Haplotypes of the HRES-1 endogenous retrovirus are associated with development and disease manifestations of systemic lupus erythematosus.
OBJECTIVE
Endogenous retroviral sequences represent a link between viral and genetic factors that may influence the development of systemic lupus erythematosus (SLE). The HRES-1 human endogenous retroviral sequence is centrally located at the 1q42 chromosomal region relative to microsatellites previously associated with SLE. We therefore undertook the present study to determine the haplotypes of the HRES-1 locus and their linkage to SLE.


METHODS
One hundred six patients with SLE, 82 unrelated healthy Caucasian individuals, and 70 healthy members of 34 lupus families were examined. HRES-1 was amplified by polymerase chain reaction (PCR) and analyzed by sequencing and restriction enzyme mapping. Microsatellites were analyzed by PCR. Haplotype construction and transmission disequilibrium testing (TDT) were performed in lupus families.


RESULTS
Based on 4 single-nucleotide polymorphisms (SNPs) within a 935-base interval, we detected 6 HRES-1 haplotypes that were differentially segregated in unrelated Caucasian patients and control subjects (chi(2) = 16.86, P = 0.0048) and were in linkage disequilibrium (LD) with the D1S225 microsatellite (P = 0.0002). The microsatellites D1S225, D1S235, and D1S2785 (but not D1S229) were linked to SLE by TDT. Interestingly, LD between HRES-1 SNPs at bases 653 and 1259 was reduced in patients with SLE (P = 0.048). The HRES-1 653C/1259C-harboring alleles were associated with the presence of renal disease (P = 0.0021) and with the absence of lung disease (P = 0.0323), while the 956A allele was associated with the antiphospholipid syndrome in patients with SLE (P = 0.0036).


CONCLUSIONS
The HRES-1 locus represents a recombination hot spot at the 1q42 chromosomal region that influences the development and disease manifestations of SLE.
Pullmann
Rudolf
R
State University of New York, Syracuse, NY 13210, USA.
Bonilla
Eduardo
E
Phillips
Paul E
PE
Middleton
Frank A
FA
Perl
Andras
A
D001741:Black or African American / Q000235:genetics; D034961:Antigens, Nuclear / Q000235:genetics*; D001213:Asian / Q000235:genetics; D001324:Autoantigens / Q000235:genetics*; D015252:Deoxyribonucleases, Type II Site-Specific; D005260:Female; D020022:Genetic Predisposition to Disease / Q000208:ethnology; D006239:Haplotypes; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D008180:Lupus Erythematosus, Systemic / Q000208:ethnology* / Q000235:genetics* / Q000821:virology; D008297:Male; D018895:Microsatellite Repeats; D020641:Polymorphism, Single Nucleotide; D044469:Racial Groups / Q000235:genetics*; D012191:Retroviridae Proteins / Q000235:genetics*; D044465:White People / Q000235:genetics
D034961:Antigens, Nuclear; D001324:Autoantigens; C096557:HRES-1 p28 protein, human retroviral element; D012191:Retroviridae Proteins; C035801:CCSGG-specific type II deoxyribonucleases; D015252:Deoxyribonucleases, Type II Site-Specific; C024400:GTYRAC-specific type II deoxyribonucleases