Stratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases.

Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m²) compared to obese cases (BMI≥30 Kg/m²). We performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. We used 2,112 lean type 2 diabetes cases (BMI<25 kg/m²) or 4,123 obese cases (BMI≥30 kg/m²), and 54,412 un-stratified controls. Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957 un-stratified controls. To assess the effects of known signals, we tested the individual and combined effects of SNPs representing 36 type 2 diabetes loci. After combining data from discovery and replication datasets, we identified two signals not previously reported in Europeans. A variant (rs8090011) in the LAMA1 gene was associated with type 2 diabetes in lean cases (P = 8.4×10⁻9, OR = 1.13 [95% CI 1.09-1.18]), and this association was stronger than that in obese cases (P = 0.04, OR = 1.03 [95% CI 1.00-1.06]). A variant in HMG20A--previously identified in South Asians but not Europeans--was associated with type 2 diabetes in obese cases (P = 1.3×10⁻8, OR = 1.11 [95% CI 1.07-1.15]), although this association was not significantly stronger than that in lean cases (P = 0.02, OR = 1.09 [95% CI 1.02-1.17]). For 36 known type 2 diabetes loci, 29 had a larger odds ratio in the lean compared to obese (binomial P = 0.0002). In the lean analysis, we observed a weighted per-risk allele OR = 1.13 [95% CI 1.10-1.17], P = 3.2×10⁻¹4. This was larger than the same model fitted in the obese analysis where the OR = 1.06 [95% CI 1.05-1.08], P = 2.2×10⁻¹6. This study provides evidence that stratification of type 2 diabetes cases by BMI may help identify additional risk variants and that lean cases may have a stronger genetic predisposition to type 2 diabetes.

Comparison of nylon-flocked swab and Dacron swab cytology for anal HSIL detection in transgender women and gay, bisexual, and other men who have sex with men.

BACKGROUND: An anal histological high-grade squamous intraepithelial lesion (hHSIL) is an anal cancer precursor. Experts recommend Dacron swab anal cytology as a primary screen for anal hHSILs, especially among human immunodeficiency virus-infected and -uninfected men who have sex with men (MSM). Studies have shown that Dacron cytology inaccurately predicts anal hHSILs and results in unnecessary diagnostic procedures. Nylon-flocked (NF) swabs have been shown to trap pathogens and cells well. Thus, this study compared test characteristics of anal cytology using NF and Dacron swab collection protocols to predict anal hHSILs. METHODS: A single-visit, randomized clinical trial compared NF and Dacron swab anal cytology specimens to predict high-resolution anoscopy and biopsy-diagnosed anal hHSILs. Data for 326 gay men, bisexual men, other MSM, and male-to-female transgender women contributed descriptive and tabular statistics with which unadjusted and fully adjusted logistic regression models were constructed. The models estimated the odds of hHSILs, test accuracy (area under the curve [AUC]) and sensitivity, and specificity as well as the positive and negative predictive values of abnormal NF and Dacron cytology for predicting hHSILs. RESULTS: In the fully adjusted model, the sensitivities for NF and Dacron cytology were nearly equal (48% vs 47%), but the specificity was higher with NF cytology (76% vs 69%). Comparisons of the areas under receiver operating characteristic curves showed that NF cytology alone predicted hHSILs better than the covariate model (AUC, 0.69 vs 0.63; P = .02), but NF and Dacron cytology comparisons showed no statistically significant differences (AUC, 0.69 vs 0.67; P = .3). CONCLUSIONS: NF cytology and Dacron cytology provide modest sensitivity, but NF cytology has higher specificity and accuracy, and this is important for lowering the costs of population-based screening.

Mercury Exposure and Antinuclear Antibodies among Females of Reproductive Age in the United States: NHANES.

BACKGROUND: Immune dysregulation associated with mercury has been suggested, although data in the general population are lacking. Chronic exposure to low levels of methylmercury (organic) and inorganic mercury is common, such as through fish consumption and dental amalgams. OBJECTIVE: We examined associations between mercury biomarkers and antinuclear antibody (ANA) positivity and titer strength. METHODS: Among females 16-49 years of age (n = 1,352) from the National Health and Nutrition Examination Survey (NHANES) 1999-2004, we examined cross-sectional associations between mercury and ANAs (indirect immunofluorescence; cutoff ≥ 1:80). Three biomarkers of mercury exposure were used: hair (available 1999-2000) and total blood (1999-2004) predominantly represented methylmercury, and urine (1999-2002) represented inorganic mercury. Survey statistics were used. Multivariable modeling adjusted for several covariates, including age and omega-3 fatty acids. RESULTS: Sixteen percent of females were ANA positive; 96% of ANA positives had a nuclear speckled staining pattern. Geometric mean (geometric SD) mercury concentrations were 0.22 (0.03) ppm in hair, 0.92 (0.05) µg/L blood, and 0.62 (0.04) µg/L urine. Hair and blood, but not urinary, mercury were associated with ANA positivity (sample sizes 452, 1,352, and 804, respectively), after adjusting for confounders: for hair, odds ratio (OR) = 4.10 (95% CI: 1.66, 10.13); for blood, OR = 2.32 (95% CI: 1.07, 5.03) comparing highest versus lowest quantiles. Magnitudes of association were strongest for high-titer (≥ 1:1,280) ANA: hair, OR = 11.41 (95% CI: 1.60, 81.23); blood, OR = 5.93 (95% CI: 1.57, 22.47). CONCLUSIONS: Methylmercury, at low levels generally considered safe, was associated with subclinical autoimmunity among reproductive-age females. Autoantibodies may predate clinical disease by years; thus, methylmercury exposure may be relevant to future autoimmune disease risk.

Increased usage of special educational services by children born to mothers with systemic lupus erythematosus and antiphospholipid antibodies.

