Differences in Minority Stress Experiences, Mental Health, and Relationship Quality Outcomes Among Bisexual, Pansexual, and Queer Women.

The majority of sexual minority women in the United States today identify as bi+. Recent research suggests that "non-traditional" bi+ labels such as pansexual and queer are being adopted more frequently than ever before, making it increasingly important to evaluate whether these women have unique needs. In the current study, we explored differences in minority stress experiences, mental health, and relationship quality outcomes by sexual identity label among women who identify with the most common bi+ labels: bisexual, pansexual, and queer. Participants were 285 bi+ cisgender women in romantic relationships. They completed online measures of minority stress (antibisexual experiences, identity concealment, disconnection from the sexual and gender minority (SGM) community, and internalized stigma), mental health (depression and anxiety), and relationship quality (satisfaction and commitment). Overall, participants reported similar experiences of minority stress and few differences in their mental health outcomes. However, there were differences in antibisexual experiences by sexual identity label, such that pansexual women reported more frequent antibisexual experiences than bisexual and queer women. There were also differences in relationship quality by sexual identity label, such that bisexual women reported higher satisfaction than pansexual women and higher commitment than both pansexual and queer women. Findings suggest that pansexual and queer women may be facing their own unique challenges, even compared to bisexual women. Clinical prevention and intervention efforts can be tailored for these women to include strategies to cope with more frequent exposure to antibisexual experiences, as well as relationship education and skill-building to promote healthy romantic relationships.

Weight change predicts college adjustment and depressive symptoms among first-year college students.

ObjectiveWeight change is common during the first year of college and may be related to different outcomes for men and women. This study examined the moderating effects of gender on the association between weight change and college adjustment and depressive symptoms. Participants: One-hundred and eighty-one 18-19-year-old college freshmen (56.9% female; 84.5% Caucasian). Methods: Students completed a one-time survey about demographics, weight, college adjustment, and depressive symptoms during their second semester of college. Results: Increased weight change was associated with fewer depressive symptoms for both men and women (p < .04). For men, increased weight change was associated with better overall college adjustment, more positivity about college, less negativity about college, and less homesickness (all p < .02). Conclusions: Universities could target men and women differently in regard to weight, college adjustment, and mental health to promote a positive college experience and optimal mental health.

Relationship, marriage, and parenthood aspirations among sexual and gender minority youth assigned female at birth.

This study examined aspirations for future long-term committed relationships, marriage, and parenthood in a sample of 392 racially diverse sexual and gender minority (SGM) youth assigned female at birth (AFAB) aged 16-20. Differences by gender identity, sexual identity, and race/ethnicity were assessed, as were associations with contextual variables including minority stressors, SGM community involvement, perceived partner availability, and relationship experiences. Results showed that the majority of SGM-AFAB youth viewed long-term committed relationships as important and likely, whereas only about half of participants had high aspirations to get married and have children someday. Those who did view marriage and parenthood as important perceived that it is feasible for them to achieve these outcomes someday. These constructs did not differ by race/ethnicity. There were differences by gender identity and sexual identity, such that cisgender women reported higher aspirations for marriage and parenthood than did gender minorities, and those with binary sexual identities reported higher aspirations for marriage than did those with nonbinary sexual identities. Examination of the contextual variables revealed that relationship experience variables were the most consistently associated with aspirations for committed relationships, marriage, and parenthood. In contrast, victimization and perceived partner availability were not associated with any of the family formation aspirations. As SGM individuals are increasingly granted legal rights affecting their ability to marry and form families, research is needed to help inform efforts to promote their relationship health while considering that they may have unique aspirations for relationships, marriage, and parenthood compared to the general public. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Within-person associations between romantic involvement and mental health among sexual and gender minorities assigned female-at-birth.

