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At least 973 records · Page 54Linked to original sources
PubMed2006

Genomic DNA pooling for whole-genome association scans in complex disease: empirical demonstration of efficacy in rheumatoid arthritis.

A pragmatic approach that balances the benefit of a whole-genome association (WGA) experiment against the cost of individual genotyping is to use pooled genomic DNA samples. We aimed to determine the feasibility of this approach in a WGA scan in rheumatoid arthritis (RA) using the validated human leucocyte antigen (HLA) and PTPN22 associations as test loci. A total of 203 269 single-nucleotide polymorphisms (SNPs) on the Affymetrix 100K GeneChip and Illumina Infinium microarrays were examined. A new approach to the estimation of allele frequencies from Affymetrix hybridization intensities was developed involving weighting for quality signals from the probe quartets. SNPs were ranked by z-scores, combined from United Kingdom and New Zealand case-control cohorts. Within a 1.7 Mb HLA region, 33 of the 257 SNPs and at PTPN22, 21 of the 45 SNPs, were ranked within the top 100 associated SNPs genome wide. Within PTPN22, individual genotyping of SNP rs1343125 within MAGI3 confirmed association and provided some evidence for association independent of the PTPN22 620W variant (P=0.03). Our results emphasize the feasibility of using genomic DNA pooling for the detection of association with complex disease susceptibility alleles. The results also underscore the importance of the HLA and PTPN22 loci in RA aetiology.

Arthritis, Rheumatoid↗
PubMed2004

Evidence for genetic linkage between a polymorphism in the adenosine 2A receptor and panic disorder.

Data from clinical and behavioral pharmacological studies have implicated adenosine in anxiety behaviors, while genetic studies have suggested that adenosine receptors may be associated with panic disorder. We have undertaken an analysis of several DNA sequence variations in the adenosine 2A receptor (ADORA2A) in a large sample of panic disorder pedigrees. Individuals from 70 panic disorder pedigrees, and 83 child-parent 'trios', were genotyped at five single-nucleotide polymorphisms (SNPs) in and near the ADORA2A gene and were analyzed for genetic linkage and association. Linkage analysis revealed elevated LOD scores for a silent substitution (1083C/T, SNP-4) in the second coding exon. This SNP has been previously reported to be associated with panic disorder. We observed a maximal heterogeneity LOD score of 2.98 (theta=0) under a recessive genetic model and narrow diagnostic model. Other SNPs showed no evidence for linkage. Association tests were not significant for any of the five ADORA2A SNPs. When SNP haplotypes were assessed in the triads with TRANSMIT, one 3-marker haplotype (SNPs 1, 4, 5) was nominally significantly associated with panic disorder (p=0.029). Pairwise estimations of linkage disequilibrium between the SNPs showed strong patterns of linkage disequilibrium across the ADORA2A locus. Analyses carried out by broadening the panic disorder phenotype to include agoraphobia continued to support linkage to ADORA2A. Our findings provide evidence for a susceptibility locus for panic disorder, and possibly including agoraphobia, either within the ADORA2A gene or in a nearby region of chromosome 22, and serves as the first successful candidate gene replication study in panic disorder.

Female↗
PubMed2002

Efficient discovery of single-nucleotide polymorphisms in coding regions of human genes.

Single nucleotide polymorphisms in protein coding regions (cSNPs) are of great interest for their effects on phenotype and potential for mapping disease genes. We have identified 5,400 novel exonic SNPs from alignments of public EST data to the draft human genome sequence, and approximately 12,000 more novel exonic SNPs from EST cluster alignments. We found 82% of the genomic-aligned SNPs and 63% of the EST-only SNPs to be detectably polymorphic in 20 Finnish DNA samples. 37% of the SNPs mapped to known protein coding regions, yielding 6,500 distinct, novel cSNPs from the two datasets. These data reveal selection against mutations that alter protein structure, and distinct classes of genes under strongly positive vs. negative pressure from natural selection for amino acid replacement (detected by K(A)/K(S)ratio). We have searched these cSNPs for compatibility with the amino acid profile at each site and structural impact on protein core stability.

Chromosome Mapping↗
PubMed2006

Pharmacogenetic of antirheumatic treatments: clinical implications.

