Complement. Second of two parts.

Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with complex etiology but strong clustering in families (lambda(S) = approximately 30). We performed a genome-wide association scan using 317,501 SNPs in 720 women of European ancestry with SLE and in 2,337 controls, and we genotyped consistently associated SNPs in two additional independent sample sets totaling 1,846 affected women and 1,825 controls. Aside from the expected strong association between SLE and the HLA region on chromosome 6p21 and the previously confirmed non-HLA locus IRF5 on chromosome 7q32, we found evidence of association with replication (1.1 x 10(-7) or =9 other loci (P < 2 x 10(-7)). Our results show that numerous genes, some with known immune-related functions, predispose to SLE.

/pdf/genome-wide-association-scan-in-women-with-systemic-lupus-iyym71kkxh.pdf

Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci.

Mercury is a toxic and hazardous metal that occurs naturally in the earth's crust. Natural phenomena such as erosion and volcanic eruptions, and anthropogenic activities like metal smelting and industrial production and use may lead to substantial contamination of the environment with mercury. Through consumption of mercury in food, the populations of many areas, particularly in the developing world, have been confronted with catastrophic outbreaks of mercury-induced diseases and mortality. Countries such as Japan, Iraq, Ghana, the Seychelles, and the Faroe Islands have faced such epidemics, which have unraveled the insidious and debilitating nature of mercury poisoning. Its creeping neurotoxicity is highly devastating, particularly in the central and peripheral nervous systems of children. Central nervous system defects and erethism as well as arrythmias, cardiomyopathies, and kidney damage have been associated with mercury exposure. Necrotizing bronchitis and pneumonitis arising from inhalation of mercury vapor can result in respiratory failure. Mercury is also considered a potent immunostimulant and -suppressant, depending on exposure dose and individual susceptibility, producing a number of pathologic sequelae including lymphoproliferation, hypergammaglobulinemia, and total systemic hyper- and hyporeactivities. In this review we discuss the sources of mercury and the potential for human exposure; its biogeochemical cycling in the environment; its systemic, immunotoxic, genotoxic/carcinogenic, and teratogenic health effects; and the dietary influences on its toxicity; as well as the important considerations in risk assessment and management of mercury poisoning.

Review: Environmental exposure to mercury and its toxicopathologic implications for public health

Genetic-environmental interactions probably underlie spontaneous human autoimmune disorders, a category of complex traits thought to include multiple sclerosis (MS). The geographical distribution and familial aggregation of this disease have often been ascribed to the role of infectious agents, but there is no consensus. Increased family risks range from 300-fold for monozygotic twins to 20-40-fold for biological first-degree relatives over the general population prevalence of 0.1% (ref. 6). We screened a population-based sample of 15,000 individuals with MS by using standardized, personally administered questionnaires to identify adopted index cases and/or those who had adopted relatives. The frequency of MS among first-degree non-biological relatives living with the index case was no greater than expected from Canadian population prevalence data and significantly less than for biological relatives. These findings indicate that familial aggregation of MS is genetically determined: no effect of shared environment was detectable.

A genetic basis for familial aggregation in multiple sclerosis

Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE.

/pdf/genetic-association-analyses-implicate-aberrant-regulation-2dqp9ocwkl.pdf

Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus

Objective. Based on a small clinical series and previously published case reports, concordance for systemic lupus erythematosus (SLE) among monozygous (MZ) twins has been reported to be as high as 69%. Using a larger and less biased sample, we provide another estimate of this percentage.



Methods. We established a registry of twins with SLE, based upon self-reports and information provided by the patients' physicians. We used DNA fingerprinting to validate the reported zygosity in a sample of these twins.



Results. Of 107 twin pairs meeting the American College of Rheumatology 1982 revised criteria for the diagnosis of SLE, 24% of 45 MZ pairs and 2% of 62 dizygous (DZ) pairs were concordant. The frequency distributions of diagnostic criteria and disease symptoms in the SLE patients were similar to those in other published reports of SLE patients. Zygosity was confirmed by DNA fingerprinting in a subsample of 15 self-described MZ twins and 7 self-described DZ twins. AH individuals had correctly predicted their zygosity.



Conclusion. MZ concordance for SLE is similar to that for other autoimmune diseases and is much lower than previously believed.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.1780350310

Lisa Weinrib

Papers

A revised estimate of twin concordance in systemic lupus erythematosus