Genetic Risk For Type Research Articles

252-OR: Failed Genetic Protection: Type 1 Diabetes in the Presence of HLA-DQB1*06:02

Human leucocyte antigen (HLA) class II genes confer significant genetic risk for type 1 diabetes (T1D) development and protection. The dominant protection afforded by the DRB1*15:01 (DR15)-DQA1*01:02-DQB1*06:02 (DQ6) haplotype across all stages of T1D is well documented. This is a common haplotype found in Caucasians but present in <1% of people with T1D. Knowing which metabolic, immunologic and genetic features are unique to individuals who fail genetic protection and develop T1D is important for defining the underlying mechanisms of DQB1*06:02-mediated protection. We describe a T1D cohort with DQB1*06:02 (n=50) and compare them to a T1D cohort lacking DQB1*06:02 (n=2,759), which were both identified over the last 26 years at the Barbara Davis Center, a large tertiary referral center in the Rocky Mountain Region. As expected, the average A1C was 10.8 ± 2.8% at diagnosis in 0602+ individuals. The age at diagnosis was similar between the 0602+ and 0602- participants (10.8 ± 6.0 vs. 12.5 ± 8.7 years, respectively, p=0.069) and normally distributed throughout childhood and early adulthood. The majority of 0602+ individuals with T1D were positive for one or more islet autoantibodies; however, there was a greater proportion that were islet autoantibody negative compared to 0602- individuals with T1D (p=0.004). The presence of autoantibodies directed against insulinoma antigen-2 (IA-2) was less common in 0602+ individuals (p=0.005), while the percentage of antibodies directed against GAD65, insulin and zinc transporter 8 were similar between 0602+ and 0602- individuals. Interestingly, the DQ allele on the other chromosome, DQB1*03:02 (DQ8) which confers significant T1D risk, was present in 0602+ individuals with islet autoantibodies and not in individuals without autoantibodies (p=0.002). In conclusion, studying the clinical, immunologic and genetic features of individuals that failed genetic protection holds promise for understanding mechanisms that ultimately lead to beta cell destruction in T1D. Disclosure K. Simmons: None. A.M. Mitchell: None. A. Alkanani: None. K. McDaniel: None. E. Baschal: None. T. Armstrong: None. L. Pyle: None. L. Yu: None. A.W. Michels: Other Relationship; Self; ImmunoMolecular Therapeutics, LLC. Funding National Institutes of Health (DK095995, DK108868, DK110845, DK032083, K12DK094712-08); JDRF/Children’s Diabetes Foundation (2-SRA-2016-202-5-B); Colorado Clinical and Translational Science Institute (TR001082)

Genetic Risk for Type 2 Diabetes is Associated With Impaired Structural Brain Connectivity and Worse Cognitive Performance in Nondiabetic Patients With Major Depressive Disorder

Genetic Risk for Type 2 Diabetes is Associated With Impaired Structural Brain Connectivity and Worse Cognitive Performance in Nondiabetic Patients With Major Depressive Disorder

HLA class II genotyping of admixed Brazilian patients with type 1 diabetes according to self-reported color/race in a nationwide study

