Combined regulation of pro-inflammatory cytokines production by STAT3 and STAT5 in a model of B. pertussis infection of alveolar macrophages.

Bordetella pertussis is a highly contagious respiratory pathogen responsible for whooping-cough or pertussis. Despite high vaccination coverage worldwide, this gram-negative bacterium continues to spread among the population. B. pertussis is transmitted by aerosol droplets from an infected individual to a new host and will colonize its upper respiratory tract. Alveolar macrophages (AMs) are effector cells of the innate immune system that phagocytose B. pertussis and secrete both pro-inflammatory and antimicrobial mediators in the lungs. However, understanding their role in B. pertussis pathogenesis at the molecular level is hampered by the limited number of primary AMs that can be collected in vivo. In order to decipher the regulation of innate response induced by B. pertussis infection, we used for the first time self-renewing, non-transformed cells, called Max Planck Institute (MPI) cells, which are phenotypically and functionally very close to pulmonary AMs. Using optimized infection conditions, we characterized the entry and the clearance of B. pertussis within MPI macrophages. We showed that under these conditions, MPI cells exhibit a pro-inflammatory phenotype with the production of TNF, IL-1ß, IL-6 and MIP-2α, similarly to primary AMs purified from broncho-alveolar fluids of mice. In addition, we explored the yet uncharacterized role of the signal transduction activator of transcription (STAT) proteins family in the innate immune response to B. pertussis infection and showed for the first time the parallel regulation of pro-inflammatory cytokines by STAT3 and STAT5 in MPI macrophages infected by B. pertussis. Altogether, this work highlights the interest of using MPI cells for experiments optimization and preliminary data acquisition to understand B. pertussis interaction with AMs, and thus significantly reduce the number of animals to be sacrificed.

Live attenuated pertussis vaccine for prevention and treatment of allergic airway inflammation in mice.

Live attenuated vaccines often have beneficial non-specific effects, protecting against heterologous infectious and non-infectious diseases. We have developed a live attenuated pertussis vaccine, named BPZE1, currently in advanced clinical development. Here, we examined the prophylactic and therapeutic potential of its pertactin-deficient derivative BPZE1P in a mouse model of house dust mite (HDM)-induced allergic airway inflammation (AAI). BPZE1P was given nasally either before or after sensitization with HDM, followed by HDM challenge, or between two challenge episodes. Vaccination prior to sensitization reduced resistance in the airways, the numbers of infiltrating eosinophils and the concentrations of proinflammatory cytokines, such as IL-1α, IL-1ß and IL-33, in the lungs but had no effect on Th2 cytokine levels. BPZE1P also protected when delivered after sensitization or between two challenge episodes. However, in this case the levels of Th2 cytokines in the lung were decreased without significant effects on IL-1α, IL-1ß and IL-33 production. The vaccine restored lung function and decreased eosinophil influx in the lungs of HDM-treated mice. BPZE1P has a better take than BPZE1 in hosts vaccinated with acellular pertussis vaccines. Therefore, it has interesting potential as a preventive and therapeutic agent against AAI, even in acellular pertussis-vaccinated populations.

Association of DNA methylation and genetic variations of the APOE gene with the risk of diabetic dyslipidemia.

Apolipoprotein E (APOE) is a key regulator of lipoprotein metabolism, and consequently, affects the plasma and tissue lipid contents. The aim of the present study was to investigate the parallel effects of APOE genetic variants and promoter methylation levels of six CpGs on the risk of diabetic dyslipidemia. A total of 204 Palestinian type 2 diabetes (T2D) patients (mean age ± SD: 62.7±10.2) were enrolled in the present study (n=96 with dyslipidemia and n=108 without dyslipidemia). Next generation sequencing was performed to analyze five single nucleotide polymorphisms: Two variants rs7412 and rs429358 that determine APOE ε alleles, and three variants in the promoter region (rs769446, rs449647, and rs405509). For all subjects, the most common genotype was ε3/ε3 (79.4%). No statistical differences were observed in the APOE ε polymorphisms and the three promoter variants among T2D patients with and without dyslipidemia (P>0.05). A comparison of lipid parameters between ε3/ε3 subjects and ε4 carriers in both groups revealed no significant differences in the mean values of LDL-C, HDL-C, TG, and TC levels (P>0.05). Six CpG sites in the APOE promoter on chromosome 19:44905755-44906078 were identified, and differential DNA methylation in these CpGs were observed between the study groups. Logistic regression analysis revealed a significant association of DNA methylation level at the six CpGs with an increased risk of diabetic dyslipidemia (odds ratio, 1.038; 95% confidence interval, 1.012-1.064; P=0.004). In conclusion, the present study revealed that DNA methylation levels in six CpGs in the APOE promoter region was associated with the risk of diabetic dyslipidemia independently of the APOE ε4 variant which could be a potential therapeutic target to reverse the methylation of the APOE promoter.

