Adrian Scott

Sporadic inclusion body myositis: HLA-DRB1 allele interactions influence disease risk and clinical phenotype

Susceptibility to sIBM is strongly associated with the HLA-DRB1*03 allele and the 8.1 MHC ancestral haplotype (HLA-A1, B8, DRB1*03) but little is known about the effects of allelic interactions at the DRB1 locus or disease-modifying effects of HLA alleles. HLA-A, B and DRB1 genotyping was performed in 80 Australian sIBM cases and the frequencies of different alleles and allele combinations were compared with those in a group of 190 healthy controls. Genotype-phenotype correlations were also investigated. Amongst carriers of the HLA-DRB1*03 allele, DRB1*03/*01 heterozygotes were over-represented in the sIBM group (p<0.003) while. DRB1*03/*04 heterozygotes were under-represented (p<0.008). The mean age-at-onset (AAO) was 6.5 years earlier in DRB1*03/*01 heterozygotes who also had more severe quadriceps muscle weakness than the rest of the cohort. The findings indicate that interactions between the HLA-DRB1*03 allele and other alleles at the DRB1 locus can influence disease susceptibility and the clinical phenotype in sIBM.

High-resolution HLA-DRB1 genotyping in an Australian inclusion body myositis (s-IBM) cohort: An analysis of disease-associated alleles and diplotypes

We performed high-resolution (4-digit) HLA-DRB1 genotyping in an Australian cohort of 105s-IBM patients and 189 controls. Our findings showed that whilst the strongest association was with the HLA-DRB1*03:01 allele and the HLA-DRB1*03:01/*01:01 diplotype, HLA-DRB1*01:01 and HLA-DRB1*13:01 are also risk alleles. A number of other alleles, HLA-DRB1*04:01, *04:04, *07:01, *09:01, *11:01 and *15:01, as well as the HLA-DRB1*03:01/*04:01 and HLA-DRB1*03:01/*07:01 diplotypes were reduced in s-IBM cases and may be protective. The HLA-DRB1*03:01 and HLA-DRB1*13:01 alleles also appear to have an influence on the age at onset of the disease and severity of muscle weakness. Our findings indicate that the influence of HLA-DRB1 in s-IBM is complex and that epistatic interactions at the HLA-DRB1 locus contribute both to disease susceptibility and to the clinical phenotype.

Apoptotic Engulfment Pathway and Schizophrenia

Background Apoptosis has been speculated to be involved in schizophrenia. In a previously study, we reported the association of the MEGF10 gene with the disease. In this study, we followed the apoptotic engulfment pathway involving the MEGF10, GULP1, ABCA1 and ABCA7 genes and tested their association with the disease. Methodology/Principal Findings Ten, eleven and five SNPs were genotyped in the GULP1, ABCA1 and ABCA7 genes respectively for the ISHDSF and ICCSS samples. In all 3 genes, we observed nominally significant associations. Rs2004888 at GULP1 was significant in both ISHDSF and ICCSS samples (p = 0.0083 and 0.0437 respectively). We sought replication in independent samples for this marker and found highly significant association (p = 0.0003) in 3 Caucasian replication samples. But it was not significant in the 2 Chinese replication samples. In addition, we found a significant 2-marker (rs2242436 * rs3858075) interaction between the ABCA1 and ABCA7 genes in the ISHDSF sample (p = 0.0022) and a 3-marker interaction (rs246896 * rs4522565 * rs3858075) amongst the MEGF10, GULP1 and ABCA1 genes in the ICCSS sample (p = 0.0120). Rs3858075 in the ABCA1 gene was involved in both 2- and 3-marker interactions in the two samples. Conclusions/Significance From these data, we concluded that the GULP1 gene and the apoptotic engulfment pathway are involved in schizophrenia in subjects of European ancestry and multiple genes in the pathway may interactively increase the risks to the disease.