The HLA region is responsible for almost 50% of the genetic risk of type 1 diabetes (T1D). However, haplotypes and their effects on risk or protection vary among different ethnic groups, mainly in an admixed population. We aimed to evaluate the HLA class II genetic profile of Brazilian individuals with T1D and its relationship with self-reported color/race. This was a nationwide multicenter study conducted in 10 Brazilian cities. We included 1,019 T1D individuals and 5,116 controls matched for the region of birth and self-reported color/race. Control participants belonged to the bone marrow transplant donor registry of Brazil (REDOME). HLA-class II alleles (DRB1, DQA1, and DQB1) were genotyped using the SSO and NGS methods. The most frequent risk and protection haplotypes were HLA~DRB1*03:01~DQA1*05:01 g~DQB1*02:01 (OR 5.8, p < 0.00001) and HLA~DRB1*07:01~DQA1*02:01~DQB1*02:02 (OR 0.54, p < 0.0001), respectively, regardless of self-reported color/race. Haplotypes HLA~DRB1*03:01~DQA1*05:01 g~DQB1*02:01 and HLA~DRB1*04:02~DQA1*03:01 g~DQB1*03:02 were more prevalent in the self-reported White group than in the Black group (p = 0.04 and p = 0.02, respectively). The frequency of haplotype HLA~DRB1*09:01~DQA1*03:01 g~DQB1*02:02 was higher in individuals self-reported as Black than White (p = <0.00001). No difference between the Brazilian geographical regions was found. Individuals with T1D presented differences in frequencies of haplotypes within self-reported color/race, but the more prevalent haplotypes, regardless of self-reported color/race, were the ones described previously in Europeans. We hypothesize that, in the T1D population of Brazil, although highly admixed, the disease risk alleles come mostly from Europeans as a result of centuries of colonization and migration.

Obesity, unfavourable lifestyle and genetic risk of type 2 diabetes: a case-cohort study.

We aimed to investigate whether the impact of obesity and unfavourable lifestyle on type 2 diabetes risk is accentuated by genetic predisposition. We examined the joint association of genetic predisposition, obesity and unfavourable lifestyle with incident type 2 diabetes using a case-cohort study nested within the Diet, Cancer and Health cohort in Denmark. The study sample included 4729 individuals who developed type 2 diabetes during a median 14.7years of follow-up, and a randomly selected cohort sample of 5402 individuals. Genetic predisposition was quantified using a genetic risk score (GRS) comprising 193 known type 2 diabetes-associated loci (excluding known BMI loci) and stratified into low (quintile 1), intermediate and high (quintile 5) genetic risk groups. Lifestyle was assessed by a lifestyle score composed of smoking, alcohol consumption, physical activity and diet. We used Prentice-weighted Cox proportional-hazards models to test the associations of the GRS, obesity and lifestyle score with incident type 2 diabetes, as well as the interactions of the GRS with obesity and unfavourable lifestyle in relation to incident type 2 diabetes. Obesity (BMI ≥ 30kg/m2) and unfavourable lifestyle were associated with higher risk for incident type 2 diabetes regardless of genetic predisposition (p > 0.05 for GRS-obesity and GRS-lifestyle interaction). The effect of obesity on type 2 diabetes risk (HR 5.81 [95% CI 5.16, 6.55]) was high, whereas the effects of high genetic risk (HR 2.00 [95% CI 1.76, 2.27]) and unfavourable lifestyle (HR 1.18 [95% CI 1.06, 1.30]) were relatively modest. Even among individuals with low GRS and favourable lifestyle, obesity was associated with a >8-fold risk of type 2 diabetes compared with normal-weight individuals in the same GRS and lifestyle stratum. Having normal body weight is crucial in the prevention of type 2 diabetes, regardless of genetic predisposition.

P.226 Genetic risk for type 2 diabetes is associated with brain connectivity, cognition and disease severity in depression

P.226 Genetic risk for type 2 diabetes is associated with brain connectivity, cognition and disease severity in depression

Dietary Fat and the Genetic Risk of Type 2 Diabetes

We review recent evidence of the relationship between dietary fat intake and risk of type 2 diabetes (T2D), the role of epigenetic alterations as a mediator of this relationship, and the impact of gene-dietary fat interactions in the development of the disease. Based on the observations made, we will discuss whether there is evidence to support genetic personalization of fat intake recommendations in T2D prevention. Strong evidence suggests that polyunsaturated fatty acids (PUFA) have a protective effect on T2D risk, whereas the roles of saturated and monounsaturated fatty acids (SFA and MUFA) remain unclear. Diets enriched with PUFA vs SFA lead to distinct epigenetic alterations that may mediate their effects on T2D risk by changing gene function. However, it is not currently known which of the epigenetic alterations, if any, are causal for T2D. The current literature shows no replicated evidence of genetic variants modifying the effect of dietary fat intake on T2D risk. There is consistent evidence of a protective role of PUFA in T2D prevention. No evidence supports genetic personalization of dietary recommendations in T2D prevention.