Sexual and gender minorities assigned female at birth (SGM-AFAB) experience significant mental health disparities, making it important to identify protective factors against psychological and substance use problems in this population. We examined whether romantic relationship involvement, a well-established protective factor for mental health in heterosexual adults, is protective for SGM-AFAB young people. Using five waves of data from 488 racially diverse SGM-AFAB (ages 16-31 years at baseline), we assessed within-person associations between relationship involvement and depressive symptoms, anxiety symptoms, and problematic alcohol and cannabis use. We tested for differences in these associations by age; sexual, gender, and racial identity; relationship status; and partner gender, and whether romantic involvement buffers the negative effects of anti-SGM victimization. Multilevel models indicated that participants reported fewer depressive symptoms, alcohol use problems, and cannabis use problems when romantically involved than when single. Romantic involvement was associated with fewer anxiety symptoms for Latinx participants only. Associations did not differ by age and were generally consistent (with some exceptions) across sexual, gender, and racial identity. Effects on substance use were stronger for long-term commitments than dating relationships. Participants reported less depression and anxiety, but more alcohol or cannabis use, when romantically involved with cisgender women than with cisgender men or gender minority partners. Together, findings suggest that relationship involvement is broadly protective of mental health among SGM-AFAB, though it may not buffer the negative effects of SGM victimization. Efforts to reduce SGM-AFAB mental health disparities should consider including strategies to support healthy relationship involvement. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Development of a LC-MS/MS method for the quantification of toxic payload DM1 cleaved from BT1718 in a Phase I study.

Background: BT1718 is a novel bicyclic peptide anticancer drug targeting membrane type I matrix metalloproteinase to release its toxic payload DM1. A LC-MS/MS method was validated to quantify DM1 generated from BT1718 in a Phase I/IIa clinical trial. Materials & methods: Plasma samples underwent a reduction reaction to artificially cleave BT1718 into DM1 and its bicycle components. An alkylation step was carried out to stabilize the reaction products, and plasma proteins extracted using acetonitrile. LC-MS/MS analysis utilized a C18 column and Agilent 6460 triple quadrupole mass spectrometer (Agilent, Cheshire, UK). Results: The method was fully validated over a linear range of 200-50,000 ng/ml BT1718, with overall precision ≤10% and accuracy 89-102%. Conclusion: A novel method for quantifying DM1 yielded from BT1718 has been validated and is now being utilized clinically.

Mental health outcomes among individuals with 46,XY disorders of sex development: A systematic review.

This review summarizes research on the mental health outcomes of genetic males with a disorder of sex development (46,XY DSD). Databases were systematically searched, yielding 19 studies included in this review. Results varied widely, with mental health outcomes ranging from very poor to similar to comparison groups. A small number of studies demonstrated that patients with hypospadias or complete androgen insensitivity syndrome reported better mental health than patients with other 46,XY (DSD) diagnoses. Future studies should include larger samples of patients within a similar developmental stage, display results separately by DSD diagnosis and gender identity, and consider the potential impact of medical/surgical events on their mental health.

Sexual Agreements Among Young Sexual and Gender Minorities Assigned Male at Birth: Associations with Relationship Quality and Break-Up.

Previous studies have shown that sexual non-monogamy is not associated with lower relationship satisfaction among adult male same-sex couples and may therefore be a viable alternative to monogamy. However, sexual minority men with non-monogamous agreements have reported lower commitment and trust in their relationships than those with monogamous agreements-potentially raising their risk of break-up. In this study, we investigated whether sexual agreements (monogamous, non-monogamous, or no sexual agreement) were associated with relationship quality and rates of break-up over 1 year in a sample of 338 young sexual and gender minorities assigned male at birth (SGM-AMAB). Participants reported their sexual agreement and indices of relationship quality (satisfaction, trust, and commitment) at baseline, as well as their relationship status (intact or broken up) at 6- and 12-month follow-up. Results showed no significant differences by sexual agreement in concurrent trust, but participants with monogamous agreements reported higher satisfaction and commitment than those with non-monogamous agreements or no sexual agreement. Despite these significant differences in relationship quality, there were no significant differences in rates of break-up at 6- or 12-month follow-up across the sexual agreement types. However, having a monogamous agreement was indirectly associated with lower rates of break-up through relationship commitment. Although results were mixed, findings provide some preliminary support that young SGM-AMAB in relationships with monogamous agreements may have higher satisfaction and commitment at early relationship stages, and that monogamous agreements may be a protective factor against break-up over 1 year through the mechanism of relationship commitment.

