Dense Genotyping of Immune-Related Loci Identifies Variants Associated with Clearance of HPV among HIV-Positive Women in the HIV Epidemiology Research Study (HERS)

<div><p>Persistent high-risk human papillomavirus (HR-HPV) is a necessary and causal factor of cervical cancer. Most women naturally clear HPV infections; however, the biological mechanisms related to HPV pathogenesis have not been clearly elucidated. Host genetic factors that specifically regulate immune response could play an important role. All HIV-positive women in the HIV Epidemiology Research Study (HERS) with a HR-HPV infection and at least one follow-up biannual visit were included in the study. Cervicovaginal lavage samples were tested for HPV using type-specific HPV hybridization assays. Type-specific HPV clearance was defined as two consecutive HPV-negative tests after a positive test. DNA from participants was genotyped for 196,524 variants within 186 known immune related loci using the custom ImmunoChip microarray. To assess the influence of each single-nucleotide polymorphism (SNP) with HR-HPV clearance, the Cox proportional hazards model with the Wei-Lin-Weissfeld approach was used, adjusting for CD4+ count, low risk HPV (LR-HPV) co-infection, and relevant confounders. Three analytical models were performed: race-specific (African Americans (n = 258), European Americans (n = 87), Hispanics (n = 55), race-adjusted combined analysis, and meta-analysis of pooled independent race-specific analyses. Women were followed for a median time of 1,617 days. Overall, three SNPs (rs1112085, rs11102637, and rs12030900) in the <i>MAGI-3</i> gene and one SNP (rs8031627) in the <i>SMAD3</i> gene were associated with HR-HPV clearance (p<10⁻⁶). A variant (rs1633038) in <i>HLA-G</i> were also significantly associated in African American. Results from this study support associations of immune-related genes, having potential biological mechanism, with differential cervical HR-HPV infection outcomes.</p> </div

Manhattan plot showing the association P-values of single nucleotide polymorphisms (SNPs) in the ImmunoChip with the time to clearance of HR-HPV.

<p>The X-axes display the chromosome on which the SNP is located, the Y-axes display −log₁₀ P-value. The dashed black line represents a significance level needed for multiple testing using the K effective method. Panel A.) Race-adjusted analysis B.) African Americans only C.) European Americans only, and D.) Hispanics only.</p

Cox proportional Hazard Ratios (HR) for the SNPS associated with time to clearance of high-risk (HR-HPV) HPV infection in the race-adjusted analysis, individual race-specific analysis, and pooled analysis of the three races separately.

<p>Cox proportional Hazard Ratios (HR) for the SNPS associated with time to clearance of high-risk (HR-HPV) HPV infection in the race-adjusted analysis, individual race-specific analysis, and pooled analysis of the three races separately.</p

Analyse systématique des anomalies retrouvées à l'IRM cérébrale chez les patients atteints d'une paraplégie spastique héréditaire associée aux mutations de l'AP4

peer reviewed[en] BACKGROUND AND OBJECTIVES: AP-4-associated hereditary spastic paraplegia (AP-4-HSP: SPG47, SPG50, SPG51, SPG52) is an emerging cause of childhood-onset hereditary spastic paraplegia and mimic of cerebral palsy. This study aims to define the spectrum of brain MRI findings in AP-4-HSP and to investigate radioclinical correlations. METHODS: We performed a systematic qualitative and quantitative analysis of 107 brain MRI studies from 76 individuals with genetically confirmed AP-4-HSP and correlation with clinical findings including surrogates of disease severity. RESULTS: We define AP-4-HSP as a disorder of gray and white matter and demonstrate that abnormal myelination is common and that metrics of reduced white matter volume correlate with severity of motor symptoms. We identify a common diagnostic imaging signature consisting of (1) a thin splenium of the corpus callosum, (2) an absent or thin anterior commissure, (3) characteristic signal abnormalities of the forceps minor ("ears of the grizzly sign"), and (4) periventricular white matter abnormalities. The presence of 2 or more of these findings has a sensitivity of ∼99% for detecting AP-4-HSP; the combination of all 4 is found in ∼45% of cases. Compared to other HSPs with a thin corpus callosum, the absent anterior commissure appears to be specific to AP-4-HSP. Our analysis identified a subset of patients with polymicrogyria, underscoring the role of AP-4 in early brain development. These patients displayed a higher prevalence of seizures and status epilepticus, many at a young age. DISCUSSION: Our findings define the MRI spectrum of AP-4-HSP, providing opportunities for early diagnosis, identification of individuals at risk for complications, and a window into the role of the AP-4 complex in brain development and neurodegeneration