Additive and Multiplicative Interactions Between Genetic Risk Score and Family History and Lifestyle in Relation to Risk of Type 2 Diabetes.

We examined interactions between lifestyle factors and genetic risk of type 2 diabetes (T2D-GR), captured by genetic risk score (GRS) and family history (FH). Our initial study cohort included 20,524 European-ancestry participants, of whom 1,897 developed incident T2D, in the Nurses' Health Study (1984-2016), Nurses' Health Study II (1989-2016), and Health Professionals Follow-up Study (1986-2016). The analyses were replicated in 19,183 European-ancestry controls and 2,850 incident T2D cases in the Women's Genome Health Study (1992-2016). We defined 2 categories of T2D-GR: high GRS (upper one-third) with FH and low GRS or without FH. Compared with participants with the healthiest lifestyle and low T2D-GR, the relative risk of T2D for participants with the healthiest lifestyle and high T2D-GR was 2.24 (95% confidence interval (CI): 1.76, 2.86); for participants with the least healthy lifestyle and low T2D-GR, it was 4.05 (95% CI: 3.56, 4.62); and for participants with the least healthy lifestyle and high T2D-GR, it was 8.72 (95% CI: 7.46, 10.19). We found a significant departure from an additive risk difference model in both the initial and replication cohorts, suggesting that adherence to a healthy lifestyle could lead to greater absolute risk reduction among those with high T2D-GR. The public health implication is that a healthy lifestyle is important for diabetes prevention, especially for individuals with high GRS and FH of T2D.

Quality of dietary fat and genetic risk of type 2 diabetes: individual participant data meta-analysis

Quality of dietary fat and genetic risk of type 2 diabetes: individual participant data meta-analysis

Quality of dietary fat and genetic risk of type 2 diabetes: individual participant data meta-analysis

ObjectiveTo investigate whether the genetic burden of type 2 diabetes modifies the association between the quality of dietary fat and the incidence of type 2 diabetes.DesignIndividual participant data meta-analysis.Data sourcesEligible...

Common patterns of gene regulation associated with Cesarean section and the development of islet autoimmunity \u2013 indications of immune cell activation

Birth by Cesarean section increases the risk of developing type 1 diabetes later in life. We aimed to elucidate common regulatory processes observed after Cesarean section and the development of islet autoimmunity, which precedes type 1 diabetes, by investigating the transcriptome of blood cells in the developing immune system. To investigate Cesarean section effects, we analyzed longitudinal gene expression profiles from peripheral blood mononuclear cells taken at several time points from children with increased familial and genetic risk for type 1 diabetes. For islet autoimmunity, we compared gene expression differences between children after initiation of islet autoimmunity and age-matched children who did not develop islet autoantibodies. Finally, we compared both results to identify common regulatory patterns. We identified the pentose phosphate pathway and pyrimidine metabolism - both involved in nucleotide synthesis and cell proliferation - to be differentially expressed in children born by Cesarean section and after islet autoimmunity. Comparison of global gene expression signatures showed that transcriptomic changes were systematically and significantly correlated between Cesarean section and islet autoimmunity. Moreover, signatures of both Cesarean section and islet autoimmunity correlated with transcriptional changes observed during activation of isolated CD4+ T lymphocytes. In conclusion, we identified shared molecular changes relating to immune cell activation in children born by Cesarean section and children who developed autoimmunity. Our results serve as a starting point for further investigations on how a type 1 diabetes risk factor impacts the young immune system at a molecular level.

