Pathogenic mitochondrial DNA mutations are common in the general population.

Mitochondrial DNA (mtDNA) mutations are a major cause of genetic disease, but their prevalence in the general population is not known. We determined the frequency of ten mitochondrial point mutations in 3168 neonatal-cord-blood samples from sequential live births, analyzing matched maternal-blood samples to estimate the de novo mutation rate. mtDNA mutations were detected in 15 offspring (0.54%, 95% CI = 0.30-0.89%). Of these live births, 0.00107% (95% CI = 0.00087-0.0127) harbored a mutation not detected in the mother's blood, providing an estimate of the de novo mutation rate. The most common mutation was m.3243A-->G. m.14484T-->C was only found on sub-branches of mtDNA haplogroup J. In conclusion, at least one in 200 healthy humans harbors a pathogenic mtDNA mutation that potentially causes disease in the offspring of female carriers. The exclusive detection of m.14484T-->C on haplogroup J implicates the background mtDNA haplotype in mutagenesis. These findings emphasize the importance of developing new approaches to prevent transmission.

Analysis of the Fc receptor-like-3 (FCRL3) locus in Caucasians with autoimmune disorders suggests a complex pattern of disease association.

CONTEXT: A four-marker haplotype in the 5' region of the Fc receptor-like 3 gene (markers FCRL3_3 to FCRL3_6) has been identified recently as contributing to rheumatoid arthritis (RA) susceptibility in the Japanese population. The promoter FCRL3_3*C allele also showed significant association with autoimmune thyroid disease and systemic lupus erythematosus. These findings raise the possibility that this locus may influence autoimmune disease susceptibility across many populations. PATIENTS AND DESIGN: We analyzed the same four 5' FCRL3 single nucleotide polymorphism markers, together with three additional exonic single nucleotide polymorphisms in the FCRL3 gene, in cohorts of white Caucasians with Graves' disease (n = 625), type 1 diabetes (n = 279), autoimmune Addison's disease (AAD; n = 200), and RA (n = 769). Healthy controls from the United Kingdom (n = 490) and New Zealand (n = 593) were used. RESULTS: Six of the seven FCRL3 markers showed association with AAD (P = 0.005-0.0001), with maximum evidence at the FCRL3_3*T allele [P([corrected]) = 0.0008; odds ratio (OR), 1.61; 5-95% confidence intervals (CIs), 1.26-2.05]. The most common seven-marker FCRL3 haplotype (TGGGAAA) was also found to be significantly associated with AAD (P([corrected]) = 1.1 x 10(-4); OR, 1.71; 5-95% CIs, 1.33-2.18). There was nominal evidence for allelic association at the marker FCRL3_8 in Graves' disease (OR, 1.50; 5-95% CIs, 1.06-2.13) and at FCRL3_9 with RA (OR, 1.25; 5-95% CIs, 1.01-1.54). CONCLUSIONS: The FCRL3 haplotype that is associated with AAD in Caucasians appears to be protective for autoimmune diseases in the Japanese population, demonstrating that this haplotype is unlikely to contain a single primary etiological allele for autoimmunity. Our observations suggest that the susceptibility to autoimmunity at the FCRL3 locus is more complex than initially thought and may extend either side of the currently associated region to include the adjacent FCRL2 gene.

Genetic association studies of the FOXP3 gene in Graves' disease and autoimmune Addison's disease in the United Kingdom population.

Regulatory T lymphocytes play a crucial role in modulating potentially self-reactive clones, and dysfunction of this cell type contributes to autoimmune disease. FOXP3 is a critical determinant of CD(4+)CD(25+)T regulatory (T(reg)) cell development and function. The aim of this study was to investigate whether genetic polymorphisms at the FOXP3 locus predispose to autoimmune endocrinopathies. Five single nucleotide polymorphisms (SNPs) and two microsatellite polymorphisms were genotyped in our Caucasian cohorts of 633 unrelated Graves' disease (GD) subjects, 104 autoimmune Addison's disease (AAD) subjects and 528 healthy controls. SNP genotyping was performed by either restriction enzyme digestion or by primer-extension-MALDI-TOF (matrix-assisted laser desorption/ionisation time-of-flight) assay. Microsatellites were analysed using fluorescent PCR. Case-control analysis was performed using chi(2) testing on contingency tables for allele frequency. Haplotype analysis was performed using the UNPHASED package. No evidence for disease association was found with any of the seven polymorphisms in either of the GD or AAD subjects as compared with controls (P = 0.26-0.94). Haplotype analysis found a weak evidence for the association of a minor haplotype with GD; this was not significant when corrected for multiple testing. This study has found no robust evidence that FOXP3 gene polymorphism contributes to the susceptibility to GD or AAD in the UK population.