Live attenuated Bordetella pertussis vaccine candidate BPZE1 transiently protects against lethal pneumococcal disease in mice.

BPZE1 is a live attenuated vaccine against infection by Bordetella pertussis, the causative agent of whooping cough. It was previously shown that BPZE1 provides heterologous protection in mouse models of disease caused by unrelated pathogens, such as influenza virus and respiratory syncytial virus. Protection was also observed in mouse models of asthma and contact dermatitis. In this study, we demonstrate that BPZE1 also displays protection against an unrelated bacterial pathogen in a mouse model of invasive pneumococcal disease mediated by Streptococcus pneumoniae. While a single administration of BPZE1 provided no protection, two doses of 106 colony-forming units of BPZE1 given in a three-week interval protected against mortality, lung colonization and dissemination in both BALB/c and C57BL/6 mice. Unlike for the previously reported influenza challenge model, protection was short-lived, and waned within days after booster vaccination. Formaldehyde-killed BPZE1 protected only when administered following a live prime, indicating that priming requires live BPZE1 for protection. Protection against mortality was directly linked to substantially decreased bacterial dissemination in the blood and was lost in MyD88 knock-out mice, demonstrating the role of the innate immune system in the mechanism of protection. This is the first report on a heterologous protective effect of the live BPZE1 vaccine candidate against an unrelated bacterial infection.

Estrogen receptor 1 gene polymorphisms (PvuII and XbaI) are associated with type 2 diabetes in Palestinian women.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a multifactorial disease where both genetic and environmental factors contribute to its pathogenesis. The PvuII and XbaI polymorphisms of the estrogen receptor 1 (ESR1) gene have been variably associated with T2DM in several populations. This association has not been studied in the Palestinian population. Therefore, the aim of this study was to investigate the association between the PvuII and XbaI variants in the ESR1 and T2DM and its related metabolic traits among Palestinian women. METHODS: This case-control study included 102 T2DM and 112 controls in which PvuII and XbaI variants of the ESR1 gene were genotyped using amplicon based next generation sequencing (NGS). RESULTS: Allele frequencies of both PvuII and XbaI variants were not significantly different between patients and control subjects (P > 0.05). In logestic regression analysis adjusted for age and BMI, the ESR1 PvuII variant was associated with risk of T2DM in three genotypic models (P < 0.025) but the strongest association was observed under over-dominant model (TT+CC vs. TC) (OR = 2.32, CI [1.18-4.55] adjusted P = 0.013). A similar but non-significant trend was also observed for the ESR1 XbaI variant under the over-dominant model (AA+GG vs. AG) (OR = 2.03, CI [1.05-3.95]; adjusted P = 0.035). The frequencies of the four haplotypes (TA, CG, CA, TG) were not significantly different in the T2DM patients compared with control group (P > 0.025). Among diabetic group, an inverse trend with risk of cardio vascular diseases was shown in carriers of CG haplotype compared to those with TA haplotype (OR = 0.28, CI [0.09-0.90]; adjusted P = 0.035). Further, stratified analyses based on ESR1 PvuII and XbaI genotypes revealed no evidence for association with lipid levels (TC, TG, HDL, LDL). CONCLUSIONS: This is the first Palestinian study to conclude that ESR1 PuvII and XbaI variants may contribute to diabetes susceptibility in Palestinian women. Identification of genetic risk markers can be used in defining high risk subjects and in prevention trials.

Non-specific Effects of Live Attenuated Pertussis Vaccine Against Heterologous Infectious and Inflammatory Diseases.

