Corticobasal and ataxia syndromes widen the spectrum of C9ORF72 hexanucleotide expansion disease

Recently, a hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 was reported as the cause of chromosome 9p21‐linked frontotemporal dementia‐amyotrophic lateral sclerosis (FTD‐ALS). We here report the prevalence of the expansion in a hospital‐based cohort and associated clinical features indicating a wider clinical spectrum of C9ORF72 disease than previously described. We studied 280 patients previously screened for mutations in genes involved in early onset autosomal dominant inherited dementia disorders. A repeat‐primed polymerase chain reaction amplification assay was used to identify pathogenic GGGGCC expansions. As a potential modifier, confirmed cases were further investigated for abnormal CAG expansions in ATXN2. A pathogenic GGGGCC expansion was identified in a total of 14 probands. Three of these presented with atypical clinical features and were previously diagnosed with clinical olivopontocerebellar degeneration (OPCD), atypical Parkinsonian syndrome (APS) and a corticobasal syndrome (CBS). Further, the pathogenic expansion was identified in six FTD patients, four patients with FTD‐ALS and one ALS patient. All confirmed cases had normal ATXN2 repeat sizes. Our study widens the clinical spectrum of C9ORF72related disease and confirms the hexanucleotide expansion as a prevalent cause of FTD‐ALS disorders. There was no indication of a modifying effect of the ATXN2 gene.     

DNA Methylation Variants at HIF3A Locus,B-Vitamin Intake,and Long-term Weight Change: Gene-Diet Interactions in Two U.S. Cohorts

The first epigenome-wide association study of BMI identified DNA methylation at an HIF3A locus associated with BMI. We tested the hypothesis that DNA methylation variants are associated with BMI according to intake of B vitamins. In two large cohorts, we found significant interactions between the DNA methylation–associated HIF3A single nucleotide polymorphism (SNP) rs3826795 and intake of B vitamins on 10-year changes in BMI. The association between rs3826795 and BMI changes consistently increased across the tertiles of total vitamin B₂ and B₁₂ intake (all P for interaction <0.01). The differences in the BMI changes per increment of minor allele were −0.10 (SE 0.06), −0.01 (SE 0.06), and 0.12 (SE 0.07) within subgroups defined by increasing tertiles of total vitamin B₂ intake and −0.10 (SE 0.06), −0.01 (SE 0.06), and 0.10 (SE 0.07) within subgroups defined by increasing tertiles of total vitamin B₁₂ intake. In two independent cohorts, a DNA methylation variant in HIF3A was associated with BMI changes through interactions with total or supplemental vitamin B₂, vitamin B₁₂, and folate. These findings suggest a potential causal relation between DNA methylation and adiposity.     

Early-Stage Investigators and Institutional Interface: Importance of Organization in the Mentoring Culture of Today’s Universities

Poor psychosocial health contributes to HIV risk behavior and reduced engagement in treatment and care. This study investigates depression and its correlates among 11,992 MSM recruited via respondent driven sampling in 12 cities across India using the Patient Health Questionnaire-9 and supplemented by analysis of qualitative research from 15 sites with 363 MSM. Overall prevalence of depression was 11 %, with substantial variation across sites and subgroups of MSM, and high prevalence of suicidal thoughts among depressed MSM. In multivariable analyses identification as a kothi (feminine sexual identity) [adjusted odds ratio (aOR) = 1.91], disclosure of being MSM to non-family (aOR = 1.7) and family (aOR = 2.4), disclosure of HIV-status (aOR = 5.6), and substance use were associated with significantly higher odds of depression. Qualitative results emphasized dire social consequences of disclosing MSM- and HIV-status, especially to family, including suicidality. Combination prevention interventions should include mental health services that address disclosure, suicidality, and substance use.     