Preliminary pharmacogenetic data suggest that germline genetic informations might be of value in individualizing disease-modifying antirheumatic drugs (DMARDs) therapy in various autoimmune chronic inflammatory diseases. Either DMARDs small molecules (DMARDs-SM) or DMARDs biological therapies (DMARDs-BT) might be selected for their lower toxicity or better efficacy based on single-nucleotide polymorphisms (SNPs) of genes governing the metabolism of drugs, or the response of immune cells to proinflammatory molecules, or the proinflammatory molecular activity of immune cells. Data available for one DMARDs-SM, methotrexate, suggest that a careful assessment of the SNPs of four enzymes involved in the folate metabolism allow one to construct a genetic index of toxicity (toxicogenetic index) that might be employed in daily practice to find the patient's most at risk. Only the full knowledge of the various gene polymorphisms controlling the phenotypic manifestations of the inflammatory-immunological milieu of each rheumatic disease will allow one to obtain the clear definition of a personalized medicine. Few different cytokine gene SNPs seem to be of importance in determining the susceptibility to diseases, or the aggressiveness of diseases. The role of genetics in affecting a possible clinical response to DMARDs-BT targeting specific inflammatory molecules or their receptors still has to be defined. However, the available data suggest that cytokine (and/or receptors) gene SNPs might indeed play a role in determining the biological effects, hence the clinical effectiveness of DMARDs-BT. Crucial to this aim will be the prospective analysis of clinical benefits and safety on the basis of the at baseline stratification of gene SNPs in each chronic inflammatory rheumatic disease before starting any new DMARDs-SM or DMARDs-BT.

Animals↗
PubMed2003

Putative SNP discovery in interspecific hybrids of catfish by comparative EST analysis.

In this study, we identified putative SNP markers within genes by comparative analysis of expressed sequence tags (ESTs). Comparison of 849 ESTs from blue catfish (Ictalurus furcatus) with >11,000 ESTs from channel catfish (I. punctatus) deposited in GenBank resulted in the identification of 1020 putative SNPs within 161 genes, of which 145 were nuclear genes of known function. The observed frequency of SNPs within ESTs of the two closely related catfish species was 1.32 SNP per 100 bp. The majority of identified SNPs differed between the two species and, therefore, these SNPs are useful for mapping genes in channel catfish x blue catfish interspecific resource families. The SNPs that differed within species were also observed; these can be applied to genome scans in channel catfish resource families.

Animals↗
PubMed1999

Single nucleotide polymorphisms in the equine transferrin gene.

Single nucleotide polymorphisms (SNPs) in exons 13, 15 and 16 of equine transferrin for common, rare and mutant variants were investigated. Compared with previous work a further 13 SNPs have been identified, allowing for the two previously identified clades to be subdivided into 11 groups. A combination of one or more of eight SNPs can be used to classify the equine variants into these 11 groups, since most are co-inherited. Putative sites of glycosylation in exons 13 and 16 showed no polymorphism, suggesting that presence or absence of sugar moieties does not lead to electrophoretic variation between the variants. Using the 26 SNPs currently identified in transferrin it is still not possible to differentiate variants F1 from F2, or D from H2, which represent 75% of the variants occurring in Thoroughbred equine population. This suggests that further SNPs exist in equine transferrin. The significance of the high level of variation in exon 15 is discussed.

Animals↗
PubMed2002

Single nucleotide polymorphisms derived from ancestral populations show no evidence for biased diversity estimates in Drosophila melanogaster.

Single nucleotide polymorphisms (SNPs) are about to become one of the most popular genetic markers for genetic model organisms. To test the usefulness of SNPs for estimating genetic diversity, we surveyed three genomic regions in two Drosophila melanogaster populations, one from Africa and one European, collected in Austria. Diversity estimates based on the full SNP set indicated higher levels of variability in the African than in the European flies. When the analysis was based on the European SNP set, European and African flies had similar levels of variability. Interestingly, this bias was not observed for diversity estimates using SNPs derived from the ancestral African population. This result suggests that diversity estimates based on SNPs from ancestral populations could provide a general strategy to avoid biased SNP diversity estimates. Finally, the potential of SNPs for nonmodel organisms is discussed.

Animals↗
PubMed2003

SNP subset selection for genetic association studies.

