Genetic determinants of 21-hydroxylase autoantibodies amongst patients of the Type 1 Diabetes Genetics Consortium.

BACKGROUND: Autoantibodies to 21-hydroxylase (21OH-AA) precede the onset of autoimmune Addison's disease (AD) and are found in 1.5% of individuals with type 1 diabetes mellitus (T1DM). The greatest genetic risk for both disorders is found in the major histocompatibility complex (MHC), suggesting a common pathophysiology between AD and T1DM. Screening for 21OH-AA in newly diagnosed T1DM patients is a valuable prognostic tool, made stronger when MHC genotype is considered. METHODS: The Type 1 Diabetes Genetics Consortium has collected genotype data in T1DM subjects with tissue-specific autoantibody typing. Genotype and phenotype data in individuals positive and negative for 21OH-AA are compared. RESULTS: Major genetic risk for 21OH-AA is in the MHC haplotypes DRB1*04-DQB1*0302 (primarily DRB1*0404) and DRB1*0301-DQB1*0201. Protective effects in class II MHC haplotypes DRB1*0101-DQB1*0501 and DRB1*0701-DQB1*0202 also were detected. There is no difference in the presence of HLA-B15 and little difference in the presence of HLA-B8 (after class II effects are accounted for) in T1DM patients with 21OH-AA compared with known associations (HLA-B8 positive and HLA-B15 negative) in AD. CONCLUSIONS: In 21OH-AA(+) subjects, genetic risk is found mainly in MHC class II haplotypes DR3 and DR4 but not class I alleles (HLA-B8 or HLA-B15). This suggests a difference between autoantibody formation (class II dependent) and progression to overt disease (class I dependent) in AD.

Dominant suppression of Addison's disease associated with HLA-B15.

CONTEXT: Autoimmune Addison's disease (AD) is the major cause of primary adrenal failure in developed nations. Autoantibodies to 21-hydroxylase (21OH-AA) are associated with increased risk of progression to AD. Highest genetic risk is associated with the Major Histocompatibility region (MHC), specifically human leukocyte antigen (HLA)-DR3 haplotypes (containing HLA-B8) and HLA-DR4. OBJECTIVE: The objective of the study was the further characterization of AD risk associated with MHC alleles. DESIGN, SETTING, AND PARTICIPANTS: MHC genotypes were determined for HLA-DRB1, DQA1, DQB1, MICA, HLA-B, and HLA-A in 168 total individuals with 21OH-AA (85 with AD at referral and 83 with positive 21OH-AA but without AD at referral). MAIN OUTCOME MEASURE(S): Genotype was evaluated in 21OH-AA-positive individuals. Outcomes were compared with general population controls and type 1 diabetes patients. RESULTS: In HLA-DR4+ individuals, HLA-B15 was found in only one of 55 (2%) with AD vs. 24 of 63 (40%) 21OH-AA-positive nonprogressors (P = 2 × 10(-7)) and 518 of 1558 (33%) HLA-DR4 patients with type 1 diabetes (P = 1 × 10(-8)). On prospective follow-up, none of the HLA-B15-positive, 21-hydroxylase-positive individuals progressed to AD vs. 25% non-HLA-B15 autoantibody-positive individuals by life table analysis (P = 0.03). Single nucleotide polymorphism analysis revealed the HLA-DR/DQ region associated with risk and HLA-B15 were separated by multiple intervening single-nucleotide polymorphism haplotypes. CONCLUSIONS: HLA-B15 is not associated with protection from 21OH-AA formation but is associated with protection from progression to AD in 21OH-AA-positive individuals. To our knowledge, this is one of the most dramatic examples of genetic disease suppression in individuals who already have developed autoantibodies and of novel dominant suppression of an autoimmune disease by a class I HLA allele.

Haplotype analysis discriminates genetic risk for DR3-associated endocrine autoimmunity and helps define extreme risk for Addison's disease.

