High Genetic Susceptibility Research Articles

Oxytocin receptor gene and parental bonding modulate prefrontal responses to cries: a NIRS Study

The ability to interpret and regulate emotions relies on experiences of emotional socialization, obtained firstly through the interaction with the parents, and on genetic features that affect how individuals take on social situations. Evidence from the genetic field states that specific allelic variations of the oxytocin receptor gene polymorphisms regulate physiological modulation of human behavior, especially concerning responses to social cues and affiliative behaviors. Starting from this gene-by-environment interaction frame, we assessed 102 young adults for OXTr rs53576 and rs2254298, recalled parental bonding (using the Parental Bonding Instrument), and recorded participants’ neural responses to social stressors using Near InfraRed Spectroscopy (NIRS). The results highlight that higher genetic susceptibility (G/G homozygous) to familiar context and positive early life interactions modulate more optimal neural responses to general social cues, in terms of promptness to action. With regards to the dimensions of parental bonding, we found lateralized effects, with greater activation in the right prefrontal cortex for Care subscales, and on the left side of the prefrontal cortex for Overprotection. Results provide evidence to understand the neurological mechanisms behind the negative impact of poor parenting practices on the child.

Effects of Chronic Artificial Sweetener Consumption on Type 1 Diabetes Susceptibility

As the diabetes epidemic grows worldwide, there is a heightened awareness of how modern day diets may contribute to the increased incidence of disease. To combat the dietary intake of sugar, there has been a drastic increase in the daily consumption of non‐caloric artificial sweeteners (NCAS). However, a number of studies suggest that NCAS cause counterintuitive metabolic derangements that may contribute to negative health outcomes. Conversely, there are limited duration studies focused on weight management suggesting the opposite, thus creating controversy. The impact of chronic NCAS consumption in type 1 diabetes (T1D) patients or those with a high genetic susceptibility for T1D is also unknown. T1D has a strong genetic basis; however, environmental factors likely underlie the rapid increase in T1D incidence in the past few decades. Children with T1D frequently consume NCAS as a way of managing postprandial hyperglycemia and insulin doses. Increased availability of NCAS within the home likely also translates to more NCAS consumption by non‐diabetic siblings with a higher risk to develop T1D. Our study aimed to test the effects of chronic consumption of NCAS subtypes on high T1D susceptibility backgrounds. To test this, we supplemented the diet of T1D susceptible BioBreeding DR+/+ rats with aspartame (metabolized) and acesulfame potassium (Ace‐K+, not metabolized) for three weeks in their drinking water. DR+/+ rats consuming NCAS water had a significant increase in blood glucose versus normal water controls. Metabolomics analysis of plasma from these rats revealed alterations in lipid and energy metabolism, with a greater effect resulting from Ace‐K+. Using a novel mass spectrometry‐based quantification assay we developed, we found that Ace‐K+ also accumulated in the plasma these DR+/+ rats (21+10 μM; N=6) following chronic consumption. Further follow‐up was performed in vitro using rat cardiac microvascular endothelial cells (RCMVECs) to measure cardiometabolic effects. The RCMVECs were treated with an Ace‐K+ dose‐response for three weeks and they exhibited impairment during in vitro tube formation and cell viability tests (p<0.05; N=3). Gene expression analysis of the RCMVECs displayed significant differences in insulin signaling, glucose metabolism, and inflammatory regulation (p<0.05; N=4). In further tests, we also observed that chronic Ace‐K+ consumption accelerated the rate of type 1 diabetes onset in DRlyp/lyp rats. Overall, these results suggest that the accumulation of absorbed intact NCAS subtypes, like Ace‐K+, have the potential to lead to metabolic flux that may be important in pre‐ and post‐onset T1D, whereas the metabolized aspartame caused less fluctuation. We are now focused on translating these studies to a pediatric T1D population and are implementing a novel NCAS food frequency questionnaire and plasma quantification test to better measure consumption clinically.Support or Funding InformationSupport for this project was provided by the Medical College of Wisconsin Clinical and Translational Science Institute, the Mayo Clinic Metabolomics Resource Core (pilot award provided by the U24DK100469 grant to BRH), and the Children’s Research Institute (CRI19301 to MH).

