A second-generation genomic screen for multiple sclerosis

Multiple sclerosis (MS) is a debilitating neuroimmunological and neurodegenerative disorder. Despite substantial evidence for polygenic inheritance of the disease, the major histocompatibility complex is the only region that clearly and consistently demonstrates linkage and association in MS studies. The goal of this study was to identify additional chromosomal regions that harbor susceptibility genes for MS. With a panel of 390 microsatellite markers genotyped in 245 U.S. and French multiplex families (456 affected relative pairs), this is the largest genomic screen for MS conducted to date. Four regions met both of our primary criteria for further interest (heterogeneity LOD [HLOD] and Z scores >2.0): 1q (HLOD=2.17; Z=3.38), 6p (HLOD=4.21; Z=2.26), 9q (HLOD; Z=2.71), and 16p (HLOD=2.64; Z=2.05). Two additional regions met only the Z score criterion: 3q (Z=2.39) and 5q (Z=2.17). Further examination of the data by country (United States vs. France) identified one additional region demonstrating suggestive linkage in the U.S. subset (18p [HLOD=2.39]) and two additional regions generating suggestive linkage in the French subset (1p [HLOD=2.08] and 22q [HLOD=2.06]). Examination of the data by human leukocyte antigen (HLA)-DR2 stratification identified four additional regions demonstrating suggestive linkage: 2q (HLOD=3.09 in the U.S. DR2- families), 6q (HLOD=3.10 in the French DR2- families), 13q (HLOD=2.32 in all DR2+ families and HLOD=2.17 in the U.S. DR2+ families), and 16q (HLOD=2.32 in all DR2+ families and HLOD=2.13 in the U.S. DR2+ families). These data suggest several regions that warrant further investigation in the search for MS susceptibility genes.     

A genome screen for linkage disequilibrium in HLA-DRB1*15-positive Germans with multiple sclerosis based on 4666 microsatellite markers

Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system with putative autoimmune aetiology and complex genetic background. Here, we report the results of a genome screen for linkage disequilibrium (LD) by using 6000 microsatellite markers in 198 HLA-DRB1*15-positive MS patients and 198 unrelated controls (pooled DNA); 4666 analysed markers could be included in the resulting association map, from which 87 revealed significant differences between MS cases and controls.     

A high-density SNP genomewide linkage scan for chronic lymphocytic leukemia-susceptibility loci

Chronic lymphocytic leukemia (CLL) and other B-cell lymphoproliferative disorders (LPDs) show clear evidence of familial aggregation, but the inherited basis is largely unknown. To identify a susceptibility gene for CLL, we conducted a genomewide linkage analysis of 115 pedigrees, using a high-density single-nucleotide polymorphism (SNP) array containing 11,560 markers. Multipoint linkage analyses were undertaken using both nonparametric (model-free) and parametric (model-based) methods. Our results confirm that the presence of high linkage disequilibrium (LD) between SNP markers can lead to inflated nonparametric linkage (NPL) and LOD scores. After the removal of high-LD SNPs, we obtained a maximum NPL of 3.14 (P=.0008) on chromosome 11p11. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) score under both dominant (HLOD 1.95) and recessive (HLOD 2.78) models. In addition, four other chromosomal positions (5q22-23, 6p22, 10q25, and 14q32) displayed HLOD scores >1.15 (which corresponds to a nominal P value <.01). None of the regions coincided with areas of common chromosomal abnormalities frequently observed for CLL. These findings strengthen the argument for an inherited predisposition to CLL and related B-cell LPDs.     

A high-density linkage map of the RN region in pigs

The porcine RN locus affects muscle glycogen content and meat quality. We previously mapped the RN locus to chromosome 15. This study describes the identification of polymorphisms for four class I and four class II markers located in the RN region. Resource families were genotyped with F-SSCP markers (fluorescent single strand conformation polymorphism) and microsatellite markers. Subsequent multipoint linkage analysis revealed the order FN1-IGFBP5-S1000-S1001-IL8RB-VIL1-RN-Sw936-Sw906. The gene order is identical to the previously reported porcine RH map of the same region. The described map will facilitate positional cloning of the RN gene.     

A high-density linkage map of Theobroma cacao L.