Bordetella pertussis is the agent of pertussis, also referred to as whooping cough, a disease that remains an important public health issue. Vaccine-induced immunity to pertussis wanes over time. In industrialized countries, high vaccine coverage has not prevented infection and transmission of B. pertussis, leading to periodic outbreaks in people of all ages. The consequence is the formation of a large source for transmission to children, who show the highest susceptibility of developing severe whooping cough and mortality. With the aim of providing protection against both disease and infection, a live attenuated pertussis vaccine, in which three toxins have been genetically inactivated or removed, is now in clinical development. This vaccine, named BPZE1, offers strong protection in mice and non-human primates. It has completed a phase I clinical trial in which safety, transient colonization of the human airway and immunogenicity could be demonstrated. In mice, BPZE1 was also found to protect against inflammation resulting from heterologous airway infections, including those caused by other Bordetella species, influenza virus and respiratory syncytial virus. Furthermore, the heterologous protection conferred by BPZE1 was also observed for non-infectious inflammatory diseases, such as allergic asthma, as well as for inflammatory disorders outside of the respiratory tract, such as contact dermatitis. Current studies focus on the mechanisms underlying the anti-inflammatory effects associated with nasal BPZE1 administration. Given the increasing importance of inflammatory disorders, novel preventive and therapeutic approaches are urgently needed. Therefore, live vaccines, such as BPZE1, may offer attractive solutions. It is now essential to understand the cellular and molecular mechanisms of action before translating these biological findings into new healthcare solutions.

Common FTO rs9939609 variant and risk of type 2 diabetes in Palestine.

BACKGROUND: Genetic and environmental factors play a crucial role in the development of type 2 diabetes mellitus (T2DM) and obesity. This study aimed to investigate the association of the fat-mass and obesity-associated gene (FTO) rs9939609 variant with T2DM and body mass index (BMI) among Palestinian population. METHODS: A total of 399 subjects were recruited, of whom 281 were type 2 diabetic patients and 118 normoglycemic subjects. All of them were unrelated, aged > 40 years and recruited within the period 2016-2017. The A allele of FTO rs9939609 was identified by PCR-RFLP. RESULTS: Significant association of the minor allele A of FTO rs9939609 and T2DM risk was observed with an allelic odd ratio of 1.92 (95% CI [1.09-3.29], p = 0.02) adjusted for age and gender, this association partly attenuated when adjusted for BMI with OR of 1.84, (95%CI [1.04-3.05], p = 0.03). Stratified data by glycemic status across FTO genotypes showed that A allele was marginally associated with increased BMI among diabetic group (p = 0.057) but not in control group (p = 0.7). Moreover, no significant association was observed between FTO genotypes and covariates of age, gender, T2DM complications or any tested metabolic trait in both diabetic and nondiabetic individuals (p > 0.05). CONCLUSIONS: The variant rs9939609 of the FTO gene was associated with T2DM in Palestine. This is the first study conducted on this gene in the Palestinian population and provides valuable information for comparison with other ethnic groups. Further analysis with larger sample size is required to elucidate the role of this variant on the predisposition to increased BMI in Palestinians.

Increased Hepatic PDGF-AA Signaling Mediates Liver Insulin Resistance in Obesity-Associated Type 2 Diabetes.

In type 2 diabetes (T2D), hepatic insulin resistance is strongly associated with nonalcoholic fatty liver disease (NAFLD). In this study, we hypothesized that the DNA methylome of livers from patients with T2D compared with livers of individuals with normal plasma glucose levels can unveil some mechanism of hepatic insulin resistance that could link to NAFLD. Using DNA methylome and transcriptome analyses of livers from obese individuals, we found that hypomethylation at a CpG site in PDGFA (encoding platelet-derived growth factor α) and PDGFA overexpression are both associated with increased T2D risk, hyperinsulinemia, increased insulin resistance, and increased steatohepatitis risk. Genetic risk score studies and human cell modeling pointed to a causative effect of high insulin levels on PDGFA CpG site hypomethylation, PDGFA overexpression, and increased PDGF-AA secretion from the liver. We found that PDGF-AA secretion further stimulates its own expression through protein kinase C activity and contributes to insulin resistance through decreased expression of insulin receptor substrate 1 and of insulin receptor. Importantly, hepatocyte insulin sensitivity can be restored by PDGF-AA-blocking antibodies, PDGF receptor inhibitors, and by metformin, opening therapeutic avenues. Therefore, in the liver of obese patients with T2D, the increased PDGF-AA signaling contributes to insulin resistance, opening new therapeutic avenues against T2D and possibly NAFLD.

KLB is associated with alcohol drinking, and its gene product ß-Klotho is necessary for FGF21 regulation of alcohol preference.

Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified ß-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 × 10-12). ß-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific ß-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver-brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.

Fine-scale human genetic structure in Western France.

The difficulties arising from association analysis with rare variants underline the importance of suitable reference population cohorts, which integrate detailed spatial information. We analyzed a sample of 1684 individuals from Western France, who were genotyped at genome-wide level, from two cohorts D.E.S.I.R and CavsGen. We found that fine-scale population structure occurs at the scale of Western France, with distinct admixture proportions for individuals originating from the Brittany Region and the Vendée Department. Genetic differentiation increases with distance at a high rate in these two parts of Northwestern France and linkage disequilibrium is higher in Brittany suggesting a lower effective population size. When looking for genomic regions informative about Breton origin, we found two prominent associated regions that include the lactase region and the HLA complex. For both the lactase and the HLA regions, there is a low differentiation between Bretons and Irish, and this is also found at the genome-wide level. At a more refined scale, and within the Pays de la Loire Region, we also found evidence of fine-scale population structure, although principal component analysis showed that individuals from different departments cannot be confidently discriminated. Because of the evidence for fine-scale genetic structure in Western France, we anticipate that rare and geographically localized variants will be identified in future full-sequence analyses.

Weight loss independent association of TCF7 L2 gene polymorphism with fasting blood glucose after Roux-en-Y gastric bypass in type 2 diabetic patients.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) surgery improves glucose control in most but not all patients with type 2 diabetes mellitus (T2 DM). Transcription factor 7-like 2 (TCF7 L2) gene variation (rs7903146, C: wild-type allele, T: risk-allele) is the strongest contributor to T2 DM risk. Until now, there are no studies investigating gene interactions with changes of glycemia in obese patients with T2 DM after RYGB. The objective of this study was to assess the effect of TCF7 L2 genotype on RYGB-induced changes in glucose homeostasis in 99 obese patients with T2 DM at 1-year follow-up. METHODS: Body mass index (BMI) and fasting blood glucose (FBG) were measured before and 1, 3, 6, and 12 months after RYGB. Genotyping was performed with TaqMan technology. The effect of the interaction between TCF7 L2 genotype and postoperative time on BMI and FBG changes was analyzed with a linear mixed model. RESULTS: Preoperatively, there was no difference in BMI, FBG, and other diabetes associated traits between homozygous (CC) (n = 49) and heterozygous (CT) or homozygous (TT) T risk-allele carriers (n = 50). One year after RYGB, 48 out of 99 patients had glycosylated hemoglobin (HbA1 c) lower than 6.5% in absence of any antidiabetic medication. BMI decreased similarly in both groups (P = .769, genotype-time interaction), however, the decrease in FBG over time was lower in T risk-allele carriers (P = .016, genotype-time interaction). At 1 year, FBG was 6.42 ± 2.98 mmol/L in CT/TT versus 5.36 ± 0.98 mmol/L in CC (P = .022, t test). CONCLUSION: TCF7 L2 gene variation affected the decrease of FBG after RYGB in obese patients with T2 DM, independently of weight loss.

Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.

To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.

Coffee and tea consumption, genotype-based CYP1A2 and NAT2 activity and colorectal cancer risk-results from the EPIC cohort study.

Coffee and tea contain numerous antimutagenic and antioxidant components and high levels of caffeine that may protect against colorectal cancer (CRC). We investigated the association between coffee and tea consumption and CRC risk and studied potential effect modification by CYP1A2 and NAT2 genotypes, enzymes involved in the metabolization of caffeine. Data from 477,071 participants (70.2% female) of the European Investigation into Cancer and Nutrition (EPIC) cohort study were analyzed. At baseline (1992-2000) habitual (total, caffeinated and decaffeinated) coffee and tea consumption was assessed with dietary questionnaires. Cox proportional hazards models were used to estimate adjusted hazard ratio's (HR) and 95% confidence intervals (95% CI). Potential effect modification by genotype-based CYP1A2 and NAT2 activity was studied in a nested case-control set of 1,252 cases and 2,175 controls. After a median follow-up of 11.6 years, 4,234 participants developed CRC (mean age 64.7 ± 8.3 years). Total coffee consumption (high vs. non/low) was not associated with CRC risk (HR 1.06, 95% CI 0.95-1.18) or subsite cancers, and no significant associations were found for caffeinated (HR 1.10, 95% CI 0.97-1.26) and decaffeinated coffee (HR 0.96, 95% CI 0.84-1.11) and tea (HR 0.97, 95% CI 0.86-1.09). High coffee and tea consuming subjects with slow CYP1A2 or NAT2 activity had a similar CRC risk compared to non/low coffee and tea consuming subjects with a fast CYP1A2 or NAT2 activity, which suggests that caffeine metabolism does not affect the link between coffee and tea consumption and CRC risk. This study shows that coffee and tea consumption is not likely to be associated with overall CRC.

Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity.

Patients with established type 2 diabetes display both ß-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin sensitivity. We included data from up to 58,614 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used additive genetic models with adjustment for sex, age, and BMI, followed by fixed-effects, inverse-variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second cluster (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.

Meal frequencies modify the effect of common genetic variants on body mass index in adolescents of the northern Finland birth cohort 1986.

Recent studies suggest that meal frequencies influence the risk of obesity in children and adolescents. It has also been shown that multiple genetic loci predispose to obesity already in youth. However, it is unknown whether meal frequencies could modulate the association between single nucleotide polymorphisms (SNPs) and the risk of obesity. We examined the effect of two meal patterns on weekdays -5 meals including breakfast (regular) and ≤ 4 meals with or without breakfast (meal skipping) - on the genetic susceptibility to increased body mass index (BMI) in Finnish adolescents. Eight variants representing 8 early-life obesity-susceptibility loci, including FTO and MC4R, were genotyped in 2215 boys and 2449 girls aged 16 years from the population-based Northern Finland Birth Cohort 1986. A genetic risk score (GRS) was calculated for each individual by summing the number of BMI-increasing alleles across the 8 loci. Weight and height were measured and dietary data were collected using self-administered questionnaires. Among meal skippers, the difference in BMI between high-GRS and low-GRS (<8 and ≥ 8 BMI-increasing alleles) groups was 0.90 (95% CI 0.63,1.17) kg/m(2), whereas in regular eaters, this difference was 0.32 (95% CI 0.06,0.57) kg/m(2) (p interaction = 0.003). The effect of each MC4R rs17782313 risk allele on BMI in meal skippers (0.47 [95% CI 0.22,0.73] kg/m(2)) was nearly three-fold compared with regular eaters (0.18 [95% CI -0.06,0.41] kg/m(2)) (p interaction = 0.016). Further, the per-allele effect of the FTO rs1421085 was 0.24 (95% CI 0.05,0.42) kg/m(2) in regular eaters and 0.46 (95% CI 0.27,0.66) kg/m(2) in meal skippers but the interaction between FTO genotype and meal frequencies on BMI was significant only in boys (p interaction = 0.015). In summary, the regular five-meal pattern attenuated the increasing effect of common SNPs on BMI in adolescents. Considering the epidemic of obesity in youth, the promotion of regular eating may have substantial public health implications.

Parental history of type 2 diabetes, TCF7L2 variant and lower insulin secretion are associated with incident hypertension. Data from the DESIR and RISC cohorts.

AIMS/HYPOTHESIS: The relationship between insulin secretion and the incidence of hypertension has not been well characterised. We hypothesised that both a parental history of diabetes and TCF7L2 rs7903146 polymorphism, which increases susceptibility to diabetes because of impaired beta cell function, are associated with incident hypertension. In a separate cohort, we assessed whether low insulin secretion is related to incident hypertension. METHODS: Nine year incident hypertension was studied in 2,391 normotensive participants from the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort. The relationship between insulin secretion and 3 year incident hypertension was investigated in 1,047 non-diabetic, normotensive individuals from the Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) cohort. Insulin secretion during OGTT was expressed in relation to the degree of insulin resistance, as assessed by a hyperinsulinaemic-euglycaemic clamp. RESULTS: In the DESIR cohort, a parental history of diabetes and the TCF7L2 at-risk variant were both associated with hypertension incidence at year 9, independently of waist circumference, BP, fasting glucose, insulin levels and HOMA-IR at inclusion (p = 0.02 for parental history, p = 0.006 for TCF7L2). In the RISC cohort, a lower insulin secretion rate during the OGTT at baseline was associated with both higher BP and a greater risk of hypertension at year 3. This inverse correlation between the insulin secretion rate and incident hypertension persisted after controlling for baseline insulin resistance, glycaemia and BP (p = 0.007). CONCLUSIONS/INTERPRETATION: Parental history of diabetes, TCF7L2 rs7903146 polymorphism and a reduced insulin secretion rate were consistently associated with incident hypertension. A low insulin secretion rate might be a new risk factor for incident hypertension, beyond insulin resistance.

