Among 163 patients with sporadic MS, DeLuca et al. (2007) observed an association between relatively benign outcome and HLA-DRB1*01. The allele was present in 19% of 112 patients with milder disease compared to 3.9% of 51 patients with ... Among 163 patients with sporadic MS, DeLuca et al. (2007) observed an association between relatively benign outcome and HLA-DRB1*01. The allele was present in 19% of 112 patients with milder disease compared to 3.9% of 51 patients with severe disease, yielding an odds ratio of 4.85. Severity analysis of a cohort of affected sib pairs discordant for the DRB1*01 allele confirmed the protective effect, but only reached significance when combined in the DRB1*1501 allele. Another group of Sardinian MS patients showed that 19 with benign disease had the DRB1*01 allele, compared to none with malignant disease. DeLuca et al. (2007) suggested that the DRB1*01 allele acts as a modifier of disease progression in MS. Epidemiologic evidence implicating epigenetic factors in MS includes complex distortion of disease transmission seen in aunt/uncle-niece/nephew (AUNN) pairs. In AUNN families, Chao et al. (2009) found that allele frequencies for HLA-DRB1*1501 were different between the first and second generations affected. Affected aunts had significantly lower HLA-DRB1*15 frequency compared with their affected nieces (P = 0.0016), whereas HLA-DRB1*15 frequency in affected males remained unaltered across the 2 generations (P = 0.63). The authors compared transmissions for the HLA-DRB1*15 allele using a family-based transmission disequilibrium test approach in 1,690 individuals from 350 affected sib-pair (ASP) families and 960 individuals from 187 AUNN families. Transmissions differed between the ASP and the AUNN families (P = 0.0085). The risk carried by HLA-DRB1*15 was increased in families with affected second-degree relatives (AUNN: OR = 4.07) when compared with those consisting only first-degree relatives (ASP: OR = 2.17), establishing heterogeneity of risk among HLA-DRB1*15 haplotypes based on whether collateral parental relatives are affected. The authors proposed gene-environment interactions in susceptibility and more specifically, that epigenetic modifications may differentiate among human leukocyte antigen class II risk haplotypes and may be involved in the determination of the gender bias in MS. The authors suggested that the female-specific increasing risk of MS is mediated through these alleles or adjacent variation. - Modifier Genes Among 939 German patients with multiple sclerosis, Kroner et al. (2005) reported an association between the A allele of a SNP in the PDCD1 gene (600244) and disease progression. Of 94 patients with primary progressive MS, 44% had the G/G genotype, and 53% had the A/G genotype. Of 5 MS patients who were homozygous for the A allele, 3 had primary progressive MS, and 1 had secondary progressive MS. In vitro studies showed that PDCD1-mediated inhibition of T-cell activation and cytokine secretion was impaired in cells from patients with the A allele compared to cells from patients with only the G allele. Presence of the A allele did not confer susceptibility to disease development. Barcellos et al. (2000) found that patients with multiple sclerosis carrying the CCR5 (601373)-delta-32 deletion showed an age at onset approximately 3 years later than did patients without the deletion. Studying 256 Israeli patients with MS, Kantor et al. (2003) presented evidence suggesting that the CCR5-delta-32 deletion may contribute to a slower rate of disease progression in MS.
Pugliatti et al. (2002) demonstrated a hotspot of MS in the southwestern part of Sassari province in Sardinia, bordering with the commune of Macomer, where MS was once hypothesized as having occurred as an epidemic. These areas of ... Pugliatti et al. (2002) demonstrated a hotspot of MS in the southwestern part of Sassari province in Sardinia, bordering with the commune of Macomer, where MS was once hypothesized as having occurred as an epidemic. These areas of MS clustering comprised the Common Logudorese linguistic domain. The Catalan area, which is linguistically and genetically distant from the remaining Sardinian domains, did not show such high estimates.