Effect of 15 BMI-Associated Polymorphisms, Reported for Europeans, across Ethnicities and Degrees of Amerindian Ancestry in Mexican Children.

In Mexico, the genetic mechanisms underlying childhood obesity are poorly known. We evaluated the effect of loci, known to be associated with childhood body mass index (BMI) in Europeans, in Mexican children from different ethnic groups. We performed linear and logistic analyses of BMI and obesity, respectively, in Mestizos and Amerindians (Seris, Yaquis and Nahuatl speakers) from Northern (n = 369) and Central Mexico (n = 8545). We used linear models to understand the effect of degree of Amerindian ancestry (AMA) and genetic risk score (GRS) on BMI z-score. Northern Mexican Mestizos showed the highest overweight-obesity prevalence (47.4%), followed by Seri (36.2%) and Central Mexican (31.5%) children. Eleven loci (SEC16B/rs543874, OLFM4/rs12429545/rs9568856, FTO/rs9939609, MC4R/rs6567160, GNPDA2/rs13130484, FAIM2/rs7132908, FAM120AOS/rs944990, LMX1B/rs3829849, ADAM23/rs13387838, HOXB5/rs9299) were associated with BMI and seven (SEC16B/rs543874, OLFM4/rs12429545/rs9568856, FTO/rs9939609, MC4R/rs6567160, GNPDA2 rs13130484, LMX1B/rs3829849) were associated with obesity in Central Mexican children. One SNP was associated with obesity in Northern Mexicans and Yaquis (SEC16B/rs543874). We found higher BMI z-score at higher GRS (β = 0.11, p = 0.2 × 10−16) and at lower AMA (β = −0.05, p = 6.8 × 10−7). The GRS interacts with AMA to increase BMI (β = 0.03, p = 6.08 × 10−3). High genetic BMI susceptibility increase the risk of higher BMI, including in Amerindian children.

Age-related Macular Degeneration (AMD): A Review on its Epidemiology and Risk Factors

Age-related Macular Degeneration (AMD) is a type of maculopathy that results in irreversible visual impairment among the aged population in developed countries. The early stages of AMD can be diagnosed by the presence of drusen beneath the retinal pigment epithelial (RPE) cells. The advanced stages of AMD are geographical atrophy (dry type) and neovascular AMD (wet type), which lead to progressive and severe vision loss. The advanced stage of dry AMD can be identified by extensive large drusen, detachment of the RPE layer and finally degeneration of photoreceptors leading to central vision loss. The late stage of wet AMD is diagnosed by the presence of Choroidal Neovascularization (CNV) identified by Optical Coherence Tomography (OCT) or retinal angiography. The principal of AMD management is to impede the progression of early AMD to advanced levels. Patients with CNV are treated with anti-VEGF (Vascular Endothelial Growth Factor) compounds to inhibit blood vessel growth and thereby reducing vision loss. Although preventive methods for dry AMD are under investigation, there are no proven effective treatments.A variety of environmental and genetic related risk factors are associated with increased incidence and progression of AMD. The genetic factors are found in the complement, angiogenic and lipid pathways. However, environmental factors, such as smoking and nutrition, are also major risk factors. Smoking is a modifiable environmental risk factor, which greatly increases the incidence and progress of AMD compared to non-smokers. There is growing evidence for the positive influence of a healthy diet containing high levels of anti-oxidant supplements. The reduction of serum lipids is another effective strategy for prevention AMD. Although no single preventive approach has been identified, knowing the high risk factors of AMD, along with modification of lifestyle is important for this multifactorial disease, especially in populations with higher genetic susceptibility. Though recent progress in early diagnosis of the disease has facilitated early and efficient intervention, further studies are required to gain more clarification of specific pathophysiology.In spite of decades of focused research on AMD, the pathogenesis of AMD is still not completely understood. Recently, numerous novel methods, including imaging techniques, new drug delivery routes, and therapeutic strategies, are improving the management of AMD. In this review, we discuss the current knowledge related to epidemiology and classifications of AMD.

Genetic susceptibility, lifestyle intervention and glycemic changes among women with prior gestational diabetes.