INTRODUCTION: Surveys of long-term health and developmental outcomes of children born to mothers with systemic lupus erythematosus (SLE) have suggested an increase in learning disabilities among these children. We performed this observational study to investigate the relationship between maternal autoantibodies and antiphospholipid antibody syndrome (APS) in maternal lupus patients and neurocognitive development among their offspring. METHODS: SLE mothers with at least one live birth postlupus diagnosis were enrolled. Data on maternal medical/obstetric history and children's perinatal/medical history were collected by structured interview and medical record reviews. The primary outcome was requirement for special educational (SE) services, a proxy for developmental delays. Multiple logistic regression modelling was used to examine associations between APS and autoantibodies with SE usage, accounting for SLE disease severity and potential confounders. RESULTS: Data on 38 mothers and 60 offspring were analysed: SE service usage was reported for 15 of 60 (25%) offspring. Maternal APS history was significantly associated with increased use of SE services among offspring, including after adjustment for lupus anticoagulant (LA) positivity and potential confounders (OR 5.5-9.4 for delays age ≥2; p<0.05). The presence of LA, but not other antiphospholipid antibodies, was also associated with increased SE services usage. CONCLUSIONS: Maternal APS and LA were independently associated with increased usage of special educational services among offspring of women with SLE.

In utero azathioprine exposure and increased utilization of special educational services in children born to mothers with systemic lupus erythematosus.

OBJECTIVE: Azathioprine (AZA) is recognized among immunosuppressive medications as relatively safe during pregnancy for women with systemic lupus erythematosus (SLE) requiring aggressive treatment. This pilot study aimed to determine whether SLE therapy during pregnancy was associated with developmental delays in offspring. METHODS: This cohort study included SLE patients with at least one live birth postdiagnosis. Medical histories were obtained via interviews and chart review. Multiple logistic regression was used to examine associations between SLE therapy during pregnancy and maternal report of special educational (SE) requirements (as proxy for developmental delays) among offspring. Propensity scoring (incorporating corticosteroid use, lupus flare, and lupus nephritis) was used to account for disease severity. RESULTS: Of 60 eligible offspring from 38 mothers, 15 required SE services, the most common indication for which was speech delay. Seven (54%) of the 13 children with in utero AZA exposure utilized SE services versus 8 (17%) of 47 nonexposed children (P < 0.01). After adjustment for pregnancy duration, small for gestational age, propensity score, maternal education level, and antiphospholipid antibody syndrome, AZA was significantly associated with SE utilization occurring from age 2 years onward (odds ratio 6.6, 95% confidence interval 1.0-43.3), and bordered on significance for utilization at any age or age <2 years. CONCLUSION: AZA exposure during SLE pregnancy was independently associated with increased SE utilization in offspring, after controlling for confounders. Further research is indicated to fully characterize developmental outcomes among offspring with in utero AZA exposure. Vigilance and early interventions for suspected developmental delays among exposed offspring may be warranted.

Ovarian Damage During chemotherapy in Autoimmune Diseases: Broad Health Implications beyond Fertility.

Women with autoimmune diseases such as lupus, scleroderma, and vasculitis receiving cyclophosphamide for severe disease manifestations risk primary ovarian insufficiency(POI) due to gonadotoxicity of this therapy. In addition to loss of reproductive potential, POI is associated with increased risk of morbidity and mortality. Practitioners caring for women requiring gonadotoxic therapies should be familiar with long-term health implications of POI and strategies for ovarian preservation. Accumulating evidence supports the effectiveness of adjunctive gonadotropin releasing hormone analog (GnRH-a) for ovarian protection during gonadotoxic therapy in cancer and autoimmune populations. GnRH-a is less costly and invasive than assisted reproductive technologies used for achievement of future pregnancies, but is not Food and Drug Administration approved for ovarian preservation. This review focuses on POI comorbidities and strategies for mitigation of related sequelae, which can accumulate over decades of hypoesteogenism. These issues are arguably more pronounced for women with chronic autoimmune diseases, in whom superimposed POI further heightens risks of cardiovascular disease and osteoporosis. Therefore, even if future pregnancy is not desired, ovarian protection during gonadotoxic therapy should be a major goal of disease management.

A preliminary study of a cloud-computing model for chronic illness self-care support in an underdeveloped country.

BACKGROUND: Although interactive voice response (IVR) calls can be an effective tool for chronic disease management, many regions of the world lack the infrastructure to provide these services. PURPOSE: This study evaluated the feasibility and potential impact of an IVR program using a cloud-computing model to improve diabetes management in Honduras. METHODS: A single-group, pre-post study was conducted between June and August 2010. The telecommunications infrastructure was maintained on a U.S. server, and calls were directed to patients' cell phones using VoIP. Eighty-five diabetes patients in Honduras received weekly IVR disease management calls for 6 weeks, with automated follow-up e-mails to clinicians, and voicemail reports to family caregivers. Patients completed interviews at enrollment and a 6-week follow-up. Other measures included patients' glycemic control (HbA1c) and data from the IVR calling system. RESULTS: A total of 53% of participants completed at least half of their IVR calls and 23% of participants completed 80% or more. Higher baseline blood pressures, greater diabetes burden, greater distance from the clinic, and better medication adherence were related to higher call completion rates. Nearly all participants (98%) reported that because of the program, they improved in aspects of diabetes management such as glycemic control (56%) or foot care (89%). Mean HbA1c's decreased from 10.0% at baseline to 8.9% at follow-up (p<0.01). Most participants (92%) said that if the service were available in their clinic they would use it again. CONCLUSIONS: Cloud computing is a feasible strategy for providing IVR services globally. IVR self-care support may improve self-care and glycemic control for patients in underdeveloped countries.

Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis.

By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P<5x10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.