Romantic Involvement and Mental Health in Sexual and Gender Minority Emerging Adults Assigned Female at Birth.

We examined whether romantic relationship involvement, a well-established protective factor against mental health problems among heterosexual adults, is also protective for sexual and gender minority emerging adults assigned female at birth (SGM-AFAB), a group at high risk for mental health issues. Using cross-sectional data from a community sample of 222 SGM-AFAB ages 18-20 years, we assessed associations between current relationship involvement and five mental health variables: depressive symptoms, anxiety symptoms, alcohol use problems, cannabis use problems, and illicit drug use. There were no differences by romantic involvement in problematic cannabis use or other illicit drug use. Overall, participants in a relationship reported fewer depressive symptoms, fewer anxiety symptoms, and less problematic alcohol use than participants who were single. Some associations differed, however, by participant gender identity, sexual orientation identity, and partner gender. Specifically, relationship involvement was associated with fewer depressive and anxiety symptoms for cisgender female participants (n=154) but not for gender minority participants (n=68), and for lesbian participants (n=38) but not for bisexual/pansexual participants (n=134) or those with other sexual orientation identities (n=50). Participants romantically involved with a cisgender female partner (n=43) had fewer depressive and anxiety symptoms than single participants (n=100), those with a cisgender male partner (n=56), and those with a gender minority partner (n=23). Together, these findings suggest that romantic involvement may promote mental health for many, but not all, SGM young adults, highlighting the importance of attending to differences among SGM subgroups in research and efforts to reduce mental health and substance use disparities.

Pharmacokinetics, safety, and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial.

BACKGROUND: The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib potentiated radiation and temozolomide (TMZ) chemotherapy in preclinical glioblastoma models but brain penetration was poor. Clinically, PARP inhibitors exacerbate the hematological side effects of TMZ. The OPARATIC trial was conducted to measure penetration of recurrent glioblastoma by olaparib and assess the safety and tolerability of its combination with TMZ. METHODS: Preclinical pharmacokinetic studies evaluated olaparib tissue distribution in rats and tumor-bearing mice. Adult patients with recurrent glioblastoma received various doses and schedules of olaparib and low-dose TMZ in a 3 + 3 design. Suitable patients received olaparib prior to neurosurgical resection; olaparib concentrations in plasma, tumor core and tumor margin specimens were measured by mass spectrometry. A dose expansion cohort tested tolerability and efficacy of the recommended phase II dose (RP2D). Radiosensitizing effects of olaparib were measured by clonogenic survival in glioblastoma cell lines. RESULTS: Olaparib was a substrate for multidrug resistance protein 1 and showed no brain penetration in rats but was detected in orthotopic glioblastoma xenografts. Clinically, olaparib was detected in 71/71 tumor core specimens (27 patients; median, 496 nM) and 21/21 tumor margin specimens (9 patients; median, 512.3 nM). Olaparib exacerbated TMZ-related hematological toxicity, necessitating intermittent dosing. RP2D was olaparib 150 mg (3 days/week) with TMZ 75 mg/m2 daily for 42 days. Fourteen (36%) of 39 evaluable patients were progression free at 6 months. Olaparib radiosensitized 6 glioblastoma cell lines at clinically relevant concentrations of 100 and 500 nM. CONCLUSION: Olaparib reliably penetrates recurrent glioblastoma at radiosensitizing concentrations, supporting further clinical development and highlighting the need for better preclinical models.

Partner Assisted Smoking Cessation Treatment: A Randomized Clinical Trial.