Women with prior gestational diabetes mellitus (GDM) or high genetic susceptibility are prone to development of type 2 diabetes. We examined whether a lifestyle intervention modified the genetic effect on changes in glycemic markers among women with prior GDM. This study included 560 women with prior GDM from a randomized controlled trial, the Tianjin Gestational Diabetes Mellitus Prevention Program, who were assigned into an intervention arm (improved physical activity and healthy dietary intakes) or a control arm. We assessed associations of GDM related genetic variants in/near the CDKAL1 (rs7754840) and MTNR1B (rs10830962) genes with changes in fasting levels of glucose and insulin, β-cell function (HOMA-B) and insulin resistance (HOMA-IR) at 1 year and 2 years after the baseline. We found significant interactions between CDKAL1 variant rs7754840 and lifestyle intervention on changes in fasting insulin and HOMA-IR at 1 year (P for interactions=0.008 and 0.006, respectively). The GDM-increasing C allele was associated with a 0.07-unit greater increase in fasting insulin (P=0.048) and HOMA-IR (P=0.045) in the control group, while opposite-directional associations were observed in the intervention group; women with the C allele seemed to decrease more in these glycemic markers than the non-C-carriers (both P≤0.06). The interactions between the CDKAL1 genetic variant and lifestyle intervention on changes in fasting insulin (P=0.035) and HOMA-IR (P=0.024) remained significant over the 2-year period, even though the effects of lifestyle intervention were attenuated at 2-year. The MTNR1B variant rs10830962 did not show interaction with lifestyle intervention on changes in the glycemic markers. Healthy lifestyle intervention may be beneficial for women with the GDM predisposing CDKAL1 genetic variant in improvement of insulin resistance. ClinicalTrials.gov NCT01554358. URL OF REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01554358.

Trajectories and Predictors of Children's Early-Starting Conduct Problems: Child, Family, Genetic, and Intervention Effects.

Several research teams have previously traced patterns of emerging conduct problems (CP) from early or middle childhood. The current study expands on this previous literature by using a genetically-informed, experimental, and long-term longitudinal design to examine trajectories of early-emerging conduct problems and early childhood discriminators of such patterns from the toddler period to adolescence. The sample represents a cohort of 731 toddlers and diverse families recruited based on socioeconomic, child, and family risk, varying in urbanicity and assessed on nine occasions between ages 2 and 14. In addition to examining child, family, and community level discriminators of patterns of emerging conduct problems, we were able to account for genetic susceptibility using polygenic scores and the study's experimental design to determine whether random assignment to the Family Check-Up (FCU) discriminated trajectory groups. In addition, in accord with differential susceptibility theory, we tested whether the effects of the FCU were stronger for those children with higher genetic susceptibility. Results augmented previous findings documenting the influence of child (inhibitory control [IC], gender) and family (harsh parenting, parental depression, and educational attainment) risk. In addition, children in the FCU were overrepresented in the persistent low versus persistent high CP group, but such direct effects were qualified by an interaction between the intervention and genetic susceptibility that was consistent with differential susceptibility. Implications are discussed for early identification and specifically, prevention efforts addressing early child and family risk.

Role of polygenic risk in susceptibility to accelerated pubertal onset following chronic stress exposure.

Previous finding suggests that children growing up under chronic stress tend to experience earlier sexual maturity. The present study aims to examine polygenic risk by experience interaction in predicting pubertal timing, as well as provide insight regarding the relevance of two G × E paradigms. Data were analyzed from a 3-year prospective puberty cohort in Anhui Province, China. Breast Tanner stage and testicular volume (TV) of 997 children were annually assessed. The polygenic risk score (PRS) was computed based on 17 SNPs for early pubertal timing. Hair cortisol concentrations (HCC) were assessed in the first 3 cm hair segment as a biological marker of chronic stress. Comparing with participants under moderate levels of stress as measured by HCC, the puberty-accelerating effects of chronic stress were only observed among girls with moderate (1.7 months earlier, P = 0.007) and low genetic susceptibility (2.2 months earlier, P < 0.001) and among boys with high genetic susceptibility (2.0 months earlier, P = 0.005). Polygenic differences (PRSs) in age at thelarche was most prominent in those with low levels of stress by HCC (9.06, 9.36 and 9.53 years for high, moderate and low PRS, respectively; F = 105.06, P < 0.0001), while polygenic differences in age at TV ≥4 mL was strongest in those under chronic stress (10.91, 11.06 and 11.17 years for high, moderate and low PRS, respectively; F = 100.48, P < 0.0001). Chronic stress predicts earlier age at pubertal onset in a sex-specific and genetic background-dependent manner. The bioecological G × E model for girls and diathesis stress model for boys in pubertal timing warrants further investigation.

