Single-Point Haplotype Scores Telomeric to Human Leukocyte Antigen-C Give a High Susceptibility Major Histocompatability Complex Haplotype for Psoriasis in a Caucasian Population

Lench, Nicholas; Iles, Mark M.; Mackay, Ian; Patel, Ramila; Sagoo, Gurdeep S.; Ward, Simon; Dechairo, Bryan; Olavesen, Mark G.; Carey, Alisoun H.; Duff, Gordon W.; Cork, Michael J.; Tazi-Ahnini, Rachid

doi:10.1111/j.0022-202x.2005.23604.x

Cited by 11 publications

(11 citation statements)

References 51 publications

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“…The minimal candidate region of PSORS1 mapped by our study overlaps the regions mapped in an American Caucasian population [14] and a Jewish population [11], but is different from the ones mapped by other studies in Caucasian, Japanese and Sardinian psoriatic populations [9],[10],[12] (Fig 2). This difference could be due to the existence of different risk haplotypes in other populations.…”

Section: Discussioncontrasting

confidence: 83%

“…A 150-kb region telometic to HLA-C was also shown to be associated with psoriasis in a Jewish population [11]. More recently, Lench et al [12] performed a SNP-based association analysis and found strong association to a 46-kb interval telomeric to HLA-C in both Caucasian and Japanese populations. Helm et al [13] also performed a comprehensive case/control and family-based association study using SNPs and located the PSORS1 to a haplotype block harboring HLA-C and distinct from CDSN and HCR .…”

Section: Introductionmentioning

confidence: 98%

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Fine Mapping of the Psoriasis Susceptibility Locus PSORS1 Supports HLA-C as the Susceptibility Gene in the Han Chinese Population

et al. 2008

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PSORS1 (psoriasis susceptibility gene 1) is a major susceptibility locus for psoriasis. Several fine-mapping studies have highlighted a 300-kb candidate region of PSORS1 where multiple biologically plausible candidate genes were suggested. The most recent study has indicated HLA-Cw6 as the primary PSORS1 risk allele within the candidate region in a Caucasian population. In this study, a family-based association analysis of the PSORS1 locus was performed by analyzing 10 polymorphic microsatellite markers from the PSORS1 region as well as HLA-B, HLA-C and CDSN loci in 163 Chinese families of psoriasis. Five marker loci show strong evidence (P<10−3), and one marker locus shows weak evidence (P = 0.04) for association. The haplotype cluster analysis showed that all the risk haplotypes are Cw6 positive and share a 369-kb region of homologous marker alleles which carries all the risk alleles, including HLA-Cw6 and CDSN*TTC, identified in this study. The recombinant haplotype analysis of the HLA-Cw6 and CDSN*TTC alleles in 228 Chinese families showed that the HLA-Cw6 −/CDSN*TTC + recombinant haplotype is clearly not associated with risk for psoriasis (T∶NT = 29:57, p = 0.0025) in a Chinese population, suggesting that the CDSN*TTC allele itself does not confer risk without the presence of the HLA-Cw6 allele. The further exclusion analysis of the non-risk HLA-Cw6 −/CDSN*TTC + recombinant haplotypes with common recombination breakpoints has allowed us to refine the location of PSORS1 to a small candidate region. Finally, we performed a conditional linkage analysis and showed that the HLA-Cw6 is a major risk allele but does not explain the full linkage evidence of the PSORS1 locus in a Chinese population. By performing a series of family-based association analyses of haplotypes as well as an exclusion analysis of recombinant haplotypes, we were able to refine the PSORS1 gene to a small critical region where HLA-C is a strong candidate to be the PSORS1 susceptibility gene.

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Section: Discussioncontrasting

confidence: 83%

Section: Introductionmentioning

confidence: 98%

Fine Mapping of the Psoriasis Susceptibility Locus PSORS1 Supports HLA-C as the Susceptibility Gene in the Han Chinese Population

et al. 2008

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“…cgi), and MHC studies [9,11,18]. Comparing the prevalence of inherited diseases in Han Chinese and Caucasian populations, atherosclerosis related to AIF1 and psoriasis related to C6orf18 are more prevalent in Caucasians [26,27]; allopurinolinduced severe cutaneous adverse reaction related to BAT3 [18] and hepatitis B virus related to HLA-DRA are more prevalent in Han Chinese [28,29]. Furthermore, we also investigated genomic regions highly linked to the 101 SNPs and found that some are related to the etiology of diseases such as nasopharyngeal carcinoma, which is highly prevalent in Asian populations.…”

Section: Resultsmentioning

confidence: 99%

A comparison of major histocompatibility complex SNPs in Han Chinese residing in Taiwan and Caucasians