Background: Partner Assisted Smoking Cessation Treatment (PACT) was designed to improve smoking abstinence rates by integrating evidence-based relationship education strategies to build effective couple support into standard cognitive behavioral smoking cessation treatment (CBT). Methods: This small randomized clinical trial examined the feasibility, acceptability, and efficacy of PACT versus CBT in improving couple support processes and smoking outcomes, focusing on effect sizes. Thirty-eight smokers and their nonsmoking partners were randomized to and completed either PACT or CBT. Both treatments included 8 weekly group sessions and nicotine replacement therapy. Results: Treatment credibility and satisfaction were high and comparable between conditions, though perceived helpfulness and treatment engagement were higher in PACT (ds = .48-.68). Compared to CBT, PACT showed no difference in effects on perceived partner support, small effects on observed social support behaviors (ds = .23 to .46), a medium effect on dyadic efficacy (d = .63), and a large effect on active listening (d = .85). Biochemically-verified smoking abstinence rates did not differ between conditions at 12-week follow-up (CBT: 27.3%, PACT: 37.5%). Conclusions: PACT may have stronger effects than standard CBT on treatment engagement and some couple support processes, but not abstinence. Program refinement and testing in larger samples are needed.

Plasma rich in growth factor gel as an autologous filler for facial volume restoration.

BACKGROUND: Skin aging is characterized by moderate to severe wrinkles, laxity, roughness, and volume loss as a result of cutaneous atrophy and connective tissue degradation. Plasma rich in growth factor gel (PRGF-gel) is a novel formulation obtained from the patient's own blood that has demonstrated optimal biomechanical and bioactive properties for soft tissue restoration. OBJECTIVES: Following a retrospective design, the clinical safety and efficacy of PRGF-gel for facial volume restoration and skin rejuvenation were evaluated. METHODS: Twenty women clinically diagnosed for aged skin symptoms were treated with PRGF-gel. Participants received an individualized regimen depending on their therapeutic needs. At the end of the follow-up periods, clinical performance analysis was evaluated by standardized macrophotographs along with clinical and patient surveys based on Likert's scales. RESULTS: Based on their initial expectations, patients referred to be highly satisfied after PRGF-gel treatment in terms of fine line amelioration, wrinkle reduction, and sagging improvement (overall satisfaction of 8/10). Pre/post-photograph clinical evaluation showed an improvement of 2.5/3 and patients presented a noticeable face rejuvenation due to the soft tissue augmentation effect which was translated into surface texture softening and tone recovery. CONCLUSIONS: Although additional randomized clinical trials should be carried out, this study provides preliminary data supporting the use of PRGF-gel for facial volume restoration.

Unusual Enthalpy Driven Self Assembly at Room Temperature with Chitosan Amphiphiles.

BACKGROUND: GCPQ (N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl- 6-O-glycolchitosan) is a self-assembling polymer being investigated as a pharmaceutical nano-carrier. GCPQ nanoparticles shuttle drugs across biological barriers, improving drug performance. The exact chemistry of GCPQ is varied by the relative proportion of hydrophobic (N-palmitoyl) and hydrophilic (quaternary ammonium) groups and molecular weight. OBJECTIVE: We hypothesised that the thermodynamics of self-assembly is controlled by the polymer molecular weight and hydrophobicity. METHOD: The thermodynamics of self-assembly was investigated using isothermal calorimetry. RESULTS: GCPQs (Mw = 8-15 kDa) formed micellar aggregates at critical micellar concentrations of 1-2.4 µM at 25°C and micellisation was unusually enthalpy driven. There was a positive correlation between ΔHmic and mole% quaternary groups (Q): ΔHmic = 3.8 Q- 159 (r2 = 0.93) and a negative correlation between ΔHmic and molecular weight (Mw): ΔHmic = -13.5 Mw-26.3 (r2 = 0.99). CONCLUSION: These findings provide insights into the positive drivers of stable selfassemblies, namely hydrophobicity and molecular weight, as both hydrophobicity and molecular weight are associated with an increased enthalpy contribution to micellisation.

Nanoparticulate peptide delivery exclusively to the brain produces tolerance free analgesia.