Dietary Zinc and Risk of Prostate Cancer in Spain: MCC-Spain Study.

Zinc is a key trace element in normal prostate cell metabolism, and is decreased in neoplastic cells. However, the association between dietary zinc and prostate cancer (PC) in epidemiologic studies is a conflicting one. Our aim was to explore this association in an MCC-Spain case-control study, considering tumor aggressiveness and extension, as well as genetic susceptibility to PC. 733 incident cases and 1228 population-based controls were included for this study. Dietary zinc was assessed using a food frequency questionnaire, and genetic susceptibility was assessed with a single nucleotide polymorphisms (SNP)-based polygenic risk score (PRS). The association between zinc intake and PC was evaluated with mixed logistic and multinomial regression models. They showed an increased risk of PC in those with higher intake of zinc (Odds Ratio (OR) tertile 3vs1: 1.39; 95% Confidence interval (CI):1.00–1.95). This association was mainly observed in low grade PC (Gleason = 6 RRR tertile 3vs1: 1.76; 95% CI:1.18–2.63) as well as in localized tumors (cT1-cT2a RRR tertile 3vs1: 1.40; 95% CI:1.00–1.95) and among those with higher PRS (OR tertile 3vs1: 1.50; 95% CI:0.89–2.53). In conclusion, a higher dietary zinc intake could increase the risk of low grade and localized tumors. Men with higher genetic susceptibility might also have a higher risk of PC associated with this nutrient intake.

Considerations on the use of the terms radiosensitivity and radiosusceptibility

The separate use of the terms ‘radiosensitivity’ and ‘radiosusceptibility’ has been suggested to describe variability in the risk of, respectively, adverse tissue reactions (deterministic effect) following radiotherapy and radiation-induced cancer (stochastic effect). The aim of this note is to present arguments against such distinction. We feel that it is premature to make a concrete final judgement on these definitions because of the limited understanding of the mechanisms underlying individual sensitivity to both radiation-related cancers and radiation-related tissue injury. Moreover, the exclusive application of ‘radiosensitivity’ in relation to deterministic effects and the term ‘radiosusceptibility’ in relation to cancer carries the risk of being wrongly interpreted as evidence for a high, genetically driven sensitivity to radiation in all patients who develop adverse tissue reactions and a high genetic susceptibility to cancer in those who develop radiation-induced malignancies. There is a need for further research to better define these phenomena and their interrelationships.

Genetic factors in schizophrenia linked to response to lithium

Patients with bipolar disorder who had a high genetic susceptibility to schizophrenia showed weaker response to lithium, according to a genomewide association study published online Nov. 9, 2017, in JAMA Psychiatry. This research is believed to offer the first evidence that genetic characterization can help guide clinicians' medication treatment decision‐making for patients with bipolar disorder.

Polygenic risk for alcohol consumption and its association with alcohol-related phenotypes: Do stress and life satisfaction moderate these relationships?

BackgroundGenetic and environmental factors contribute about equally to alcohol-related phenotypes in adulthood. In the present study, we examined whether more stress at home or low satisfaction with life might be associated with heavier drinking or more alcohol-related problems in individuals with a high genetic susceptibility to alcohol use. MethodsInformation on polygenic scores and drinking behavior was available in 6705 adults (65% female; 18–83 years) registered with the Netherlands Twin Register. Polygenic risk scores (PRSs) were constructed for all subjects based on the summary statistics of a large genome-wide association meta-analysis on alcohol consumption (grams per day). Outcome measures were quantity of alcohol consumption and alcohol-related problems assessed with the Alcohol Use Disorders Identification Test (AUDIT). Stress at home and life satisfaction were moderating variables whose significance was tested by Generalized Estimating Equation analyses taking familial relatedness, age and sex into account. ResultsPRSs for alcohol were significantly associated with quantity of alcohol consumption and alcohol-related problems in the past year (R2=0.11% and 0.10% respectively). Participants who reported to have experienced more stress in the past year and lower life satisfaction, scored higher on alcohol-related problems (R2=0.27% and 0.29 respectively), but not on alcohol consumption. Stress and life satisfaction did not moderate the association between PRSs and the alcohol outcome measures. ConclusionsThere were significant main effects of polygenic scores and of stress and life satisfaction on drinking behavior, but there was no support for PRS-by-stress or PRS-by-life satisfaction interactions on alcohol consumption and alcohol-related problems.