The first linkage map established by Lanaud et al. (1995) was used as a starting point to produce a high-density molecular linkage map. A mapping population of 181 progenies resulting from a cross between two heterozygous genotypes, a Forastero and a Trinitario (hybrid between Forastero and Criollo), was used for the linkage analysis. A new DNA isolation protocol was established, which allows enough good quality DNA to construct a genetic map with PCR-based markers. The map comprises 424 markers with an average spacing between markers of 2.1 cM. The marker types used were five isozymes, six loci from known function genes, 65 genomic RFLPs, 104 cDNA RFLPs, three telomeric probes, 30 RAPDs, 191 AFLPs and 20 microsatellites. The use of new marker types, AFLP and microsatellites, did not disturb the original order of the RFLP loci used on the previous map. The genetic markers were distributed over ten linkage groups and cover 885.4 cM. The maximum distance observed between adjacent markers was 16.2 cM, and 9.4% of all loci showed skewed segregation. Received: 2 January 2000 / Accepted: 12 February 2000     

A high-density genome-wide association screen of sporadic ALS in US veterans

Following reports of an increased incidence of amyotrophic lateral sclerosis (ALS) in U.S. veterans, we have conducted a high-density genome-wide association study (GWAS) of ALS outcome and survival time in a sample of U.S. veterans. We tested ∼1.3 million single nucleotide polymorphisms (SNPs) for association with ALS outcome in 442 incident Caucasian veteran cases diagnosed with definite or probable ALS and 348 Caucasian veteran controls. To increase power, we also included genotypes from 5909 publicly-available non-veteran controls in the analysis. In the survival analysis, we tested for association between SNPs and post-diagnosis survival time in 639 Caucasian veteran cases with definite or probable ALS. After this discovery phase, we performed follow-up genotyping of 299 SNPs in an independent replication sample of Caucasian veterans and non-veterans (ALS outcome: 183 cases and 961 controls; survival: 118 cases). Although no SNPs reached genome-wide significance in the discovery phase for either phenotype, three SNPs were statistically significant in the replication analysis of ALS outcome: rs6080539 (177 kb from PCSK2), rs7000234 (4 kb from ZNF704), and rs3113494 (13 kb from LOC100506746). Two SNPs located in genes that were implicated by previous GWA studies of ALS were marginally significant in the pooled analysis of discovery and replication samples: rs17174381 in DPP6 (p = 4.4×10⁻⁴) and rs6985069 near ELP3 (p = 4.8×10⁻⁴). Our results underscore the difficulty of identifying and convincingly replicating genetic associations with a rare and genetically heterogeneous disorder such as ALS, and suggest that common SNPs are unlikely to account for a substantial proportion of patients affected by this devastating disorder.     

A search for susceptibility genes in multiple sclerosis

Multiple sclerosis is a chronic inflammatory, putatively autoimmune disease characterized by multifocal demyelination in the central nervous system. Two main strategies are used to identify genes influencing the susceptibility to multiple sclerosis: (i) elucidation of the role of a candidate gene chosen on the basis of the possible function of the encoded protein in etiology and/or pathogenesis of the disease, and (ii) complete genomic screen using a panel of anonymous genetic markers for identification of the chromosome regions involved in the disease development. The complete genomic search revealed multiple loci for multiple sclerosis on thirteen chromosomes, and analysis of the candidate genes added three more chromosomes to this list. The combined data prove the polygenic nature of this complex disease. Detection of individual genes responsible for susceptibility to multiple sclerosis is complicated by the genetic heterogeneity of analyzed populations and families, which is determined both by the ethnic heterogeneity and the peculiarity of clinical forms of the disease. However, it seems highly probable that HLA and non-HLA genes of the major histocompatibility complex, as well as some unidentified genes on chromosomes 5p and 17q, are involved in the disease development. In addition to HLA, some authors have also shown that a role in the disease development is played by the genes encoding other components of the trimolecular complex involved in antigen presentation: those of the T-cell receptor and the best studied autoantigen, the myelin basic protein. The most promising for further studies of the genetic susceptibility to multiple sclerosis are approaches that combine the candidate-gene strategy with the complete genomic search as well as distinguish the genetically differentiated forms of the disease.     

A parametric scale for BAEP latencies in multiple sclerosis

A parametric scale for measuring BAEP latencies is set forth here for use in multiple sclerosis (MS) therapeutic trials and similar longitudinal studies. Derived constants are used to create a synthetic I–V interpeak interval, needed for cases where V (or other waves) are absent. Transitional peaks (peaks on the verge of disappearing) were studied in MS patients and used to determine appropriate values for the weighting constants. The resulting scale or index makes use of latencies to whichever peaks are still present. In theory such a scale is more sensitive to small changes than either a simple ordinal scale of which peaks remain or a parametric scale of I–V interpeak intervals excluding the 25–40% of MS records with absent wave V. To test this synthetic I–V index in practice, we studied it in 100 MS patients entering a therapeutic trial. It was found to correlate appropriately with patients' history, physical examination, and clinical scales at entry into the trial. Parametric statistical analysis of the derived scale was able to show a statistically significant drug effect during the therapeutic trial, whereas 3 other data analysis techniques showed at best a trend that did not quite reach significance.     

A chromosome study in multiple sclerosis

Summary Chromosome studies of 30 patients with multiple sclerosis and 30 controls have been made. The results show that there is no significant increase in the frequency of structural aberrations in the multiple sclerosis patients. It is suggested that previously reported differences may have been due to technical factors, the nature of which is discussed.