The delivery of peptide drugs to the brain is challenging, principally due to the blood brain barrier and the low metabolic stability of peptides. Exclusive delivery to the brain with no peripheral exposure has hitherto not been demonstrated with brain quantification data. Here we show that polymer nanoparticles encapsulating leucine5-enkephalin hydrochloride (LENK) are able to transport LENK exclusively to the brain via the intranasal route, with no peripheral exposure and nanoparticle localisation is observed within the brain parenchyma. Animals dosed with LENK nanoparticles (NM0127) showed a strong anti-nociceptive response in multiple assays of evoked and on going pain whereas animals dosed intranasally with LENK alone were unresponsive. Animals did not develop tolerance to the anti-hyperalgesic activity of NM0127 and NM0127 was active in morphine tolerant animals. A microparticulate formulation of clustered nanoparticles was prepared to satisfy regulatory requirements for nasal dosage forms and the polymer nanoparticles alone were found to be biocompatible, via the nasal route, on chronic dosing.

Direct in vivo evidence on the mechanism by which nanoparticles facilitate the absorption of a water insoluble, P-gp substrate.

Here we examine the mechanisms by which nanoparticles enable the oral absorption of water-insoluble, P-glycoprotein efflux pump (P-gp) substrates, without recourse to P-gp inhibitors. Both 200nm paclitaxel N-(2-phenoxyacetyl)-6-O-glycolchitosan (GCPh) nanoparticles (GCPh-PTX) and a simulated Taxol formulation, facilitate drug dissolution in biorelevant media, unlike paclitaxel nanocrystals. Verapamil (40mgkg-1) increased the oral absorption from low dose Taxol (6 or 10mgkg-1) by 100%, whereas the oral absorption from high dose Taxol (20mgkg-1) or low dose GCPh-PTX (6 or 10mgkg-1) was largely unchanged by verapamil. There was virtually no absorption from control paclitaxel nanocrystals (20mgkg-1). Imaging of ex-vivo rat ileum samples showed that fluorescently labelled GCPh nanoparticles are mucoadhesive and are taken up by ileum epithelial cells. GCPh nanoparticles were also found to open Caco-2 cell tight junctions. In conclusion, mucoadhesive, drug solubilising GCPh nanoparticles enable the oral absorption of paclitaxel via the saturation of the P-gp pump (by high local drug concentrations) and by particle uptake and tight junction opening mechanisms.

Therapeutic Use of Soluble Fas Ligand Ameliorates Acute and Recurrent Herpetic Stromal Keratitis in Mice.

PURPOSE: The present study was designed to test the therapeutic value of soluble FasL (sFasL) in an acute model of herpetic stromal keratitis (HSK) and, more importantly, a recurrent model of HSK using BALB/c, BALB-lpr, and National Institutes of Health (NIH) mice. METHODS: Mice were infected either acutely with the KOS strain of herpes simplex virus 1 (HSV-1) or latently with the McKrae strain of HSV-1. Acutely infected mice as well as ultraviolet-B (UV-B) reactivated mice (recurrent infection) were treated with sFasL, or soluble TNF-related apoptosis inducing ligand (sTRAIL), or BSA daily or 3 times/wk by using either a combination of subconjunctival injection and topical ointment, or with topical ointment alone. These mice then were evaluated for corneal opacity and neovascularization for 6 weeks. RESULTS: Following acute and recurrent HSV-1 infection, wild-type BALB/c mice treated with sFasL displayed significantly reduced incidence of corneal opacity and neovascularization compared to the control animals. However, BALB-lpr mice, which are deficient in Fas+ inflammatory cells, displayed no such differences in ocular disease, as expected. Latently infected NIH mice treated with sFasL displayed similar results. Flow cytometric analysis revealed that the corneal inflammatory infiltrate in those treated with sFasL was significantly less than in sTRAIL- or BSA-treated mice. Furthermore, corneas from sFasL-treated mice displayed relatively more cells undergoing apoptosis. CONCLUSIONS: This study provides evidence that sFasL treatment has potential therapeutic benefit in reducing inflammatory infiltrate and neovascularization in primary and recurrent forms of HSK, and that it does so by augmenting the restriction of Fas+ inflammatory cells mediated by membrane FasL.