Frequency and phenotype of type 1 diabetes in the first six decades of life: a cross-sectional, genetically stratified survival analysis from UK Biobank

SummaryBackgroundType 1 diabetes is typically considered a disease of children and young adults. Genetic susceptibility to young-onset type 1 diabetes is well defined and does not predispose to type 2 diabetes. It is not known how frequently genetic susceptibility to type 1 diabetes leads to a diagnosis of diabetes after age 30 years. We aimed to investigate the frequency and phenotype of type 1 diabetes resulting from high genetic susceptibility in the first six decades of life.MethodsIn this cross-sectional analysis, we used a type 1 diabetes genetic risk score based on 29 common variants to identify individuals of white European descent in UK Biobank in the half of the population with high or low genetic susceptibility to type 1 diabetes. We used Kaplan-Meier analysis to evaluate the number of cases of diabetes in both groups in the first six decades of life. We genetically defined type 1 diabetes as the additional cases of diabetes that occurred in the high genetic susceptibility group compared with the low genetic susceptibility group. All remaining cases were defined as type 2 diabetes. We assessed the clinical characteristics of the groups with genetically defined type 1 or type 2 diabetes.Findings13 250 (3·5%) of 379 511 white European individuals in UK Biobank had developed diabetes in the first six decades of life. 1286 more cases of diabetes were in the half of the population with high genetic susceptibility to type 1 diabetes than in the half of the population with low genetic susceptibility. These genetically defined cases of type 1 diabetes were distributed across all ages of diagnosis; 537 (42%) were in individuals diagnosed when aged 31–60 years, representing 4% (537/12 233) of all diabetes cases diagnosed after age 30 years. The clinical characteristics of the group diagnosed with type 1 diabetes when aged 31–60 years were similar to the clinical characteristics of the group diagnosed with type 1 diabetes when aged 30 years or younger. For individuals diagnosed with diabetes when aged 31–60 years, the clinical characteristics of type 1 diabetes differed from those of type 2 diabetes: they had a lower BMI (27·4 kg/m2 [95% CI 26·7–28·0] vs 32·4 kg/m2 [32·2–32·5]; p<0·0001), were more likely to use insulin in the first year after diagnosis (89% [476/537] vs 6% [648/11 696]; p<0·0001), and were more likely to have diabetic ketoacidosis (11% [61/537] vs 0·3% [30/11 696]; p<0·0001).InterpretationGenetic susceptibility to type 1 diabetes results in non-obesity-related, insulin-dependent diabetes, which presents throughout the first six decades of life. Our results highlight the difficulty of identifying type 1 diabetes after age 30 years because of the increasing background prevalence of type 2 diabetes. Failure to diagnose late-onset type 1 diabetes can have serious consequences because these patients rapidly develop insulin dependency.FundingWellcome Trust and Diabetes UK.

Is there a dose-dependent effect of genetic susceptibility loci for gastric cancer on prognosis of the patients?

Literature suggests that genetic variants associated with increased susceptibility to gastric cancer (GCa) are mostly located in genes involved in carcinogenesis and possibly tumor progression. Therefore, we hypothesize that high genetic susceptibility is also associated with prognosis of the patients. To test this hypothesis, we selected a total of 42 common genetic variants that were reportedly associated with GCa risk with a high level of evidence obtained from either genome-wide association studies (GWASs) or meta-analyses and performed survival analysis of patients used in a case-control analysis. We first used 1115 GCa cases and 1172 cancer-free controls of ethnic Han Chinese to construct a weighted genetic risk score (GRS). Then, we included 633 GCa cases with available clinical information, fit GRS in a fractional polynomial Cox proportional hazards regression model to investigate whether there is a dose-dependent effect of GRS on risk of death in survival analysis. Dynamic predictive value of genetic risk for prognosis was also calculated. The results showed that the increase of GRS had no effect on risk of death in these GCa patients. Compared with GCa patients with the medium GRS, there was no significant difference in survival in patients with either a low (P = 0.349) or a high (P = 0.847) GRS. The results unchanged when data were stratified by tumor stage and Laurens classification. Time-dependent predictive value for prognosis in considering both clinical factors and GRS was comparable with that in considering clinical factors alone, for either all patients (P = 0.986) or stage- and Laruen type-based subgroups (P > 0.05 for all). In conclusion, higher polygenic susceptibility loci for GCa may not indicate worse prognosis of Chinese patients. Additional variants of relevant genes modulating GCa patients survival need to be further identified.

