0.74(0.523 – 1.047)

GT

0.145

0.16

0.255

0.792 (0.53 – 1.184)

AT

0.044

0.031

0.011

4.548(1.272-16.263)

Discussion

Systemic lupus erythematosus (SLE) is a planic irritant and autoimmune guess-work of connective tissues with hidden etiology. Divers ingredients, including endocrine and metabolic, environmental and genetic ingredients are weighty in this distemper (16, 17). DNA mischief can be flow from environmental ingredients love mutagenic elements or interior ingredients including relocomotive oxygen disposition terminationing from physiological rule (18). So remote, capacious studies on the role of oxidative importance on the immune plan and its role in causing multiform distempers and its role in changing the constitution of DNA was carried extinguished(19).Divers studies feel pretextn that smashs in DNA adulterated with nuclear proteins are restraintcible immunogens restraint bitter auto-relocomotive antibodies (Abs) in SLE patients. DNA mend power in cells is a determining ingredient restraint preventing the fruit of SLE (20, 21). XRCC1’s character as a referable attributable attributableable protein in the vital-force of BER ingredients, give to assess its influences on the couple most usual polymorphisms (22). .In this con-over, we examined couple polymorphisms in this gene. Our discoverings pretext that AA and AG genotypes are as protective ingredients and GG genotype as a endanger ingredient restraint this distemper. Save the genotypic and allelic frequencies of Arg194Trp polymorphism were referable momentously unanalogous betwixt SLE patients and moderate collection. There are divers reports pretexting the corfitness betwixt XRCC1 genes and autoimmune distempers love rheumatoid arthritis (23). However, basis on allelic deviation at the XRCC1 gene in patients with SLE are poor. Benke et al .reputed that DNA mend is deteriorated in patients with SLE (24) In 2009 Lin et al. reputed that AA genotypes of Arg399Gln gene polymorphisms were momentously near common in SLE patients than moderates in Taiwanese Han Chinese. These discoverings are awaitent with our discoverings save we observed AG genotype reckon in vigorous moderates exalt than SLE patients that is oppooffice of Lin et al. discoverings (19). Bassi and Warcho‚i reputed that AA and AG genotypes of XRCC1 Arg399Gln polymorphisms were very-much common in SLE patients than moderates in Polish Population (25, 26). These terminations are wholly inagreeing with our discoverings, owing we observed exalted reckon of the AG and AA genotype in moderate collection.

With i-elation to another contradictory Arg149Trp, our con-over failed to pretext any momentous dissimilitudes in allelic and genotypic dispensation of this polymorphism unordered the collections. In harmony with our terminations, Lin et al (19) institute no familiarity betwixt the XRCC1 Arg194Trp and sensitiveness to SLE. To-boot, Koyama et al. did referable discover any familiarity betwixt XRCC1 Arg194Gln and Arg399Gln polymorphisms and rheumatoid arthritis in Japanese population(27).

In buoyant of these discoverings, we hint that there is an familiarity betwixt the XRCC1 Arg399Gln and defencelessness to SLE in the premeditated population. Current Awaitent with the event that XRCC1 has explanation role in the BER plan thus a diversify in the amino animated alter the constitution of this protein and may be diversify its character.

Acknowledgements

This word was extracted from the M.S.essay (registered reckon 5719) at Zahedan University of Medical Sciences. The authors endow Zahedan Deputy of Inquiry Affairs restraint funding this plan.

Disclosure

The authors commend that they feel no conflicts of curiosity-behalf.

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