GWAS Identifies Risk Locus for Erectile Dysfunction and Implicates Hypothalamic Neurobiology and Diabetes in Etiology

Erectile dysfunction (ED) is a common condition affecting more than 20% of men over 60 years, yet little is known about its genetic architecture. We performed a genome-wide association study of ED in 6,175 case subjects among 223,805 European men and identified one locus at 6q16.3 (lead variant rs57989773, OR 1.20 per C-allele; p = 5.71 × 10−14), located between MCHR2 and SIM1. In silico analysis suggests SIM1 to confer ED risk through hypothalamic dysregulation. Mendelian randomization provides evidence that genetic risk of type 2 diabetes mellitus is a cause of ED (OR 1.11 per 1-log unit higher risk of type 2 diabetes). These findings provide insights into the biological underpinnings and the causes of ED and may help prioritize the development of future therapies for this common disorder.

Dietary Fat Quality and Genetic Risk of Type 2 Diabetes

Background: Type 2 diabetes (T2D) is a complex disease driven by lifestyle and genetic factors. The extent to which dietary fat quality may modify T2D genetic burden on the incidence of T2D is unknown. Methods: We used Cox proportional-hazards models to calculate adjusted hazard ratios (HRs) for T2D among 103,2participants of European descent from 15 prospective cohort studies. T2D genetic risk profile was characterized by a 68-variant genetic risk score (GRS) weighted by published effect sizes. Diet was recorded using validated cohort-specific dietary assessment tools. Findings: During a median follow-up of 12 years, 20,451 participants developed T2D. The relative risk of T2D per increment of 10 risk alleles in the GRS was 1.68 (95% confidence interval [CI] 1.62-1.74). Increasing monounsaturated fat intake in place of carbohydrates was associated with a higher risk of T2D (HR per 5% of energy 1.08, 95% CI 1.02-1.15), while increasing polyunsaturated or total ω-3 fat intake in place of carbohydrates was associated with a lower risk of T2D (HR per 5% of energy 0.92, 95% CI 0.85-1.00; and HR per increment of 1g/d 0.95, 95% CI, 0.92-0.99, respectively). We did not observe evidence of significant interactions between dietary fat subtypes and GRS on the risk of T2D. Interpretation: In the present long-term prospective study including 103,2participants, our results support that genetic risk profile and monounsaturated fat intake were each associated with a higher risk of T2D, whereas polyunsaturated fat intake was associated with a lower risk of T2D. Findings from this study suggest that dietary fat recommendations do not need to be tailored to individual T2D genetic risk profile for the primary prevention of T2D, and that dietary fat subtypes associate with the risk of T2D across the spectrum of T2D genetic risk. Disclosure J. Merino: None. H.S. Dashti: None. M. Guasch: None. C. Ellervik: None. C. Smith: None. T.O. Kilpelainen: None. D. Chasman: None. J.C. Florez: Consultant; Self; Intarcia Therapeutics, Inc.. Consultant; Spouse/Partner; Santen.

Association of Maternal and Offspring Genetic Risk for Type 2 Diabetes with Offspring Birth Weight among African-Ancestry Populations