Insulin,proinsulin, proinsulin:insulin ratio,and the risk of developing type 2 diabetes mellitus in women

PURPOSE: To assess the associations among baseline levels of fasting insulin and proinsulin, proinsulin:insulin ratio, and the development of type 2 diabetes mellitus in apparently healthy middle-aged women. METHODS: In a nested case-control study involving a nationwide cohort of 27,628 participants from the Women's Health Study, 126 women with diabetes diagnosed during a 4-year follow-up period were compared with 225 age-matched controls. Fasting insulin level and proinsulin:insulin ratio were assessed in quartiles, and proinsulin level was assessed in categories (< or =4.0 pmol/L, 4.01 to 6.99 pmol/L, > or =7.0 pmol/L). The risk of developing type 2 diabetes was determined using conditional logistic regression analysis that adjusted for body mass index and other diabetes risk factors. RESULTS: Baseline insulin and proinsulin levels and proinsulin:insulin ratios were significantly higher among cases than among controls. Women with elevated insulin levels in the highest as compared with the lowest quartile were more likely to develop diabetes (odds ratio [OR] = 5.6; 95% confidence interval [CI]: 1.8 to 17.6), as were women with elevated (> or =7.0 pmol/L vs. < or =4.0 pmol/L) proinsulin levels (OR = 16.4; 95% CI: 5.8 to 46.8) and women with proinsulin:insulin ratios in the highest quartile (OR = 9.6; 95% CI: 3.1 to 30.8). Similar results were observed among women with a baseline hemoglobin A(1c) level < or =6.0%. In time-trend analyses, fasting insulin was a consistent predictor of long-term risk. Proinsulin and proinsulin:insulin ratio, although predictive throughout the study, were especially strong predictors of rapid progression to type 2 diabetes. CONCLUSION: Elevated fasting insulin and proinsulin levels and proinsulin:insulin ratio are associated with an increased risk of developing type 2 diabetes in apparently healthy middle-aged women.     

Accuracy of supplementary serologic testing for human T-lymphotropic virus types I and II in US blood donors. Retrovirus Epidemiology Donor Study

Blood donations in the United States have been screened for antibody to human T-lymphotropic virus type I (HTLV-I) by HTLV-I enzyme immunoassay (EIA) since November 1988. Specimens repeatedly found to be reactive by EIA undergo confirmation by supplementary serologic tests. We assessed the accuracy of blood center testing of 994 HTLV-I EIA repeat-reactive specimens in five US blood centers between November 1988 and December 1991. Of 410 confirmed HTLV-I/II donations, 407 (99.3%) were infected with HTLV-I/II, as determined by polymerase chain reaction (PCR) (403 cases) and by repeat serologic testing (4 cases). The three false- positive results occurred in the first year of testing. Of 425 HTLV- indeterminate specimens, 6 (1.4%) were found to be infected by PCR (5 with HTLV-II and 1 with HTLV-I). None of 159 confirmatory test-negative donations was PCR positive. Of HTLV-I/II-seropositive specimens, 80.2% to 95.4% could be typed as HTLV-I or HTLV-II by type-specific serologic assays. These results support recommendations that HTLV-I/II- seropositive donors should be advised that they are infected with HTLV- I, HTLV-II, or HTLV-I/II (depending on results of type-specific assays). HTLV-indeterminate donors should be advised that their results only rarely indicate HTLV infection. HTLV confirmatory test-negative donors should be reassured that they are not infected with HTLV-I or HTLV-II.     

Copy number variants in patients with short stature

Height is a highly heritable and classic polygenic trait. Recent genome-wide association studies (GWAS) have revealed that at least 180 genetic variants influence adult height. However, these variants explain only about 10% of the phenotypic variation in height. Genetic analysis of short individuals can lead to the discovery of novel rare gene defects with a large effect on growth. In an effort to identify novel genes associated with short stature, genome-wide analysis for copy number variants (CNVs), using single-nucleotide polymorphism arrays, in 162 patients (149 families) with short stature was performed. Segregation analysis was performed if possible, and genes in CNVs were compared with information from GWAS, gene expression in rodents'' growth plates and published information. CNVs were detected in 40 families. In six families, a known cause of short stature was found (SHOX deletion or duplication, IGF1R deletion), in two combined with a de novo potentially pathogenic CNV. Thirty-three families had one or more potentially pathogenic CNVs (n=40). In 24 of these families, segregation analysis could be performed, identifying three de novo CNVs and nine CNVs segregating with short stature. Four were located near loci associated with height in GWAS (ADAMTS17, TULP4, PRKG2/BMP3 and PAPPA). Besides six CNVs known to be causative for short stature, 40 CNVs with possible pathogenicity were identified. Segregation studies and bioinformatics analysis suggested various potential candidate genes.