Sporadic inclusion body myositis in Japanese is associated with the MHC ancestral haplotype 52.1

In Caucasians, sporadic inclusion body myositis has been associated with the MHC ancestral haplotypes; HLA-A1, B8, DR3 (8.1AH) and HLA-B35, DR1 (35.2AH). It is not known whether these haplotypes carry susceptibility for the disease in other ethnic groups. We report here the results of HLA-B and -DRB1 typing using a high-resolution sequence-based technique in a cohort of 31 Japanese patients with definite sIBM. Patient allele frequencies were 40.3% for HLA-B*5201 (10.7% in controls: p<0.001) and 37.1% for HLA-DRB1*1502 (10% in controls: p<0.001). Both alleles were found together as part of a conserved haplotype (52.1AH) at a frequency of 37.1% in patients (8.4% in controls: p<0.001). This is the first description of a haplotypic MHC association with sporadic inclusion body myositis in Japanese patients. These findings indicate that different MHC ancestral haplotypes are associated with sIBM in different ethnic groups and further emphasize the importance of genetic factors in this condition.

Recombination mapping of the susceptibility region for sporadic inclusion body myositis within the major histocompatibility complex

Susceptibility to sporadic inclusion body myositis (sIBM) in Caucasians has been consistently associated with alleles of the major histocompatibility complex (MHC) 8.1 ancestral haplotype (AH) (defined by HLA-B*0801 and HLA-DRB1*0301). In this study recombination mapping was utilised to further refine the known 8.1AH susceptibility region near HLA-DRB1*0301. Caucasian sIBM patients carrying part of the 8.1AH were genotyped for a selection of 8.1AH-haplotypic polymorphisms. A common 8.1AH-specific susceptibility region was defined, spanning 172 kb and encompassing three genes--HLA-DRB3, HLA-DRA and BTNL2. It is thus likely that 8.1AH-derived susceptibility to sIBM originates from at least one of these genes.

Does a central MHC gene in linkage disequilibrium with HLA-DRB1 * 0401 affect susceptibility to type 1 diabetes?

Subtypes of HLA-DR4 are associated with susceptibility or protection against type 1 diabetes (T1DM). We addressed whether this reflects linkage disequilibrium with the true susceptibility locus by studying broader MHC haplotypes marked by alleles of HLA-B, IKBL (adjacent to TNFA) and complement C4. The study used a largely Caucasian cohort from Western Australia. HLA-DRB1*0401 and HLA-DRB1*0405 marked susceptibility to T1DM. In Caucasians, DRB1*0401 occurs predominantly in the 44.1 ancestral haplotype (AH; HLA-A2,B44, DRB1*0401,DQB1*0301) and the 62.1AH (HLA-A2,B15(62),DRB1*0401,DQB1*0302). HLA-B15 marked susceptibility and HLA-B44 marked with resistance to T1DM in patients and controls preselected for HLA-DRB1*0401. A gene between TNFA and HLA-B on the 8.1AH (HLA-A1,B8,;DR3,DQ2) modifies the effects of the class II alleles. Here, alleles characteristic of the 62.1AH (C4B3, IKBL+446*T and HLA-A2,B15) were screened in donors preselected for HLA-DRB1*0401. C4B3 was associated with diabetes, consistent with a diabetes gene telomeric of MHC class II. However, increases in carriage of IKBL+446*T and HLA-A2,B15 were marginal, as too few control subjects were available with the diabetogenic alleles. However, with these tools, selection of HLA-DRB1*0401, DQB1*0302 donors who are positive and negative for C4B3 will allow bidirectional mapping of diabetes genes in the central MHC.191 words

Investigation of NOTCH4 coding region polymorphisms in sporadic inclusion body myositis.

The NOTCH4 gene, located within the MHC region, is involved in cellular differentiation and has varying effects dependent on tissue type. Coding region polymorphisms haplotypic of the sIBM-associated 8.1 ancestral haplotype were identified in NOTCH4 and genotyped in two different Caucasian sIBM cohorts. In both cohorts the frequency of the minor allele of rs422951 and the 12-repeat variation for rs72555375 was increased and was higher than the frequency of the sIBM-associated allele HLA-DRB1*0301. These NOTCH4 polymorphisms can be considered to be markers for sIBM susceptibility, but require further investigation to determine whether they are directly involved in the disease pathogenesis.