Chitosan amphiphile coating of peptide nanofibres reduces liver uptake and delivers the peptide to the brain on intravenous administration.

The clinical development of neuropeptides has been limited by a combination of the short plasma half-life of these drugs and their ultimate failure to permeate the blood brain barrier. Peptide nanofibres have been used to deliver peptides across the blood brain barrier and in this work we demonstrate that the polymer coating of peptide nanofibres further enhances peptide delivery to the brain via the intravenous route. Leucine(5)-enkephalin (LENK) nanofibres formed from the LENK ester prodrug - tyrosinyl(1)palmitate-leucine(5)-enkephalin (TPLENK) were coated with the polymer - N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ) and injected intravenously. Peptide brain delivery was enhanced because the GCPQ coating on the peptide prodrug nanofibres, specifically enables the peptide prodrug to escape liver uptake, avoid enzymatic degradation to non-active sequences and thus enjoy a longer plasma half life. Plasma half-life is increased 520%, liver AUC0-4 decreased by 54% and brain AUC0-4 increased by 47% as a result of the GCPQ coating. The increased brain levels of the GCPQ coated peptide prodrug nanofibres result in the pharmacological activity of the parent drug (LENK) being significantly increased. LENK itself is inactive on intravenous injection.

Glucose-induced down regulation of thiamine transporters in the kidney proximal tubular epithelium produces thiamine insufficiency in diabetes.

Increased renal clearance of thiamine (vitamin B(1)) occurs in experimental and clinical diabetes producing thiamine insufficiency mediated by impaired tubular re-uptake and linked to the development of diabetic nephropathy. We studied the mechanism of impaired renal re-uptake of thiamine in diabetes. Expression of thiamine transporter proteins THTR-1 and THTR-2 in normal human kidney sections examined by immunohistochemistry showed intense polarised staining of the apical, luminal membranes in proximal tubules for THTR-1 and THTR-2 of the cortex and uniform, diffuse staining throughout cells of the collecting duct for THTR-1 and THTR-2 of the medulla. Human primary proximal tubule epithelial cells were incubated with low and high glucose concentration, 5 and 26 mmol/l, respectively. In high glucose concentration there was decreased expression of THTR-1 and THTR-2 (transporter mRNA: -76% and -53% respectively, p<0.001; transporter protein -77% and -83% respectively, p<0.05), concomitant with decreased expression of transcription factor specificity protein-1. High glucose concentration also produced a 37% decrease in apical to basolateral transport of thiamine transport across cell monolayers. Intensification of glycemic control corrected increased fractional excretion of thiamine in experimental diabetes. We conclude that glucose-induced decreased expression of thiamine transporters in the tubular epithelium may mediate renal mishandling of thiamine in diabetes. This is a novel mechanism of thiamine insufficiency linked to diabetic nephropathy.

Glycation of LDL by methylglyoxal increases arterial atherogenicity: a possible contributor to increased risk of cardiovascular disease in diabetes.

OBJECTIVE: To study whether modification of LDL by methylglyoxal (MG), a potent arginine-directed glycating agent that is increased in diabetes, is associated with increased atherogenicity. RESEARCH DESIGN AND METHODS: Human LDL was isolated and modified by MG in vitro to minimal extent (MG(min)-LDL) as occurs in vivo. Atherogenic characteristics of MG(min)-LDL were characterized: particle size, proteoglycan-binding, susceptibility to aggregation, LDL and non-LDL receptor-binding, and aortal deposition. The major site of modification of apolipoprotein B100 (apoB100) modification was investigated by mass spectrometric peptide mapping. RESULTS: MG(min)-LDL contained 1.6 molar equivalents of MG modification-mostly hydroimidazolone-as found in vivo. MG(min)-LDL had decreased particle size, increased binding to proteoglycans, and increased aggregation in vitro. Cell culture studies showed that MG(min)-LDL was bound by the LDL receptor but not by the scavenger receptor and had increased binding affinity for cell surface heparan sulfate-containing proteoglycan. Radiotracer studies in rats showed that MG(min)-LDL had a similar fractional clearance rate in plasma to unmodified LDL but increased partitioning onto the aortal wall. Mass spectrometry peptide mapping identified arginine-18 as the hotspot site of apoB100 modification in MG(min)-LDL. A computed structural model predicted that MG modification of apoB100 induces distortion, increasing exposure of the N-terminal proteoglycan-binding domain on the surface of LDL. This likely mediates particle remodeling and increases proteoglycan binding. CONCLUSIONS: MG modification of LDL forms small, dense LDL with increased atherogenicity that provides a new route to atherogenic LDL and may explain the escalation of cardiovascular risk in diabetes and the cardioprotective effect of metformin.