Association studies for disease susceptibility genes rely on the high density of SNPs within candidate genes. However, the linkage disequilibrium between SNPs imply that not all SNPs identified in the candidate region need be genotyped. Here we develop several approaches to SNP subset selection, which can substantially reduce the number of SNPs to be genotyped in an association study. We apply clustering algorithms to pairwise linkage disequilibrium measures, with SNP subsets determined for different cut-off values of Delta using nearest and furthest neighbour clusters. Alternatively, SNP subsets may be determined by the proportion of haplotypes they identify. We also show how power calculations, based on the average power to identify a SNP as the disease susceptibility mutation using haplotype-based or logistic regression based statistical analyses, can be used to choose SNP subsets. All these methods provide a ranking method for subsets of a specific size, but do not provide criteria for overall choice of SNP subset size. We develop such criteria by incorporating power calculations into a decision analysis, where the choice of SNP subset size depends on the genotyping costs and the perceived benefits of identifying association. These methods are illustrated using eleven SNPs in the MMP2 gene.

Cluster Analysis↗
PubMed2005

Application of the stepwise focusing method to optimize the cost-effectiveness of genome-wide association studies with limited research budgets for genotyping and phenotyping.

The recent cataloguing of a large number of SNPs enables us to perform genome-wide association studies for detecting common genetic variants associated with disease. Such studies, however, generally have limited research budgets for genotyping and phenotyping. It is therefore necessary to optimize the study design by determining the most cost-effective numbers of SNPs and individuals to analyze. In this report we applied the stepwise focusing method, with two-stage design, developed by Satagopan et al. (2002) and Saito & Kamatani (2002), to optimize the cost-effectiveness of a genome-wide direct association study using a transmission/disequilibrium test (TDT). The stepwise focusing method consists of two steps: a large number of SNPs are examined in the first focusing step, and then all the SNPs showing a significant P-value are tested again using a larger set of individuals in the second focusing step. In the framework of optimization, the numbers of SNPs and families and the significance levels in the first and second steps were regarded as variables to be considered. Our results showed that the stepwise focusing method achieves a distinct gain of power compared to a conventional method with the same research budget.

Cost Control↗
PubMed2002

Genetic polymorphisms in interferon pathway and response to interferon treatment in hepatitis B patients: A pilot study.

Interferon alfa (IFN-alpha) therapy remains a mainstay of treatment in active hepatitis B. However, sustained remission rates remain relatively low, and the search for factors important for response to therapy continues. Our study aimed to identify the host single nucleotide polymorphisms (SNPs) that predict IFN response in hepatitis B patients. We selected genes in the IFN pathway involved in antiviral and signaling activities and sequenced 22 SNPs for each of our 82 patients. Our results identified 2 SNPs in the antiviral pathway that may influence IFN response. One SNP in the regulatory region of the eIF-2alpha gene revealed A/G alleles. The rate of A/G heterozygotes is 22% in nonresponders (NR) and 2% in sustained responders (R), with an odds ratio (OR) of 12.82 (95% CI: 1.52-107.85, P =.009). After adjustment for age, sex, and HBV DNA level, the OR reaches 14.94 (95% CI: 1.45-153.71, P =.023). This marker revealed greater significance than HBV DNA levels (OR: 5, 95% CI: 1.01-2.43, P =.033) as a marker for IFN response, suggesting its potential advantage over conventional predictors. In addition, borderline significance for the SNP in MxA gene promoter at nt -88 revealed G/T alleles, with the G/T heterozygote rate being 19% in nonresponders and 43% in sustained R (P =.061), concurring with a previous study involving hepatitis C patients. In conclusion, this pilot identified SNPs as potential markers that could predict hepatitis B patient response. These observations may help guide future large-scale studies in examining host SNPs for their clinical utility in predicting IFN response.

Adult↗
PubMed2003

Polymorphisms in the IL 18 gene are associated with specific sensitization to common allergens and allergic rhinitis.