CONTEXT: Multiple autoimmune disorders (e.g. Addison's disease, type 1 diabetes, celiac disease) are associated with HLA-DR3, but it is likely that alleles of additional genes in linkage disequilibrium with HLA-DRB1 contribute to disease. OBJECTIVE: The objective of the study was to characterize major histocompatability complex (MHC) haplotypes conferring extreme risk for autoimmune Addison's disease (AD). DESIGN, SETTING, AND PARTICIPANTS: Eighty-six 21-hydroxylase autoantibody-positive, nonautoimmune polyendocrine syndrome type 1, Caucasian individuals collected from 1992 to 2009 with clinical AD from 68 families (12 multiplex and 56 simplex) were genotyped for HLA-DRB1, HLA-DQB1, MICA, HLA-B, and HLA-A as well as high density MHC single-nucleotide polymorphism (SNP) analysis for 34. MAIN OUTCOME MEASURES: AD and genotype were measured. RESULT: Ninety-seven percent of the multiplex individuals had both HLA-DR3 and HLA-B8 vs. 60% of simplex AD patients (P = 9.72 × 10(-4)) and 13% of general population controls (P = 3.00 × 10(-19)). The genotype DR3/DR4 with B8 was present in 85% of AD multiplex patients, 24% of simplex patients, and 1.5% of control individuals (P = 4.92 × 10(-191)). The DR3-B8 haplotype of AD patients had HLA-A1 less often (47%) than controls (81%, P = 7.00 × 10(-5)) and type 1 diabetes patients (73%, P = 1.93 × 10(-3)). Analysis of 1228 SNPs across the MHC for individuals with AD revealed a shorter conserved haplotype (3.8) with the loss of the extended conserved 3.8.1 haplotype approximately halfway between HLA-B and HLA-A. CONCLUSION: Extreme risk for AD, especially in multiplex families, is associated with haplotypic DR3 variants, in particular a portion (3.8) but not all of the conserved 3.8.1 haplotype.

A susceptibility locus on chromosome 6q greatly increases lung cancer risk among light and never smokers.

Cigarette smoking is the major cause for lung cancer, but genetic factors also affect susceptibility. We studied families that included multiple relatives affected by lung cancer. Results from linkage analysis showed strong evidence that a region of chromosome 6q affects lung cancer risk. To characterize the effects that this region of chromosome 6q region has on lung cancer risk, we identified a haplotype that segregated with lung cancer. We then performed Cox regression analysis to estimate the differential effects that smoking behaviors have on lung cancer risk according to whether each individual carried a risk-associated haplotype or could not be classified and was assigned unknown haplotypic status. We divided smoking exposures into never smokers, light smokers (<20 pack-years), moderate smokers (20 to <40 pack-years), and heavy smokers (>or=40 pack-years). Comparing results according to smoking behavior stratified by carrier status, compared with never smokers, there was weakly increasing risk for increasing smoking behaviors, with the hazards ratios being 3.44, 4.91, and 5.18, respectively, for light, moderate, or heavy smokers, whereas among the individuals from families without the risk haplotype, the risks associated with smoking increased strongly with exposure, the hazards ratios being, respectively, 4.25, 9.17, and 11.89 for light, moderate, and heavy smokers. The never smoking carriers had a 4.71-fold higher risk than the never smoking individuals without known risk haplotypes. These results identify a region of chromosome 6q that increases risk for lung cancer and that confers particularly higher risks to never and light smokers.

SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia.

BACKGROUND: We studied a large family affected by an autosomal dominant cardiac conduction disorder associated with sinus node dysfunction, arrhythmia, and right and occasionally left ventricular dilatation and dysfunction. Previous linkage analysis mapped the disease phenotype to a 30-cM region on chromosome 3p22-p25 (CMD1E). This region also contains a locus for right ventricular cardiomyopathy (ARVD5) and the cardiac sodium channel gene (SCN5A), mutations that cause isolated progressive cardiac conduction defect (Lenegre syndrome), long-QT syndrome (LQT3), and Brugada syndrome. METHODS AND RESULTS: Family members were studied, and the positional candidate gene SCN5A was screened for mutations. We identified, by direct sequencing, a heterozygous G-to-A mutation at position 3823 that changed an aspartic acid to asparagine (D1275N) in a highly conserved residue of exon 21. This mutation was present in all affected family members, was absent in 300 control chromosomes, and predicted a change of charge within the S3 segment of domain III. CONCLUSIONS: Our findings expand the clinical spectrum of disorders of the cardiac sodium channel to include cardiac dilation and dysfunction and support the hypothesis that genes encoding ion channels can be implicated in dilated cardiomyopathies.

Genetics of type 1A (immune mediated) diabetes.

Type 1A (immune mediated) diabetes is genetically heterogeneous with important examples for man and animal models with major mutations (autosomal recessive and X-linked recessive) identified as well as oligogenic/polygenic inheritance. For the most common forms of type 1A diabetes alleles of DQ and DR within the major histocompatibility complex are important determinants of disease and allow identification of high risk individuals at birth. Further understanding of both common and rare genetic determinants of type 1A diabetes will contribute to understanding the pathogenesis of diabetes and of autoimmunity.