Sequencing-based genotyping and association analysis of the MICA and MICB genes in type 1 diabetes.

OBJECTIVE: The nonclassical major histocompatibility complex (MHC) class I chain-related molecules (MICs), encoded within the MHC, function in immunity. The transmembrane polymorphism in MICA (MICA-STR) has been reported to be associated with type 1 diabetes. In this study, we directly sequenced both of the highly polymorphic MIC genes (MICA and MICB) in order to establish whether they are associated with type 1 diabetes independently of the known type 1 diabetes MHC class II genes HLA-DRB1 and HLA-DQB1. RESEARCH DESIGN AND METHODS: We developed a sequencing-based typing method and genotyped MICA and MICB in 818 families (2,944 individuals) with type 1 diabetes from the U.K. and U.S. (constructing the genotype from single nucleotide polymorphisms in exons 2-4 of MICA and 2-5 of MICB) and additionally genotyped the MICA-STR in 2,023 type 1 diabetic case subjects and 1,748 control subjects from the U.K. We analyzed the association of the MICA and MICB alleles and genotypes with type 1 diabetes using regression methods. RESULTS: We identified known MICA and MICB alleles and discovered four new MICB alleles. Based on this large-scale and detailed genotype data, we found no evidence for association of MICA and MICB with type 1 diabetes independently of the MHC class II genes (MICA P = 0.08, MICA-STR P = 0.76, MICB P = 0.03, after conditioning on HLA-DRB1 and HLA-DQB1). CONCLUSIONS: Common MICA and MICB genetic variations including the MICA-STR are not associated, in a primary way, with susceptibility to type 1 diabetes.

The candidate genes TAF5L, TCF7, PDCD1, IL6 and ICAM1 cannot be excluded from having effects in type 1 diabetes.

BACKGROUND: As genes associated with immune-mediated diseases have an increased prior probability of being associated with other immune-mediated diseases, we tested three such genes, IL23R, IRF5 and CD40, for an association with type 1 diabetes. In addition, we tested seven genes, TAF5L, PDCD1, TCF7, IL12B, IL6, ICAM1 and TBX21, with published marginal or inconsistent evidence of an association with type 1 diabetes. METHODS: We genotyped reported polymorphisms of the ten genes, nonsynonymous SNPs (nsSNPs) and, for the IL12B and IL6 regions, tag SNPs in up to 7,888 case, 8,858 control and 3,142 parent-child trio samples. In addition, we analysed data from the Wellcome Trust Case Control Consortium genome-wide association study to determine whether there was any further evidence of an association in each gene region. RESULTS: We found some evidence of associations between type 1 diabetes and TAF5L, PDCD1, TCF7 and IL6 (ORs = 1.05 - 1.13; P = 0.0291 - 4.16 x 10-4). No evidence of an association was obtained for IL12B, IRF5, IL23R, ICAM1, TBX21 and CD40, although there was some evidence of an association (OR = 1.10; P = 0.0257) from the genome-wide association study for the ICAM1 region. CONCLUSION: We failed to exclude the possibility of some effect in type 1 diabetes for TAF5L, PDCD1, TCF7, IL6 and ICAM1. Additional studies, of these and other candidate genes, employing much larger sample sizes and analysis of additional polymorphisms in each gene and its flanking region will be required to ascertain their contributions to type 1 diabetes susceptibility.