Cognitive Profiling Useful for Unraveling Cross-Disorder Mechanisms

Cognitive subtyping may be essential for understanding shared mechanisms underlying attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Participants from a population-based sample ( n = 360) and an ASD/ADHD clinic-based sample ( n = 254), ages 5 to 17 years, were administered a broad cognitive battery. Latent class analyses revealed a similar four-cognitive-class solution in both samples mainly characterized by speed–accuracy tradeoff differences instead of specific strengths and weaknesses. The classes were strongly predictive of both ASD and ADHD (and comorbid) symptoms in the clinical, but not the population, sample. Results support the hypothesis that both disorders are manifestations of the same overarching disorder and illustrate the effectiveness of subtyping based on cognitive profiles. Results also support a step-function endophenotype model, in which cognitive problems mediate the gene–psychopathology associations but only in a clinically relevant way in the subgroup of children with high genetic susceptibility. Pre-onset longitudinal research is needed to corroborate this.

Caffeine intake and genetic susceptibility to Parkinson's disease

Objectives: The interaction between caffeine intake and genetic susceptibility to Parkinson's disease (PD) has seldom been studied We examined if caffeine intake has a differential effect in subjects with high and low genetic susceptibility to Parkinson’s disease (PD), a common neurodegenerative disorder.

Differential effect of caffeine intake in subjects with genetic susceptibility to Parkinson's Disease.

We examined if caffeine intake has a differential effect in subjects with high and low genetic susceptibility to Parkinson’s disease (PD), a common neurodegenerative disorder. A case control study involving 812 subjects consisting of PD and healthy controls were conducted. Caffeine intake assessed by a validated questionnaire and genotyping of PD gene risk variant (LRRK2 R1628P) was carried out. Compared to caffeine takers with the wild-type genotype (low genetic susceptibility), non-caffeine takers with R1628P variant (high genetic susceptibility) had a 15 times increased risk of developing PD (OR = 15.4, 95% CI = (1.94, 122), P = 0.01), whereas caffeine takers with R1628P (intermediate susceptibility) had a 3 times risk (OR = 3.07, 95% CI = (2.02, 4.66), P < 0.001). Caffeine intake would significantly reduce the risk of PD much more in those with high genetic susceptibility compared to those with low genetic susceptibility.

Therapy-Related Myeloid Neoplasms.

In the 2008 World Health Organization classification, cases of acute myeloid leukemia (AML) and myelodysplastic syndrome that arise after chemotherapy or radiation therapy for a primary neoplasm are considered together as therapy-related myeloid neoplasms (TR-MNs). This concept, however, is not universally accepted since there are confounding variables in attributing myeloid neoplasms to earlier therapies. Cases in session 6 of the 2013 Workshop of the Society for Hematopathology/European Association for Haematopathology illustrated myeloid neoplasms thought likely to be TR-MNs, and discussed the differences and biologic similarities with de novo myeloid neoplasms. We reviewed data showing that diagnosis of TR-MN alters patient outcome only in specific subsets. The session also included examples of therapy-related AML with recurrent genetic abnormalities, such as t(15;17), inv(16), and t(8;21), and reports were highlighted showing that patients with these neoplasms have clinical outcomes similar to patients with their de novo counterparts. The study of TR-MNs will likely provide insight into the pathogenesis of de novo myeloid disease and may explain why some patients with cancer develop TR-MN and evidently have a higher genetic susceptibility, whereas most patients treated with the same agents do not. These studies will also result in critical reappraisal of current concepts related to TR-MNs.

Family history and ethnicity influencing clinical presentation of type 1 diabetes in childhood.