Yang

Lin²,

Hsu

et al. 2006

J Biomed Sci

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SummaryGenetic dissection of complex diseases is both important and challenging. The human major histocompatibility complex is involved in many human diseases and genetic mechanisms. This highly polymorphic chromosome region has been extensively studied in Caucasians but not as well in Asians. Thus, we compared genotypic distributions, linkage disequilibria and haplotype blocks between Caucasian and TaiwanÕs Han Chinese populations. Moreover, we investigated the population admixture and phylogenetic system in Han Chinese residing in Taiwan. The results show that TaiwanÕs Han Chinese differ drastically in genotypic information compared with Caucasians but are relatively homogeneous among the three major ethnic subgroups, Minnan, Hakka and Mainlanders. Differences in allele frequency (AF) between Taiwanese and Caucasians in some disease-associated loci may reveal clues to differences in disease prevalence. The results of ethnic heterogeneity imply that public databases should be used with caution in cases where the study population(s) differs from the population characterized in the database. The high homogeneity we observed among the Taiwanese subpopulations mitigates the possibility of spurious association caused by ignoring population stratification in Taiwanese disease gene association studies. These results are useful for understanding our genetic background and designing future disease gene mapping studies.

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“…However, the exact location of the PSORS1 gene had been controversial, due to the extended and complicated linkage disequilibrium (LD) pattern of the region [5]. Early studies had indicated the existence of two major PSORS1 locations suggested by various fine mapping studies, one a region ∼150 kb telomeric to HLA-C [6],[7],[8],[9], harboring HCG27 , POU5F1 , TCF19 , CCHCR1 and CDSN , and the other HLA-C itself or very close [10],[11]. Recently, a combined sequencing and haplotype mapping study found that within the 298 kb homologous region between the two proposed risk haplotypes, only HLA-C encoded variants unique to these haplotypes at the level of translated protein, which at the same time conferred increased risk of psoriasis, strongly suggesting that HLA-C is the Ps susceptibility gene, and excluded the telomeric region [12].…”

Section: Introductionmentioning

confidence: 99%

Multiple Loci within the Major Histocompatibility Complex Confer Risk of Psoriasis

et al. 2009

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Psoriasis is a common inflammatory skin disease characterized by thickened scaly red plaques. Previously we have performed a genome-wide association study (GWAS) on psoriasis with 1,359 cases and 1,400 controls, which were genotyped for 447,249 SNPs. The most significant finding was for SNP rs12191877, which is in tight linkage disequilibrium with HLA-Cw*0602, the consensus risk allele for psoriasis. However, it is not known whether there are other psoriasis loci within the MHC in addition to HLA-C. In the present study, we searched for additional susceptibility loci within the human leukocyte antigen (HLA) region through in-depth analyses of the GWAS data; then, we followed up our findings in an independent Han Chinese 1,139 psoriasis cases and 1,132 controls. Using the phased CEPH dataset as a reference, we imputed the HLA-Cw*0602 in all samples with high accuracy. The association of the imputed HLA-Cw*0602 dosage with disease was much stronger than that of the most significantly associated SNP, rs12191877. Adjusting for HLA-Cw*0602, there were two remaining association signals: one demonstrated by rs2073048 (p = 2×10−6, OR = 0.66), located within c6orf10, a potential downstream effecter of TNF-alpha, and one indicated by rs13437088 (p = 9×10−6, OR = 1.3), located 30 kb centromeric of HLA-B and 16 kb telomeric of MICA. When HLA-Cw*0602, rs2073048, and rs13437088 were all included in a logistic regression model, each of them was significantly associated with disease (p = 3×10−47, 6×10−8, and 3×10−7, respectively). Both putative loci were also significantly associated in the Han Chinese samples after controlling for the imputed HLA-Cw*0602. A detailed analysis of HLA-B in both populations demonstrated that HLA-B*57 was associated with an increased risk of psoriasis and HLA-B*40 a decreased risk, independently of HLA-Cw*0602 and the C6orf10 locus, suggesting the potential pathogenic involvement of HLA-B. These results demonstrate that there are at least two additional loci within the MHC conferring risk of psoriasis.

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Single-Point Haplotype Scores Telomeric to Human Leukocyte Antigen-C Give a High Susceptibility Major Histocompatability Complex Haplotype for Psoriasis in a Caucasian Population

Cited by 11 publications

References 51 publications

Fine Mapping of the Psoriasis Susceptibility Locus PSORS1 Supports HLA-C as the Susceptibility Gene in the Han Chinese Population

Fine Mapping of the Psoriasis Susceptibility Locus PSORS1 Supports HLA-C as the Susceptibility Gene in the Han Chinese Population

A comparison of major histocompatibility complex SNPs in Han Chinese residing in Taiwan and Caucasians

Multiple Loci within the Major Histocompatibility Complex Confer Risk of Psoriasis

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