Background: Mother’s genetic risk for type 2 diabetes (T2D) may influence intra-uterine glycemia leading to increased birth weight. However, the U-shaped relation between offspring birthweight and later-life T2D risk suggests that relations of offspring’s T2D genetic susceptibility with birthweight may be U-shaped. Methods: We investigated the effects of maternal and offspring genetic risk for T2D on birthweight using genotype data from 949 mother-offspring pairs of African ancestry from the Hyperglycemia Adverse Pregnancy Outcome study. We generated a genetic risk score for T2D (dGRS) for mothers and offspring as the weighted sum of 90 T2D risk alleles. Offspring dGRS was separately calculated for birth weight-reducing and -increasing alleles based on the direction of correlation between a T2D-risk allele and birthweight in our data. We used linear regression adjusting for maternal and offspring covariates and the proportion of African ancestry to estimate the change in birthweight by quartiles of maternal and offspring dGRS. Results: Changes in birthweight across increasing quartiles of mother’s dGRS were 0 (reference), 83.3g (95% CI: 6.7, 160.0), 102g (95% CI: 25.1, 179.5), and 92.9g (95% CI: 12.7, 173.1) (P-trend=0.042). In contrast, changes in birthweight across increasing quartiles of offspring dGRS based on birthweight-reducing alleles were 0, −105.7g (95% CI: −180.9, −30.5), −105.5g (95% CI: −180.4, −30.5), and −143.2g (95% CI: −218.6, −67.8) (P-trend=0.001), whereas those of dGRS based on birthweight-increasing alleles were 0, 15.3g (95% CI: −60.7, 91.3), 113.3g (95% CI: 38.1, 188.6), and 142.4g (95% CI: 66.8, 218.1) (P-trend=0.0002). Conclusion: Maternal and offspring genetic risk for T2D exhibited a differential association with birth weight. Further characterization of individual alleles in a larger dataset will enhance our understanding of the causal roles of fetal and maternal genetic determinants of T2D on fetal growth. Disclosure M.L. Rahman: None. D. Shrestha: None. T. Workalemahu: None. J. Wu: None. C. Zhang: None. F. Tekola-Ayele: None.

Genetic Risk for Type 1 Diabetes Profoundly Influences the Core Gut Microbiome in Children

All of the gut microbiome associations with type 1 diabetes autoimmunity to date have been discovered in cohorts where all subjects are at high genetic risk for the disease. The design of such cohorts precludes an assessment of the influence HLA high risk alleles on gut microbiome composition. This question is addressed here by using stool samples from the general population All Babies in Southeast Sweden (ABIS) cohort where most children are at no genetic risk for type 1 diabetes. A proportion of ABIS children do possess high risk alleles including DR3/DQ2, DR4/DQ8, and DRB1. DNA from stool samples, collected at one year of age from 441 ABIS children (169 at high genetic risk), stored at -80°C, was extracted and 16S rRNA amplified, sequenced, and analyzed. The core microbiome for each category was computed by including only those reads from taxa found in at least 70% of all subjects within that group. The core microbiomes of the two groups were readily separated by PCoA (Fig. 1) and were significantly different (p=0.001). Each core microbiome comprised about 65% of the reads collected. Bifidobacterium was significantly higher in the no-risk group while Veillonella was higher in the risk group. Thus, HLA risk alleles appear to influence the core gut microbiome and posit a novel mechanism whereby the microbiome may influence the pathogenesis of type 1 diabetes. Disclosure J. Russell: None. L. Roesch: None. M.A. Atkinson: Other Relationship; Self; Patent Issued. D. Schatz: None. E.W. Triplett: None. J. Ludvigsson: None.

Family adjustment to diabetes diagnosis in children: Can participation in a study on type 1 diabetes genetic risk be helpful?

Diagnosis of type 1 diabetes often causes a negative psychological impact on families. We examined whether parents and children enrolled in The Environmental Determinants of Diabetes in the Young (TEDDY) study differ in their psychological adjustment to diabetes diagnosis compared to children diagnosed with diabetes in the community. TEDDY follows 8676 children at genetic risk for type 1 diabetes from birth. Fifty-four TEDDY children diagnosed with diabetes and 54 age-matched community control children diagnosed with diabetes were enrolled. Participants were aged 3 to 10 years and study visits occurred at 3, 6, and 12 months postdiagnosis. Psychological measures included an adapted diabetes-specific State Anxiety Inventory, the Pediatric Quality of Life Inventory-Diabetes Module, and the Pediatric Inventory for Parents, which measures frequency and difficulty of parenting stress. A generalized estimating equation analysis based on a difference score between TEDDY children and community controls found no significant differences between TEDDY parents and community controls on parent diabetes-specific anxiety (P = .30). However, TEDDY children exhibited better diabetes-specific quality of life (P = .03) and TEDDY parents reported lower frequency (P = .004) and difficulty (P = .008) of parenting stress compared to community controls. Children diagnosed with at-risk for type 1 diabetes who have previously enrolled in research monitoring have improved diabetes quality of life and lower parenting stress postdiagnosis compared to children diagnosed in the community. Families in follow-up studies may be more prepared if their child is diagnosed with diabetes.