Association between large detectable clonal mosaicism and type 2 diabetes with vascular complications.

Large chromosomal clonal mosaic events (CMEs) have been suggested to be linked to aging and to predict cancer. Type 2 diabetes (T2D) has been conceptualized as an accelerated-aging disease and is associated with higher prevalence of cancers. Here we aimed to assess the association between T2D and CME occurrence in blood. We evaluated the presence of CMEs in 7,659 individuals (including 2,208 with T2D) using DNA arrays. A significant association between CME occurrence and T2D was found (odds ratio (OR) = 5.3; P = 5.1 × 10(-5)) and was stronger when we only considered non-obese individuals with T2D (OR = 5.6; P = 4.9 × 10(-5)). Notably, CME carriers with T2D had higher prevalence of vascular complications than non-carriers with T2D (71.4% versus 37.1%, respectively; P = 7.7 × 10(-4)). In CME carriers, we found an increase in the percentage of abnormal cells over 6 years (P = 8.60 × 10(-3)). In conclusion, given the increased risk of cancer in CME carriers, our results may have profound clinical implications in patients with severe T2D.

The interplay of variants near LEKR and CCNL1 and social stress in relation to birth size.

BACKGROUND: We previously identified via a genome wide association study variants near LEKR and CCNL1 and in the ADCY5 genes lead to lower birthweight. Here, we study the impact of these variants and social stress during pregnancy, defined as social adversity and neighborhood disparity, on infant birth size. We aimed to determine whether the addition of genetic variance magnified the observed associations. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed data from the Northern Finland Birth Cohort 1986 (n=5369). Social adversity was defined by young maternal age (<20 years), low maternal education (<11 years), and/or single marital status. Neighborhood social disparity was assessed by discrepancy between neighborhoods relative to personal socio-economic status. These variables are indicative of social and socioeconomic stress, but also of biological risk. The adjusted multiple regression analysis showed smaller birth size in both infants of mothers who experienced social adversity (birthweight by -40.4 g, 95%CI -61.4, -19.5; birth length -0.14 cm, 95%CI -0.23, -0.05; head circumference -0.09 cm 95%CI -0.15, -0.02) and neighborhood disparity (birthweight -28.8 g, 95%CI -47.7, -10.0; birth length -0.12 cm, 95%CI -0.20, -0.05). The birthweight-lowering risk allele (SNP rs900400 near LEKR and CCNL1) magnified this association in an additive manner. However, likely due to sample size restriction, this association was not significant for the SNP rs9883204 in ADCY5. Birth size difference due to social stress was greater in the presence of birthweight-lowering alleles. CONCLUSIONS/SIGNIFICANCE: Social adversity, neighborhood disparity, and genetic variants have independent associations with infant birth size in the mutually adjusted analyses. If the newborn carried a risk allele rs900400 near LEKR/CCNL1, the impact of stress on birth size was stronger. These observations give support to the hypothesis that individuals with genetic or other biological risk are more vulnerable to environmental influences. Our study indicates the need for further research to understand the mechanisms by which genes impact individual vulnerability to environmental insults.

Low-frequency variants in HMGA1 are not associated with type 2 diabetes risk.

It has recently been suggested that the low-frequency c.136-14_136-13insC variant in high-mobility group A1 (HMGA1) may strongly contribute to insulin resistance and type 2 diabetes risk. In our study, we attempted to confirm that HMGA1 is a novel type 2 diabetes locus in French Caucasians. The gene was sequenced in 368 type 2 diabetic case subjects with a family history of type 2 diabetes and 372 normoglycemic control subjects without a family history of type 2 diabetes. None of the 41 genetic variations identified were associated with type 2 diabetes. The lack of association between the c.136-14_136-13insC variant and type 2 diabetes was confirmed in an independent French group of 4,538 case subjects and 4,015 control subjects and in a large meta-analysis of 16,605 case subjects and 46,179 control subjects. Finally, this variant had no effects on metabolic traits and was not involved in variations of HMGA1 and insulin receptor (INSR) expressions. The c.136-14_136-13insC variant was not associated with type 2 diabetes in individuals of European descent. Our study emphasizes the need to analyze a large number of subjects to reliably assess the association of low-frequency variants with the disease.