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Zusammenfassung Bei 30 Patienten mit multipler Sklerose und 30 Kontrollen wurden die Chromosomen untersucht. Es fand sich bei den Patienten kein signifikanter Anstieg in der Häufigkeit struktureller Aberrationen. Vielleicht wurden früher mitgeteilte Unterschiede durch technische Faktoren, die im einzelnen diskutiert werden, vorgetäuscht.

     

Beta-interferon for multiple sclerosis

Interferon beta is widely used as first-line treatment for relapsing remitting multiple sclerosis (RRMS). Several products are marketed world-wide, and biosimilar products are emerging. Interferon beta reduces relapse rates by about 1/3, and reduces the appearance of new MRI lesions by about 2/3, and some studies have shown reduced disability progression, and reduced rates of brain atrophy. The mechanism of action of interferon beta in MS is poorly understood, partly due to the complex nature of the biological response to interferon injections. This mini-review succinctly summarizes clinical effects, possible mechanism of action, physiochemical properties of the different interferon products, issues related to immunogenicity, and biomarkers of the interferon beta response, and proposes important unresolved issues for future research.     

Genomewide linkage screen for Waldenstrom macroglobulinemia susceptibility loci in high-risk families

Waldenstrom macroglobulinemia (WM), a distinctive subtype of non-Hodgkin lymphoma that features overproduction of immunoglobulin M (IgM), clearly has a familial component; however, no susceptibility genes have yet been identified. We performed a genomewide linkage analysis in 11 high-risk families with WM that were informative for linkage, for a total of 122 individuals with DNA samples, including 34 patients with WM and 10 patients with IgM monoclonal gammopathy of undetermined significance (IgM MGUS). We genotyped 1,058 microsatellite markers (average spacing 3.5 cM), performed both nonparametric and parametric linkage analysis, and computed both two-point and multipoint linkage statistics. The strongest evidence of linkage was found on chromosomes 1q and 4q when patients with WM and with IgM MGUS were both considered affected; nonparametric linkage scores were 2.5 (P=.0089) and 3.1 (P=.004), respectively. Other locations suggestive of linkage were found on chromosomes 3 and 6. Results of two-locus linkage analysis were consistent with independent effects. The findings from this first linkage analysis of families at high risk for WM represent important progress toward identifying gene(s) that modulate susceptibility to WM and toward understanding its complex etiology.     

A review of possible therapies for multiple sclerosis

Molecular and Cellular Biochemistry - Multiple sclerosis (MS) is an autoimmune chronic inflammatory disease of the central nervous system with a wide range of symptoms, like executive function...     

Evidence of linkage with HLA-DR in DRB1*15-negative families with multiple sclerosis

The importance of the HLA-DR locus to multiple sclerosis (MS) susceptibility was assessed in 542 sib pairs with MS and in their families. By genotyping 1,978 individuals for HLA-DRB1 alleles, we confirmed the well-established association of MS with HLA-DRB1*15 (HLA-DRB1*1501 and HLA-DRB5*0101), by the transmission/disequilibrium test (chi2=138.3; P<.0001). We obtained significant evidence of linkage throughout the whole data set (mlod=4.09; 59.9% sharing). Surprisingly, similar sharing was also observed in 58 families in which both parents lacked the DRB1*15 allele (mlod=1.56; 62.7% sharing; P=.0081). Our findings suggest that the notion that HLA-DRB1*15 is the sole major-histocompatibility-complex determinant of susceptibility in northern-European populations with MS may be incorrect. It remains possible that the association of MS with HLA-DRB1*15 is due to linkage disequilibrium with a nearby locus and/or to the presence of disease-influencing allele(s) in DRB1*15-negative haplotypes.     

A rapid screening tool for fatigue impact in multiple sclerosis

Background  

Fatigue is a common complaint in multiple sclerosis (MS) and often interferes with daily functioning. Both clinicians and researchers may need to detect high levels of fatigue impact using a time and effort efficient tool. This study evaluates the psychometric properties of a rapid screening instrument for fatigue impact in multiple sclerosis.     

HLA and the inheritance of multiple sclerosis: linkage analysis of 72 pedigrees.

Linkage analysis of 72 pedigrees by the maximum-likelihood method provides evidence of linkage between HLA and the hypothesized multiple sclerosis susceptibility gene (MSSG) for both the dominant and recessive models of inheritance and for penetrance values ranging from 5%--65% (or higher). This MSSG, if it exists, is most likely located at 15%--20% recombination units from the HLA complex, probably on the B-D side. The analysis also shows that there is no heterogeneity in the estimates of linkage, and lod scores are not artifically inflated because of the association of multiple sclerosis (MS) with HLA-B7.