A different clinical presentation of type 1 diabetes (T1DM) could be supposed in children belonging to different ethnicities, with or without family history of autoimmunity. This study investigates the effect of ethnicity and family history of T1DM on clinical characteristics at presentation in a group of T1DM children. One hundred ninety-six T1DM children <18years, consecutively diagnosed during the years 2011-2014, were studied including 91% of Caucasians of Italian ancestry and 9% of non-Caucasian origin. Children with 1st or 2nd degree relatives affected by T1DM were younger at disease onset (p=0.005) and showed lower HbA1C levels (p=0.002), and higher IAA levels (p=0.01). Non-Caucasian children were younger at disease onset (p=0.029), and showed more severe hyperglycemia (p=0.008) and ketoacidosis (pH p<0.001). HbA1C levels were negatively related to positive family history of T1DM (p=0.01), fasting C-peptide levels (p=0.003), IAA levels (p=0.03), and IA-2 levels (p=0.003). The level of pH was positively influenced by fasting C-peptide (p=0.004), and negatively impacted by C-reactive protein (p=0.01) and non-Caucasian ethnicity (p=0.03). The milder metabolic decompensation in children with a positive family history of T1DM is probably explained by the awareness of the families in terms of early symptoms of T1DM, while the younger age at onset and the higher levels of autoantibodies may suggest a stronger genetic susceptibility, associated with a more aggressive autoimmune process. The younger age in non-Caucasian children is probably explained by the higher genetic susceptibility in subjects belonging to ethnic groups with a low T1DM incidence. Social aspects and poor living conditions probably predominate in determining the increased severity of metabolic decompensation at onset in children from non-Caucasian ethnicities.

5-HTTLPR×interpersonal stress interaction and nonsuicidal self-injury in general community sample of youth

No research with youth has investigated whether measured genetic risk interacts with stressful environment (G⁎E) to explain engagement in non-suicidal self-injury (NSSI). Two independent samples of youth were used to test the a priori hypothesis that the Transporter-Linked Polymorphic Region (5-HTTLPR) would interact with chronic interpersonal stress to predict NSSI. We tested this hypothesis with children and adolescents from United States public schools in two independent samples (N׳s=300 and 271) using identical procedures and methods. They were interviewed in person with the Self-Injurious Thoughts and Behaviors Interview to assess NSSI engagement and with the UCLA Chronic Stress Interview to assess interpersonal stress. Buccal cells were collected for genotyping of 5-HTTLPR. For both samples, ANOVAs revealed the hypothesized G⁎E. Specifically, short carriers who experienced severe interpersonal stress exhibited the highest level of NSSI engagement. Replicated across two independent samples, results provide the first demonstration that youth at high genetic susceptibility (5-HTTLPR) and high environmental exposure (chronic interpersonal stress) are at heightened risk for NSSI.

Abstract 281: Diabetes in India: Insights from PINNACLE India Outpatient Registry

Background: India may have the largest diabetes (DM) population in the world. Indians have high genetic susceptibility and a low threshold for risk factors. Prevention, delay through lifestyle intervention or drug therapy has proven effective in all ethnic groups. Thus surveillance of vulnerable populations through a cardiovascular (CV) registry can assist in targeting opportunities for intervention. Methods: PINNACLE India is the first CV data collection and reporting program in India. Data are collected by transmission from paper scanners and an electronic data collection tool. Patients are followed longitudinally if they return to a data collecting site. Results: DM is documented in 14.5% of patients and 17.1% of encounters. Mean glucose was 125 mg/dL and 28.4% of values fell above 130 mg/dL. Among HbA1c values, 88.7% were high. For documented DMs, mean total cholesterol was 137.6 mg/dL, LDL was 87.8 mg/dL, HDL was 32.3 mg/dL and triglycerides were 133.7 mg/dL. Conclusion: Cholesterol is well managed among diagnosed DMs. Blood sugar is not well managed and indicates a significant number of undiagnosed DMs. DM appears underdocumented, underdiagnosed, and sub-optimally managed in the registry population. In the US, an estimated 7 million DMs are undiagnosed. A similar or higher proportion is likely in India. Reducing risk of CV disease requires prevention for non-DMs and management of those diagnosed. Data suggest a focus on DM diagnosis and management as opposed to lipid control for already diagnosed DMs.