BACKGROUND: Atopy has been linked to chromosome 11q22, a region that harbors the IL18 gene. IL-18 enhances IL-4/IL-13 production and induces IgE production that is directly associated with the pathogenesis of atopic disorders. OBJECTIVE: We sought to investigate whether genetic abnormalities in the regulatory regions of the IL18 gene predispose, in part, to susceptibility to atopy. METHODS: Among a white population of 105 families, the oldest child was examined with regard to atopic phenotypes and single-nucleotide polymorphisms (SNPs) within the IL18 gene. RESULTS: We have identified 5 novel SNPs in the IL18 gene (-920[t/c], -133[c/g], and -132[a/g] in promoter 2 [upstream of exon 2]; +179[c/a; Ser35Ser] in exon 4; and +486[c/t; Phe137Phe] in exon 6). Three SNPs are located in promoter 2, and one (-133[c/g]; nuclear factor 1 site) was significantly associated with high serum IgE levels (P =.001; odds ratio, 3.96) and specific sensitization to common allergens (P =.005; OR, 4.12). In addition, previously identified SNPs in exon 1 (+113[t/g] and +127[c/t]) and in promoter 1 (-137[g/c], GATA3 site) of the IL18 gene were significantly associated with high IgE levels (P < or =.005; OR, 3.27-3.90) and specific sensitization (P =.02 to.008; OR, 3.27-3.83). The SNP +127(g/t) in exon 1 was also a susceptibility locus for seasonal allergic rhinitis (P =.008; OR, 3.22). CONCLUSION: IL18 might be responsible for the linkage effects seen in the chromosomal region 11q22, which has been found previously with the phenotype "sensitization to mite allergen." Thus a suspected direct role of IL18 in the pathogenesis of atopy has been strengthened by the presence of 8 common SNPs in the promoter regions of IL18.

Alleles↗
PubMed2004

Genomic organisation of the chicken ghrelin gene and its single nucleotide polymorphisms detected by denaturing high-performance liquid chromatography.

(1) Ghrelin is a novel endogenous ligand for the growth hormone secretagogue receptor (GHS-R) and is expressed primarily in the stomach and hypothalamus with the probable function of stimulating GH secretion and food intake both in mammals and poultry. The complete sequences of ghrelin gene have been reported in humans and mice; however, that of chickens remains unclear. (2) Here, we report the complete sequence of chicken ghrelin gene (submitted to Genbank; accession number AY303688), which consists of 5 exons and 4 introns. As in mice, the first exon of chicken ghrelin gene does not encode any amino acid. (3) Scanning point mutations with denaturing high-performance liquid chromatography (DHPLC) using WAVE DNA Fragment Analysis Systems and confirmed with direct sequencing for polymerase chain reaction (PCR) products, we analysed the single nucleotide polymorphisms (SNPs) in the entire gene of chicken ghrelin. (4) Results showed that there were 19 SNPs in chicken ghrelin gene, and most of these SNPs were scattered in the 4 introns. In these SNPs, one mutation in exon 5 (A2355G) led to the change of amino acid from glutamine to arginine (Gln 113 Arg): as a result a different ghrelin precursor instead of a mature peptide was produced. In addition, one SNP in 5'UTR (C223G) determined the presence or absence of a potential binding site of transcription factor serum response factor (SRF), which might affect the expression of chicken ghrelin gene. Some of the SNPs detected in the present study could be used in quantitative trait loci (QTL) mapping for growth characters in chickens. (5) Because one SNP is located in a polymorphic site of restriction enzyme PagI of intron 4, it was possible to design a PCR-RFLP procedure and analyse the diversity of 10 chicken populations. Results showed the allelic frequencies of C2100T differ among these breeds, however, no significant difference was observed between imported breeds and Chinese native ones, nor between egg layers and meat type chickens. A chi-square test showed that 4 chicken populations of Beijing Fat, Xinghua, Recessive White and Silky followed the Hardy-Weinberg equilibrium.

Amino Acid Sequence↗
PubMed2003

Association of single nucleotide polymorphisms of the bile salt export pump gene with intrahepatic cholestasis of pregnancy.

BACKGROUND: We determined whether genetic variability in the gene encoding the bile salt export pump (BSEP) contributes to individual differences in susceptibility to the development of intrahepatic cholestasis of pregnancy (ICP). METHODS: The study involved 57 affected and 115 healthy control pregnant women who were genotyped for two single nucleotide polymorphisms (SNPs) in the BSEP gene. Chi-square analysis was used to assess genotype and allele frequency differences between the cholestatic and control groups. In addition, single locus analysis was expanded to pair of loci haplotype analysis to examine the estimated haplotype frequencies of the two SNPs, of unknown phase, among the cholestatic and control groups. Estimated haplotype frequencies were assessed using the maximum-likelihood method, employing an expectation-maximization (EM) algorithm. RESULTS: The genotype and allele frequency distribution of the two intragenic SNPs in the ICP and control groups revealed significant evidence of association with the exon 28 SNP (P=0.04 and P=0.02, respectively). In addition, a borderline allele association was noted with the intron 19 SNP (P=0.08). Although the overall distribution of estimated haplotypes of intron 19 and exon 28 SNPs did not differ between the ICP and control groups, the most common haplotype, A-G, was significantly overrepresented in the ICP group (P=0.02), at an odds ratio of 1.73 (95% CI: 1.08-2.74). CONCLUSIONS: The use of two intragenic SNPs in both single locus and haplotype analyses of association suggests that the BSEP gene is a susceptibility gene in intrahepatic cholestasis of pregnancy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2025

Assessing individual genetic susceptibility to metabolic syndrome: interpretable machine learning method.

