Genetic underpinnings of fasting and oral glucose-stimulated based insulin sensitivity indices.

CONTEXT: Insulin sensitivity (IS) is an important factor in type 2 diabetes (T2D) and can be estimated by many different indices. OBJECTIVE: We aimed to compare the genetic components underlying IS indices obtained from fasting and oral glucose-stimulated plasma glucose and serum insulin levels. METHODS: We computed 21 IS indices, classified as fasting, OGTT0,120 and OGTT0,30,120 indices, using fasting and oral glucose tolerance test (OGTT) data in two cohorts. We used data from a family cohort (n=313) to estimate the heritability and the genetic and phenotypic correlations of IS indices. The population cohort, Inter99 (n=5,343), was used to test for associations between IS indices and 426 genetic variants known to be associated with T2D. RESULTS: Heritability estimates of IS indices ranged between 19% and 38%. Fasting and OGTT0,30,120 indices had high genetic (ρG) and phenotypic (ρP) pairwise correlations (ρG and ρP: 0.88 to 1) The OGTT0,120 indices displayed a wide range of pairwise correlations (ρG: 0.17-1.00 and ρP: 0.13-0.97). We identified statistically significant associations between IS indices and established T2D-associated variants. The PPARG rs11709077 was associated only with fasting indices, and PIK3R rs4976033 only with OGTT0,30,120 indices. The variants in FAM63A/MINDY1, GCK, C2CD4A/B, and FTO loci were associated only with OGTT0,120 indices. CONCLUSION: Even though the IS indices mostly share a common genetic background, notable differences emerged between OGTT0,120 indices. The fasting and OGTT based indices have distinct associations with T2D risk variants. This work provides a basis for future large-scale genetic investigations into the differences between IS indices.

Risk of pancreatitis in patients with inflammatory bowel disease - a meta-analysis.

INTRODUCTION: Patients with inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are believed to be at increased risk of pancreatitis. The objective of the present study was to investigate the association between IBD and risk of pancreatitis in a systematic review and meta-analysis. METHODS: We conducted a systematic literature search in the PubMed and Embase databases. Data were extracted using predefined data fields, and risk of bias was assessed using the Risk of Bias Assessment tool for Non-randomized Studies. Random-effects meta-analyses were conducted. RESULTS: Four studies with acute pancreatitis as outcome met the eligibility criteria. The overall estimated risk ratio revealed an increased risk for acute pancreatitis in patients with IBD of 2.78 (95% confidence interval (CI): 2.40-3.22). The risk ratio was increased for both CD and UC, with estimated risk ratios of 3.62 (95% CI: 2.99-4.38) and 2.24 (95% CI: 1.85-2.71), respectively. No studies meeting the eligibility criteria had chronic pancreatitis as outcome. CONCLUSIONS: The risk of acute pancreatitis is increased in patients with IBD and higher for patients with CD. Due to the observational design of the studies included in our meta-analysis, the mechanisms underlying the increased risk of pancreatitis are unknown and remain to be investigated. Studies of the risk of chronic pancreatitis among patients with IBD are warranted. FUNDING: This work was supported by a grant from the Novo Nordisk Foundation (NNF16OC0022586). The funder had no role in the study design, collection, analysis, interpretation of the data, or the writing of the manuscript. TRIAL REGISTRATION: not relevant.

Childhood growth and risk of inflammatory bowel disease: a population-based study of 317,030 children.

Background: Growth in childhood is associated with later development of autoimmune diseases and cancer, but the impact of growth on risk of inflammatory bowel disease (IBD) remains unknown. We conducted a population-based cohort study to examine whether birth weight, childhood height, or changes in height associated with later risk of IBD. Methods: Our cohort consisted of 317,030 children from the Copenhagen School Health Records Register (born 1930-1989) with height repeatedly measured from age 7 to 13 and with data on birth weight on a subset. Through linkage to the Danish National Patients Register, cases of IBD were identified. Cox proportional hazard regression was used to examine associations between measures of childhood growth and risk of IBD. Results: During more than 9 million years of follow-up, 1612 individuals were diagnosed with Crohn's disease (CD) and 2,640 with ulcerative colitis (UC). Birth weight and childhood heights were not associated with subsequent risk of CD or UC (HRs close to 1.00). Childhood growth from 7 to 10 years (CD: HR, 1.00; 95% CI, 0.85-1.18; UC: HR, 0.92; 95% CI, 0.81-1.05) and 10 to 13 years (CD: HR, 1.02; 95% CI, 0.89-1.17; UC: HR, 0.95; 0.85-1.05) did not associate with risk of IBD either. Conclusion: In this large population-based cohort study, birth weight and childhood growth did not influence risk of IBD, which contrasts with observations in other chronic diseases. Thereby, the study also suggests that pre-clinical effects of adult IBD are not measurable in childhood and that childhood risk factors for IBD do not influence growth.

Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis.

Streptococcus pneumoniae is a common nasopharyngeal colonizer, but can also cause life-threatening invasive diseases such as empyema, bacteremia and meningitis. Genetic variation of host and pathogen is known to play a role in invasive pneumococcal disease, though to what extent is unknown. In a genome-wide association study of human and pathogen we show that human variation explains almost half of variation in susceptibility to pneumococcal meningitis and one-third of variation in severity, identifying variants in CCDC33 associated with susceptibility. Pneumococcal genetic variation explains a large amount of invasive potential (70%), but has no effect on severity. Serotype alone is insufficient to explain invasiveness, suggesting other pneumococcal factors are involved in progression to invasive disease. We identify pneumococcal genes involved in invasiveness including pspC and zmpD, and perform a human-bacteria interaction analysis. These genes are potential candidates for the development of more broadly-acting pneumococcal vaccines.

Associations between adult height and type 2 diabetes mellitus: a systematic review and meta-analysis of observational studies.

BACKGROUND: Although short adult height is generally associated with increased risks of type 2 diabetes mellitus (T2DM), there are large inconsistencies across studies. The aims of this study were to describe and quantify currently available evidence on the association between adult height and T2DM, to examine whether the reported associations differ by sex, and to examine the shapes of the height and T2DM associations. METHODS: Relevant literature was identified using PubMed (1966-May 2018), EMBASE (1947-May 2018) and Google Scholar (May 2018). We identified cross-sectional and cohort studies with original publications on human subjects, which were included in a random-effects meta-analysis. RESULTS: From 15 971 identified sources, 25 studies met the inclusion criteria for the systematic review (N=401 562 individuals). From these 25 studies, 16 (9 cross-sectional studies and 7 cohort studies) were included in the meta-analysis (n=261 496 individuals). The overall random-effects meta-analysis indicated an inverse association between adult height and T2DM (effect estimate=0.88, 95% CI 0.81 to 0.95). No sex differences in the associations between adult height and T2DM were found (effect estimate for men: 0.86, 95% CI 0.75 to 0.99; effect estimate for women: 0.90; 95% CI 0.80 to 1.01; p value for sex interaction=0.80). Due to lack of data, results on the shape of the association between height and T2DM were inconclusive. CONCLUSIONS: Shorter height is associated with an increased risk of T2DM and the association does not significantly differ by sex. The currently available data are insufficient to support conclusions regarding the shape of the association between height and T2DM. TRIAL REGISTRATION NUMBER: CRD42017062446.

Body mass index in young men and risk of inflammatory bowel disease through adult life: A population-based Danish cohort study.

Body mass index (BMI) is associated with increased future risk of inflammatory bowel disease(IBD) particularly Crohn's disease(CD), where associations with high and low BMI have been observed. Most studies are based on adult women. We aimed to explore the impact of BMI in men entering adult life on their long-term risk of developing IBD. A total of 377,957 men born during 1939-1959, with BMI measured at draft boards at mean age 19, were followed from 1977, or time of examination, to end of 2015. Risk of IBD was assessed using Cox regression. During 13 million person-years of follow-up, 1,523 developed CD and 3,323 UC. Using normal weight as reference, for CD the following HRs were observed: BMI < 18.5, 1.35; 95% CI, 1.12-1.62, BMI 25-29.9; 0.83; 95% CI, 0.68-1.02. and BMI > 30 1.20; 95% CI, 0.75-1.90). The increased risk of CD in underweight was maintained up until age 60 not explained by known effects of smoking. For UC, minor inverse associations were observed. Restricted cubic splines revealed a U-shape association between BMI and CD, but not UC. Low BMI of men entering adult life is associated with an increased incidence of CD and UC up to 40 years later.

