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Introduction. Understanding the genetic architecture of scleroderma (SSc) susceptibility is vital both in gene discovery and in determining the influence of previously identified susceptibility variants. It is particularly important in understanding disease mechanism in a disease with few therapies and great morbidity and mortality. Methods. We selected 557 cases from the Australian Scleroderma Cohort Study (ASCS), for genotyping with the Immunochip, a custom Illumina Infinium genotyping array containing 196 524 rare and common variants shown to be important in a wide variety of autoimmune disorders. A total of 4537 controls were taken from the 1958 British Birth cohort. Genotype data were analysed with PLINK. Samples and SNPs with low call rates were excluded, as were SNPs in Hardy- Weinberg disequilibrium or with less than two occurrences of the minor allele. Eigenstrat was used to analyse population structure. The final data set consisted of 505 cases, 4491 controls and 146 867 SNPs. Allelic association analyses were conducted using Fisher's exact test. Genotype clusters were manually examined for all associations of P<10-5 since calling is difficult for some rare variants. Results. Significant and suggestive associations were detected at seven loci. Several of these have been previously implicated in scleroderma susceptibility (HLA-DRB1 and STAT4) and several are novel associations, including SNPs near PXK (P=4.4x10-6) and CFDP1(P=2.6x10-6). The strongest associations were with SNPs in the Class II region of the MHC. One of the most strongly associated SNPs [rs4639334; P=1.6x10-8; odds ratio (OR)=1.8] is in linkage disequilibrium (r2=0.46) with the Class II allele HLA-DRB1 11:01. This allele has been associated with SSc. Another strongly associated SNP is rs2857130 (P=1.6x10-8; OR=0.67), which lies in the promoter region of HLA-DRB1, but is not in LD with any classical MHC alleles. Outside the MHC, there were six regions of association with P<10-5,including the

Introduction. Understanding the genetic architecture of scleroderma (SSc) susceptibility is vital both in gene discovery and in determining the influence of previously identified susceptibility variants. It is particularly important in understanding disease mechanism in a disease with few therapies and great morbidity and mortality. Methods. We selected 557 cases from the Australian Scleroderma Cohort Study (ASCS), for genotyping with the Immunochip, a custom Illumina Infinium genotyping array containing 196 524 rare and common variants shown to be important in a wide variety of autoimmune disorders. A total of 4537 controls were taken from the 1958 British Birth cohort. Genotype data were analysed with PLINK. Samples and SNPs with low call rates were excluded, as were SNPs in Hardy- Weinberg disequilibrium or with less than two occurrences of the minor allele. Eigenstrat was used to analyse population structure. The final data set consisted of 505 cases, 4491 controls and 146 867 SNPs. Allelic association analyses were conducted using Fisher's exact test. Genotype clusters were manually examined for all associations of P<10-5 since calling is difficult for some rare variants. Results. Significant and suggestive associations were detected at seven loci. Several of these have been previously implicated in scleroderma susceptibility (HLA-DRB1 and STAT4) and several are novel associations, including SNPs near PXK (P=4.4x10-6) and CFDP1(P=2.6x10-6). The strongest associations were with SNPs in the Class II region of the MHC. One of the most strongly associated SNPs [rs4639334; P=1.6x10-8; odds ratio (OR)=1.8] is in linkage disequilibrium (r2=0.46) with the Class II allele HLA-DRB1 11:01. This allele has been associated with SSc. Another strongly associated SNP is rs2857130 (P=1.6x10-8; OR=0.67), which lies in the promoter region of HLA-DRB1, but is not in LD with any classical MHC alleles. Outside the MHC, there were six regions of association with P<10-5,including the

Sir The association between HLA‐B27 (B27) and ankylosing spondylitis (AS) has been known for 25 yr. Familial aggregation in AS is well established, and first‐degree relatives of AS patients have been shown to be at increased risk of developing the disease. The recurrence risk in siblings of AS patients is quite uncertain, previous studies have variously reported recurrence risks between 6.9 and 27% [1, 2]. Accurate knowledge of the sibling recurrence risk is important both to advise families of the likelihood of disease recurrence, and in genetic statistical analyses utilizing Risch's recurrence risk ratio [3]. This study was designed to determine the risk of developing AS in siblings and to determine the role of the major histocompatibility complex in familial recurrence of AS....