BACKGROUND: Genome-wide association studies have provided profound insights into the genetic aetiology of metabolic syndrome (MetS). However, there is a lack of machine-learning (ML)-based predictive models to assess individual genetic susceptibility to MetS. This study utilized single-nucleotide polymorphisms (SNPs) as variables and employed ML-based genetic risk score (GRS) models to predict the occurrence of MetS, bringing it closer to clinical application. METHODS: Feature selection was performed using Least Absolute Shrinkage and Selection Operator. Six ML algorithms were employed to construct GRS models. A fivefold cross-validation was utilized to aid in the internal validation of models. The receiver operating characteristic (ROC) curve was used to select the better-performing GRS model. The SHapley Additive exPlanations (SHAP) was then applied to interpret the model. After extracting GRS, stratified analysis of BMI, age and gender was performed. Finally, these conventional risk factors and GRS were integrated through multivariate logistic regression to establish a combined model. RESULTS: A total of 17 SNPs were selected for analysis. Among the GRS models, the extreme gradient boosting (XGBoost) model demonstrated superior discriminative performance (AUC = 0.837). The XGBoost's optimal robustness was also validated through five-fold cross-validation (mean ROC-AUC = 0.706). The XGBoost-based SHAP algorithm not only elucidated the global effects of 17 SNPs across all samples, but also described the interaction between SNPs, providing a visual representation of how SNPs impact the prediction of MetS in an individual. There was a strong correlation between GRS and MetS risk, particularly observed among young individuals, males and overweight individuals. Furthermore, the model combining conventional risk factors and GRS exhibited excellent discriminative performance (AUC = 0.962) and outstanding robustness (mean ROC-AUC = 0.959). CONCLUSION: This study established a reliable XGBoost-based GRS model and a GRS prediction platform (https://metabolicsyndromeapps.shinyapps.io/geneticriskscore/) to assess individual genetic susceptibility to MetS. This model has high interpretability and can provide personalized reference for determining the necessity of primary prevention measures for MetS. Additionally, there may be interactions between traditional risk factors and GRS, and the integration of both in a comprehensive model is useful in the prediction of MetS occurrence.

Humans↗
PubMed2001

Screening and scanning of single nucleotide polymorphisms in the pig melanocortin 1 receptor gene (MC1R) by pyrosequencing.

The increasing interest in the discovery and characterization of single nucleotide polymorphisms (SNPs) emphasis the need for high-throughput and cost effective scoring methods. Pyrosequencing is a novel method for screening SNPs. In this study we examine breed specific SNPs in the pig melanocortin 1 receptor gene (MC1R), some causing coat color phenotypes. A total of fifteen pigs representing eight breeds and crosses were analyzed by pyrosequencing. In addition to nine previously known SNPs, we also detected one new missense mutation by pyrosequencing. We here show that the SNPs were readily scored using standard reaction conditions. Insertions as well as substitutions were unambiguously detected and all genotypes were resolved in terms of homo- and heterozygozity.

Animals↗
PubMed2003

Clinical relevance of pharmacogenetics.

Pharmacogenetics fields of research was initially restricted to drug metabolism enzymes. It has recently progressed to drug transporters, receptors, and any kind of targets that can modulate drug response. This rapid extension of pharmacogenetics to all the different medical specialties is in close relation with the recent completion of the draft sequence of the human genome and the discovery that about 0.1% of its sequence is polymorphic. The goal of pharmacogenetics for the next years is clearly to determine the clinical consequences of these 2-3 million single nucleotide polymorphisms (SNPs). Things can be schematically divided in two situations. (1) Frequent SNPs (allele frequency > 10%) which have a low impact on drug response (odds ratios < 2), even combined with other SNPs in haplotype combinations. Such situations, which are by far the most frequent, have no clinical relevance for a single patient to predict its response to a particular drug. CYP3A and MDR1 allelic variants are good examples of such frequent situations. (2) Rare SNPs, which dramatically alter the expression or the activity of a target protein, can sometimes have a real clinical relevance (odds ratios > 5), usually to predict drug side effects. Only few examples, such as TPMT and CYP2C9 genetic polymorphisms, can illustrate this rare situation. Unfortunately, less than 1% of the population is concerned by these rare SNPs, and genotyping can only explain a small part of the variability of the response to a single drug. Beside the impressive mass of data available for pharmacogenetics, it is surprising to observe its poor development in routine medical practice. This discrepancy relies mainly on educational and methodological problems, which might be solved in the decade. To promote pharmacogenetics in routine medical practice, large prospective randomized trials are needed to demonstrate that pharmacogenetic orientated prescription can sometimes predict drug response without dramatic increase in costs.