The chromosome 6q22.33 region is associated with age at diagnosis of type 1 diabetes and disease risk in those diagnosed under 5\xa0years of age

Aims/hypothesisThe genetic risk of type 1 diabetes has been extensively studied. However, the genetic determinants of age at diagnosis (AAD) of type 1 diabetes remain relatively unexplained. Identification of AAD genes and pathways could provide insight into the earliest events in the disease process.MethodsUsing ImmunoChip data from 15,696 cases, we aimed to identify regions in the genome associated with AAD.ResultsTwo regions were convincingly associated with AAD (p < 5 × 10−8): the MHC on 6p21, and 6q22.33. Fine-mapping of 6q22.33 identified two AAD-associated haplotypes in the region nearest to the genes encoding protein tyrosine phosphatase receptor kappa (PTPRK) and thymocyte-expressed molecule involved in selection (THEMIS). We examined the susceptibility to type 1 diabetes at these SNPs by performing a meta-analysis including 19,510 control participants. Although these SNPs were not associated with type 1 diabetes overall (p > 0.001), the SNP most associated with AAD, rs72975913, was associated with susceptibility to type 1 diabetes in those individuals diagnosed at less than 5 years old (p = 2.3 × 10−9).Conclusion/interpretationPTPRK and its neighbour THEMIS are required for early development of the thymus, which we can assume influences the initiation of autoimmunity. Non-HLA genes may only be detectable as risk factors for the disease in individuals diagnosed under the age 5 years because, after that period of immune development, their role in disease susceptibility has become redundant.

Vitamin D and probiotics supplement use in young children with genetic risk for type 1 diabetes.

ObjectiveVitamin D and probiotics are nutrients of interest in the context of type 1 diabetes (T1D). We assessed the prevalence of and factors associated with vitamin D and probiotic supplementations among young children with genetic risk of T1D.Subjects/MethodsUse of supplements during the first two years of life was collected prospectively from 8 674 children in the Environmental Determinants of Diabetes in the Young (TEDDY) study.ResultsSingle and/or multivitamin/mineral (MVM) supplements were reported by 81% of the children. The majority of participants in Finland, Germany, and Sweden (97-99%) and 50% in the US received vitamin D supplements that were mostly MVMs. Probiotics use varied from 6% in the US to 60% in Finland and was primarily from probiotics-only preparations. More than 80% of the vitamin D and probiotics supplementation was initiated during infancy, and more than half of the uses lasted longer than a year. Being the first child, longer duration of breastfeeding, born in a later year, older maternal age, and higher maternal education level were associated with both vitamin D and probiotics use. Shorter gestational age and mother not smoking during pregnancy were associated with a higher likelihood of probiotics supplementation only.ConclusionVitamin D and probiotics supplementations are popular in children 0–2 years old and are associated with common factors. Data documented here will allow evaluation of the relationship between early childhood dietary intake and the development of islet autoimmunity and progression to T1D.

Vitamin D intake during the first 4 years and onset of asthma by age 5: A nested case-control study.