G.P.13.17 Recombinant mapping of MHC susceptibility region in sporadic inclusion body myositis (sIBM)

Susceptibility to sIBM is associated with alleles of the major histocompatibility complex (MHC) on chromosome 6. Several studies have shown an association between sIBM and the highly conserved 8.1 ancestral haplotype (AH). However the strong linkage disequilibrium that exists within the MHC has so far prevented definitive identification of the genes responsible within a 270 kb region between AGER and HLA-DRA. This region contains nine candidate genes at least one of which must play a role in sIBM susceptibility. This study sought to refine the susceptibility region by mapping 8.1AH-specific alleles in patients possessing a complete or partial 8.1AH with the intention of isolating single or multiple alleles directly associated with sIBM. By locating a susceptibility allele(s), we hope that this will assist in elucidating the pathogenesis of sIBM and contribute to efforts in developing an effective treatment for the disease. Individuals carrying markers of the 8.1AH between HLA-DR and AGER selected from a cohort of 120 Caucasian sIBM patients were typed for alleles of multiple polymorphisms and microsatellites to define the haplotype recombination points and thus the disease susceptibility region, as defined by what part of the 8.1AH they possess. Each individual’s susceptibility region was then compared to determine overlapping tracts of DNA. Recombinant mapping showed evidence of two non-overlapping regions of the 8.1AH, from AGER to LOC401252 and from C6orf10 to HLA-DRA, shared by multiple patients. The data were also used to more accurately differentiate patients with the 8.1AH from those without. These findings indicate that there is unlikely to be a single susceptibility allele for sIBM in individuals carrying the 8.1AH, but that multiple alleles between AGER and HLA-DR may independently contribute to disease susceptibility.

G.P.63 High-resolution analysis of HLA-DRB1 alleles and diplotypes in an Australian inclusion body myositis cohort

In Caucasians, susceptibility to sporadic inclusion body myositis (s-IBM) is associated with the HLA-DR3 serotype and the HLA-DRB1∗0301 allele which encodes it, and with the extended 8.1 MHC ancestral haplotype. Most previous HLA studies in s-IBM have used serological typing or low-resolution (2-digit) genotyping to identify disease-associated alleles, and the contribution of alleles other than HLA-DRB1∗0301 and of the complementary in trans allele at the HLA-DRB1 locus has received little attention. In the present study we performed high-resolution (4-digit) HLA-DRB1 genotyping in an Australian cohort of 105 s-IBM patients and 189 controls from the Busselton Population Study and analysed risk-associated alleles and effects on age-at-onset (AAO) of the disease. Case–control logistic regression analysis showed that, apart from the strongly associated HLA-DRB1∗0301 allele (OR 13.6), HLA-DRB1∗0101 (OR 3.65) and HLA-DRB1∗1301 (OR 3.31) are independent risk alleles. A number of other alleles, HLA-DRB1∗0401, ∗0404, ∗0701, ∗0901, ∗1101 and ∗1501 were reduced in frequency in s-IBM cases and may be protective. We evaluated the influence of allele combinations on disease risk and found that the strongest estimated risk is with the HLA-DRB1∗0301/∗0101 diplotype, while other allele combinations have diminishing risk effects. HLA-DRB1∗0301 was associated with an AAO 4.3 years earlier than other alleles and DRB1∗1301 with an AAO 4.5 years later, despite it being a risk factor. The findings indicate that the influence of HLA-DRB1 in s-IBM is complex, influencing both disease risk and AAO, and that allelic interactions at the HLA-DRB1 locus contribute to disease susceptibility.

Molecular Biology of Addiction and Substance Dependence

Addictions are chronic, devastating psychiatric disorders that are characterized by a compulsive pattern of drug taking or behavior. The development of addictions relies on life style choices but also on genetic, heritable factors that put some individuals at an increased risk for these disorders. Genetic factors for addictive disorders were established by multiple epidemiological studies, showing heritability between 40 and 60%. In an effort to dissect addictive disorders, genetic research was focused on the direct interaction of a variety of drugs with the respective biological systems. Another focus was the identification of long-lasting changes in the brain reward mechanism, using animal models, and more recently brain imaging studies in humans.