Animals↗
PubMed2002

Association between single-nucleotide polymorphisms in selectin genes and immunoglobulin A nephropathy.

Although intensive efforts have been undertaken to elucidate the genetic background of immunoglobulin A nephropathy (IgAN), genetic factors associated with the pathogenesis of this disease are still not well understood. We designed a case-control association study that was based on linkage disequilibrium among single-nucleotide polymorphisms (SNPs) in the selectin gene cluster on chromosome 1q24-25, and we found two SNPs in the E-selectin gene (SELE8 and SELE13) and six SNPs in the L-selectin gene (SELL1, SELL4, SELL5, SELL6, SELL10, and SELL11) that were significantly associated with IgAN in Japanese patients. All eight SNPs were in almost complete linkage disequilibrium. SELE8 and SELL10 caused amino acid substitutions from His to Tyr and from Pro to Ser (chi2=9.02, P=.0026, odds ratio = 2.73 [95% confidence interval [CI] 1.38--5.38] for His-to-Tyr substitutions; chi2=17.4, P=.000031, odds ratio = 3.61 [95% CI 1.91--6.83] for Pro-to-Ser substitutions), and SELL1 could affect promoter activity of the L-selectin gene (chi2=19.5, P=.000010, odds ratio = 3.77 [95% CI 2.02--7.05]). The TGT haplotype at these three loci was associated significantly with IgAN (chi2=18.67, P=.000016, odds ratio = 1.88 [95% CI 1.41--2.51]). Our results suggest that these eight SNPs in selectin genes may be useful for screening populations susceptible to the IgAN phenotype that involves interstitial infiltration.

Case-Control Studies↗
PubMed2002

Family-based analysis using a dense single-nucleotide polymorphism-based map defines genetic variation at PSORS1, the major psoriasis-susceptibility locus.

Psoriasis is a common skin disorder of multifactorial origin. Genomewide scans for disease susceptibility have repeatedly demonstrated the existence of a major locus, PSORS1 (psoriasis susceptibility 1), contained within the major histocompatibility complex (MHC), on chromosome 6p21. Subsequent refinement studies have highlighted linkage disequilibrium (LD) with psoriasis, along a 150-kb segment that includes at least three candidate genes (encoding human leukocyte antigen-C [HLA-C], alpha-helix-coiled-coil-rod homologue, and corneodesmosin), each of which has been shown to harbor disease-associated alleles. However, the boundaries of the minimal PSORS1 region remain poorly defined. Moreover, interpretations of allelic association with psoriasis are compounded by limited insight of LD conservation within MHC class I interval. To address these issues, we have pursued a high-resolution genetic characterization of the PSORS1 locus. We resequenced genomic segments along a 220-kb region at chromosome 6p21 and identified a total of 119 high-frequency SNPs. Using 59 SNPs (18 coding and 41 noncoding SNPs) whose position was representative of the overall marker distribution, we genotyped a data set of 171 independently ascertained parent-affected offspring trios. Family-based association analysis of this cohort highlighted two SNPs (n.7 and n.9) respectively lying 7 and 4 kb proximal to HLA-C. These markers generated highly significant evidence of disease association (P<10-9), several orders of magnitude greater than the observed significance displayed by any other SNP that has previously been associated with disease susceptibility. This observation was replicated in a Gujarati Indian case/control data set. Haplotype-based analysis detected overtransmission of a cluster of chromosomes, which probably originated by ancestral mutation of a common disease-bearing haplotype. The only markers exclusive to the overtransmitted chromosomes are SNPs n.7 and n.9, which define a 10-kb PSORS1 core risk haplotype. These data demonstrate the power of SNP haplotype-based association analyses and provide high-resolution dissection of genetic variation across the PSORS1 interval, the major susceptibility locus for psoriasis.

Case-Control Studies↗