Early-life vitamin D intake has been linked to asthma risk in childhood, but the role of longitudinal vitamin D exposure has not been previously evaluated. We investigated the association between vitamin D intake during the first 4years of life and asthma risk by age 5. Within a Finnish population-based birth cohort, 182 incident asthma cases were matched to 728 controls on sex, genetic risk for type 1 diabetes, delivery hospital, and time of birth. Vitamin D intake was assessed by age-specific 3day food records. Parents completed a validated version of the International Study of Asthma and Allergies in Childhood questionnaire at 5years. At 3months, supplements were the main source of vitamin D intake; intake from foods increased from 3months on, mainly from fortified milk products. Vitamin D intake at each specific age was associated with an increased risk of any asthma, atopic, and non-atopic asthma, but only intake at 1 and 2years was statistically significantly associated with asthma. Longitudinal vitamin D intake was associated with an increased risk of asthma (OR 1.24; 95%CI 1.00-1.53). Increased vitamin D intake in childhood, particularly intake at 1 and 2years of age, may increase risk of childhood asthma. This might reflect a true effect or residual confounding by lifestyle or environmental factors. Repeated assessment of vitamin D intake allowed evaluation of the longitudinal and age-dependent impact of vitamin D on the risk of asthma. Further longitudinal studies are required to confirm or question these findings.

CYP2C19 activity and cardiovascular risk factors in patients with an acute coronary syndrome

IntroductionCYP2C19 is a major isoform of cytochrome P450 that metabolizes a number of drugs and is involved in the glucocorticoids synthesis. CYP2C19 polymorphisms have been associated with the genetic risk for type 2 diabetes. MethodsFive hundred and three patients with an acute coronary event were studied to assess the association between the CYP2C19 activity (CYP2C19*2, CYP2C19*3 and CYP2C19*17 variants) and the type of acute coronary syndrome, cardiovascular risk factors (arterial systemic hypertension, diabetes mellitus, dyslipidemia and smoking), analytical parameters and the extent and severity of coronary atherosclerosis. ResultsGenotype distribution in our series was similar to that expected in the Caucasian population. Among the traditional cardiovascular risk factors, very poor metabolizer patients (*2/*2, *3/*3 or *2/*3) had a greater tendency to present diabetes mellitus needing insulin (p=0.067). Conversely, when we compared very poor, poor and normal metabolizers vs. rapid and ultrarapid metabolizers we found significant differences in those diabetic patients under insulin treatment (64 patients [18%] vs. 17 patients [11%]; p=0.032). On the contrary, analytical parameters, systemic arterial hypertension, dyslipidemia, smoking or the personal/family history of coronary artery disease did not reach statistical significance regardless of CYP2C19 activity. Similarly, the number and the type of coronary disease (thrombotic, fibrotic or both) did not differ between patients with different CYP2C19 enzyme activity. ConclusionPatients with an acute coronary event and a very poor, poor and normal CYP2C19 metabolizer genotype have a higher prevalence of diabetes mellitus needing insulin than patients with the rapid and ultrarapid metabolizers CPY2C19 genotype.

Coeliac disease and psychological symptoms.

The association between coeliac disease and psychological symptoms, including depression and inattention, has not previously been studied prospectively. A multicentre study in Finland, Germany, Sweden and the USA is following children at genetic risk of type 1 diabetes and coeliac disease prospectively, from birth to 15 years.1 Children ≥2 years are screened annually for tissue transglutaminase autoantibodies. They are diagnosed with coeliac disease autoimmunity (CDA) if two consecutive samples are positive, and the parents informed. Psychological functioning was assessed at 3.5 and 4.5 years using a validated questionnaire. Parents who were aware of the diagnosis of CDA were compared with those who were not. At age 3.5 years, 66 mothers unaware their child had CDA reported significantly more anxiety and depression, withdrawn behaviour, aggressive behaviour and sleep problems than 3651 mothers whose children did not have CDA. Unaware CDA mothers also reported significantly more of the same symptoms than 440 mothers who knew their children had CDA. Surprisingly, the effect was independent of whether or not the child had been started on a gluten-free diet or of the levels of antibodies. By 4.5 years, there was no difference in reported behaviour between children whose mothers were aware and unaware, but as the data are not given it is impossible to ascertain if this is because of insufficient power to show a difference. An editorial discusses whether these findings suggest causality.2