Childhood body mass index and risk of inflammatory bowel disease in adulthood: a population-based cohort study.

BACKGROUND: The increasing incidence of inflammatory bowel disease (IBD) in western countries has led to the hypothesis that obesity-related inflammation could play a role in the etiology of IBD. However, this hypothesis lacks confirmation in studies of individuals prior to the typical onset of IBD in young adulthood. METHODS: In a cohort of 316,799 individuals from the Copenhagen School Health Records Register (CSHRR), we examined whether BMI at ages 7 through 13 years was associated with later IBD. Linking the CSHRR to the Danish National Patient Register, we identified cases of Crohn's disease (CD) and ulcerative colitis (UC) diagnosed during follow-up. Cox regression was used to estimate the hazard ratios (HR) with 95% confidence intervals. RESULTS: During 10 million person-years of follow-up, 1500 individuals were diagnosed with CD and 2732 with UC. At all examined ages, a 1 unit increase in BMI z-score was associated with a significantly decreased risk of UC (HRs = 0.9) and with a significantly increased risk of CD when diagnosed before age 30 (HRs = 1.2). We observed no associations between changes in BMI z-score between 7 and 13 years and later risk of CD or UC. CONCLUSION: We found a direct association between childhood BMI and CD diagnosed before 30 years of age, and an inverse association between childhood BMI and UC irrespective of age. Our results support the previous hypotheses of obesity being a risk factor for CD, and suggest that childhood underweight might be a risk factor for UC.

Prospective Studies Exploring the Possible Impact of an ID3 Polymorphism on Changes in Obesity Measures.

OBJECTIVE: Changes in fat mass depend on adipogenesis and angiogenesis, mechanisms regulated by the inhibitor of differentiation-3 (ID3). Id3 knockout mice showed attenuated increases in BMI and visceral fat mass. We hypothesized that the ID3 missense variant (rs11574-A) would lead to an attenuated increase over time in fat mass, BMI, waist circumference (WC), and waist-hip ratio (WHR) in humans. METHODS: The genotyped study populations included the Obesity Research Group - Genetics (ORGGEN) cohort, a cohort of men with obesity (N = 716) and of randomly selected men (N = 826) from the Danish draft register who were examined at mean ages of 20 and 46 years, and the Inter99 (N = 6,116) and Health2006 (N = 2,761) cohorts, two population-based samples of middle-aged people, followed up after 5 years. RESULTS: In meta-analyses of all data, no association was found between rs11574-A and changes in BMI, WC, WHR, or fat mass. We found an association between rs11574-A and cross-sectional BMI (N = 10,359, ß: -0.16 kg/m2 per allele, 95% CI: -0.30 to -0.01, P = 0.033) and fat mass (N = 4,188, ß: -0.52 kg/m2 per allele, 95% CI: -1.03 to -0.01, P = 0.046). CONCLUSIONS: No consistent impact of the genetic variant on changes in fat mass, BMI, or fat distribution was found in three Danish cohorts.

Antibiotic exposure in early life and childhood overweight and obesity: A systematic review and meta-analysis.

We conducted a systematic review and meta-analysis of observational studies investigating the association between antibiotic exposure in infancy and risk of childhood overweight and obesity. Thirteen studies, including a total of 527 504 children, were included in the systematic review and 8 were included in meta-analyses. Exposure to antibiotics in infancy was associated with an increased odds ratio (OR) of childhood overweight and obesity (OR 1.11, 95% confidence interval [CI] 1.02-1.20). Whereas exposure to 1 treatment only and exposure between 6 and 24 months were not associated with increased risk of childhood overweight and obesity, exposure to >1 treatment was associated with an OR of 1.24 (95% CI 1.09-1.43) and exposure within the first 6 months of life was associated with an OR of 1.20 (95% CI 1.04-1.37). In conclusion, antibiotic exposure in infancy was associated with a slightly increased risk of childhood overweight and obesity, mainly if children were exposed to repeated treatments or treatment within the first 6 months of life. It is unclear whether this association is mediated via direct effects of antibiotics on the gut microbiota.

FTO genetic variants, dietary intake and body mass index: insights from 177,330 individuals.

FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177,330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.