Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods - recursive partitioning and regression - to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; Pcombined = 2.01 × 10-19 and 2.35 × 10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. ©2007 Nature Publishing Group

Results of association between selected SNP and syndromes of severe malaria.

<p>SM = severe malaria, SMA = severe malarial anaemia, CM = cerebral malaria, RD = respiratory distress, Acid = acidosis, MinA = minor allele, MajA = major allele, ConMAF = minor allele frequency in controls, CaseMAF = minor allele frequency in cases, OR = odds ratio, 95% Confidence interval (LCL, UCL), P = P-value; for X chromosome SNPs (rs1126535 (CD40), rs1050829 (G6PD-376), rs1050828 (G6PD-202/A-), analyses are presented for separately for females (F) and males (M), NA not applicable, *.</p

Interaction between alpha-thalassaema and HbS and severe malaria.

*<p>No significant evidence of a statistical interaction P>0.4, OR = odds ratio, 95% Confidence interval (LCL, UCL), P = P-value, SM = severe malaria, SMA = severe malarial anaemia,</p>**<p>adjusted for age, gender and ethnicity.</p

Severe malaria phenotypes; minimum p-values from tests of association for the autosomal SNPs.

<p>genotypic tests of dominant, recessive, general, heterozygous advantage, and additive models, adjusted for ethnicity; the dashed line represents a p-value of 0.002.</p

Severe malaria, Minimum p-values from tests of association for the autosomal SNPs.

<p>genotypic tests of dominant, recessive, general, heterozygous advantage, and additive models, adjusted for HbS and ethnicity; in this analysis controls include uncomplicated malaria cases; the dashed line represents a p-value of 0.002.</p

Baseline and clinical characteristics of cases and controls.

*<p>in months, SMA = severe malarial anaemia, CM = cerebral malaria, RD = respiratory distress,</p>**<p>hb<5 gdl,</p>***<p>Blood lactate>5 mmol/l.</p

Candidate human genetic polymorphisms and severe malaria in a Tanzanian population.

Human genetic background strongly influences susceptibility to malaria infection and progression to severe disease and death. Classical genetic studies identified haemoglobinopathies and erythrocyte-associated polymorphisms, as protective against severe disease. High throughput genotyping by mass spectrometry allows multiple single nucleotide polymorphisms (SNPs) to be examined simultaneously. We compared the prevalence of 65 human SNP's, previously associated with altered risk of malaria, between Tanzanian children with and without severe malaria. Five hundred children, aged 1-10 years, with severe malaria were recruited from those admitted to hospital in Muheza, Tanzania and compared with matched controls. Genotyping was performed by Sequenom MassArray, and conventional PCR was used to detect deletions in the alpha-thalassaemia gene. SNPs in two X-linked genes were associated with altered risk of severe malaria in females but not in males: heterozygosity for one or other of two SNPs in the G6PD gene was associated with protection from all forms of severe disease whilst two SNPs in the gene encoding CD40L were associated with respiratory distress. A SNP in the adenyl cyclase 9 (ADCY9) gene was associated with protection from acidosis whilst a polymorphism in the IL-1α gene (IL1A) was associated with an increased risk of acidosis. SNPs in the genes encoding IL-13 and reticulon-3 (RTN3) were associated with increased risk of cerebral malaria. This study confirms previously known genetic associations with protection from severe malaria (HbS, G6PD). It identifies two X-linked genes associated with altered risk of severe malaria in females, identifies mutations in ADCY9, IL1A and CD40L as being associated with altered risk of severe respiratory distress and acidosis, both of which are characterised by high serum lactate levels, and also identifies novel genetic associations with severe malaria (TRIM5) and cerebral malaria(IL-13 and RTN3). Further studies are required to test the generality of these associations and to understand their functional consequences

Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases