Leptin and its receptor are overexpressed in breast cancer tissue of postmenopausal Mexican-Mestizo women with obesity

The aim of this study was to investigate the expression of leptin (LEP) and its receptor (LEPR) in breast cancer tissue of postmenopausal women with different body mass indexes (BMI), as well as the relationship of this expression with the rate of recurrence free survival (RFS). Leptin and LEPR expression, determined by immunohistochemistry, were studied in breast cancer tissues of 154 patients. Qualitative and semi-quantitative analysis of protein expression was performed by the H-Score method, through the ImageJ's IHC Profiler software. Kaplan–Meier survival analysis and log-rank statistic were used to estimate RFS differences. Protein expression of LEP, was significantly higher in women with overweight or with obesity, when compared to women with normal BMI (P = 0.032 and P = 0.013, respectively). We also observed a significantly higher expression of LEPR in breast tumor cells of women with obesity (58.8%), when compared to women with normal BMI (32.7%) (P = 0.007). Five-year survival rate, regarding LEPR expression, was 82.4% when positive and 94% when negative (P = 0.024). In the Cox proportional-hazards regression model, LEPR expression represented a risk factor for disease recurrence after adjustment for confounding factors (HR = 4.67; 95% CI: 1.13–19.31; P = 0.033).In conclusion, postmenopausal women with obesity and breast cancer present higher LEP and LEPR expression in breast tumors, when compared to women with normal BMI. Independently from BMI, women with tumors LEPR positive have worst RFS, when compared to women with tumors LEPR negative.     

ORIGINAL ARTICLE: Leptin Gene (TTTC)n Microsatellite Polymorphism as well as Leptin Receptor R223Q and PPARγ2 P12A Substitutions are not Associated with Hypertensive Disorders in Pregnancy

Citation Wiedemann A, Vocke F, Fitzgerald JS, Markert UR, Jeschke U, Lohse P, Toth B. Leptin gene (TTTC)_n microsatellite polymorphism as well as Leptin receptor R223Q and PPARγ2 P12A substitutions are not associated with hypertensive disorders in pregnancy. Am J Reprod Immunol 2010; 63: 310–317 Problem Pregnancy‐induced hypertension (PIH) affects up to 15% of all pregnancies. Disturbed placentation is one factor associated with PIH. Leptin and peroxisome proliferator activator receptors (PPAR) seem to play an important role in placentation, fetal development, and blood pressure regulation. Therefore, we investigated polymorphisms in the genes encoding leptin, the leptin receptor, and PPARγ2 in patients with PIH. Method of study In this retrospective case–control study, 103 patients with PIH [gestational hypertension (GH) n = 39; preeclampsia n = 27; eclampsia n = 5; HELLP n = 32] and 100 controls were analyzed for the LEP tetranucleotide repeat (TTTC)_n and the leptin receptor (LEPR) R223Q and PPARγ2 P12A substitutions. Statistical analysis was performed using the chi‐square, Mann–Whitney U‐, and Kruskal–Wallis tests (P < 0.05 significant). Results The frequency of the three possible genotypes did not differ significantly between patients and controls [LEP (TTTC)_n: P = 0.43; LEPR R223Q: P = 0.94; PPARγ2 P12A: P = 0.94]. However, postpartal diastolic blood pressure of PIH patients was significantly higher in homozygous carriers of the LEPR Q223‐encoding allele as compared with patients carrying the wild‐type allele (P < 0.01). Conclusion Hypertensive disorders in pregnancy were not associated with the LEP, LEPR, and PPARγ2 polymorphisms studied. The role of other variations in the LEP and PPAR genes in the pathophysiology of PIH and in exacerbations are the objective of ongoing research.     

Association of the HLA‐B27 antigen and the CTLA4 gene CT60/rs3087243 polymorphism with ankylosing spondylitis in Algerian population: A case–control study

Ankylosing spondylitis (AS) is a complex inflammatory disease that represents a major health problem both in Algeria and worldwide. Several lines of evidence support that genetic risk factors play a role in AS etiology and the CTLA4 gene has attracted a considerable attention. In this study, we were interested in evaluating the HLA‐B27 frequency and in exploring the CTLA4 gene in a sample of the North African population. The dataset of the current study is composed of 81 patients with AS and 123 healthy controls. All samples were genotyped by TaqMan^®allelic discrimination assay. The genetic risk of the HLA‐B27 specificity and the CTLA4/CT60 polymorphism were assessed by odds ratios (OR) with 95% confidence intervals (CI). High spondylitis risk was detected for HLA‐B27 allele (OR= 14.62, p = 10^?6) in addition to a significant association of the CT60*G allele (OR= 1.89, p = .002). After gender and age stratifications, the association of the CT60*G allele was still significant in females sample (OR= 2.10, p = .001) and when age up to 30 years (OR = 2.21, p = .008). Interestingly, the CT60*G allele revealed an increased spondylitis risk in the B27 negative group (OR= 2.81, p = .006). The present work showed in West Algerian population that the HLA‐B27 antigen and the variation in the CTLA4 3′UTR region played an important role in the ankylosing spondylitis susceptibility. The heterogeneity of this disease is deduced by genetic difference found between B27+ and B27? groups.     

IL‐12B and IL‐10 gene polymorphisms in the development of Hashimoto's thyroiditis

Functional genetic polymorphisms that altered gene expression of cytokines are candidate genetic factors that could modulate the development and progression of Hashimoto's thyroiditis (HT). IL‐12B gene encoded the IL‐12p40 subunit, which is included in the pro‐inflammatory heterodimeric cytokines IL‐12p70 and IL‐23. IL‐10 is an important Treg cytokine suppressing inflammatory cytokine production and autoimmunity. This study was designed to compare ?1082A/GIL‐10 and +1188A/C3′UTRIL‐12B genotype distribution in 130 patients with HT to a group of 157 healthy controls in attempts to determine an association with HT development. Genotyping for the 3′UTRA/C IL‐12B polymorphism was performed using RFLP‐PCR and genotyping for ?1082A/G IL‐10 by ARMS‐PCR assay. Patients with HT were divided into euthyroid and hypothyroid stages. There were no significant differences in the genotype and allele frequencies of the IL‐12B polymorphism between patients with HT and controls. We observed higher euthyroid HT risk for individuals with CC genotype, unlike to develop hypothyroidism with OR = 1.68. Regarding the polymorphism rs1800896, it was shown the significantly higher frequency of homozygous genotype GG in cases vs controls (OR = 2.19; P = 0.024). Moreover, the combination of genotype AA of 3′UTRIL‐12B with GG of ?1082IL‐10 was associated with a threefold increasing risk (OR = 3.188; P = 0.022) of developing HT compared to individuals with the presence of 3′UTR allele C (AC+CC) simultaneously with AA genotype of ?1082IL‐10. Our data raise the possibility that the combined effect of polymorphisms from proinflammatory and anti‐inflammatory cytokines may be more decisive to HT development.     

Investigation of Associations between Obesity and LEP G2548A and LEPR 668A/G Polymorphisms in a Turkish Population

Objective. Obesity is a complex heterogeneous disease that is caused by genes, environmental factors, and the interaction between the two. The leptin (LEP) and leptin receptor (LEPR) genes have been evaluated for polymorphisms that could potentially be related to the pathophysiology of obesity and its complications. The aim of this study was to investigate the role of LEP G2548A and LEPR 668A/G polymorphisms in the pathogenesis of obesity. Subjects. The study included 127 patients with obesity and 105 healthy controls. Polymerase chain reaction and restriction fragment length analysis for LEP G2548A and LEPR 668A/G polymorphisms were applied. Results. There was no statistically significant difference in the genotype frequencies of the LEP gene polymorphism between patients and control groups (P > 0.05). We found a difference in the LEPR genotypes between patients and controls, but this was not statistically significant (P = 0.05). Additionally, we found an increased risk of obesity in the LEP/LEPR GG/GG combined genotype (P < 0.05). Conclusion. Our findings indicate that the LEP G2548A polymorphism is not a relevant obesity marker and that the LEPR 668A/G polymorphism may be related to obesity in a Turkish population. Further researches with larger patient population are necessary to ascertain the implications of LEP and LEPR polymorphisms in obesity.     

Influence of the leptin G‐2548A polymorphism on leptin levels and anthropometric measurements in healthy Spanish adolescents‡

Polymorphisms in the leptin gene (LEP) have been associated with leptin levels and obesity in some studies in adults though this link has scarcely been investigated in children. In our study, we examined the relationship of the LEP G‐2548A polymorphism with leptin levels, anthropometric variables and body composition in a population‐based sample of pubescent children. Our study included 880 healthy schoolchildren (419 males and 461 females), 12–16 years of age. Plasma leptin levels were determined by ELISA. The LEP polymorphism was determined by allelic discrimination TaqMan^® assay. Male carriers of the AA genotype had significantly lower plasma leptin levels than GA (p < 0.008) and GG (p < 0.001) carriers and significantly lower mean hip circumference (HC) values than GG carriers (p = 0.04). In girls, leptin levels were also lower in A‐allele carriers than in GG carriers, and BMI and HC were significantly lower in AA carriers as compared with GG carriers. In addition, the frequency of the A allele was significantly lower (χ²: 4.58, p = 0.032) in the OW‐obese than in the NW group. In conclusion, the LEP G‐2548A polymorphism is associated with variations in leptin levels, BMI and HC in Spanish pubertal children, and evidence suggests a link between the G allele and presence of overweight in girls.     

Serum Leptin Levels,Leptin Receptor Gene (LEPR) Polymorphism,and the Risk of Systemic Lupus Erythematosus in Kashmiri Population

The study is conducted to evaluate relationship between LEPRQ223R (Gln?>?Arg) polymorphism, serum leptin levels, soluble leptin receptor (SOb-R) levels and SLE risk in Kashmiri population.LEPR genotyping was done by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in 100 unrelated SLE patients and equal number of healthy control subjects. Leptin and SOb-R levels were measured by ELISA assays. The present study showed higher frequency of variant genotype (AG?+?GG) in cases compared to controls [OR?=?2.52, CI?=?1.18–5.35, p?=?0.03]. Moreover the rare (G) allele was significantly more predominant in cases than controls [OR?=?1.49, p?=?0.04]. Interestingly a positive association between the variant genotype and the development of arthritis [OR?=?11.8, CI?=?1.6–85.1, p?=?0.002] and an inverse association with cardiac disorder [OR?=?0.09, CI?=?0.02–0.46, p?=?0.001] was observed in this study. Furthermore the study showed significant differences of leptin levels in SLE patients and controls (23.9?±?19.5 vs 14.8?±?10.4, p?<?0.001). SLE patients in the highest quartile leptin levels (≥32.5?ng/mL) were significantly more likely to have higher BMI (p?=?0.001) and increased risk of developing arthritis (p?=?0.02). Furthermore positive association was observed between the variant genotype(AG?+?GG) and leptin levels (p?=?0.001) in SLE patients. Thus, it is evident from our study that LEPRQ223R polymorphism and elevated leptin levels are associated with increased susceptibility of SLE in Kashmiri population.     

Association of the G-2548A polymorphism in the 5' region of the LEP gene with overweight

Mutations in the translated part of the leptin gene ( LEP ) have been found in only two families. Nevertheless DNA polymorphisms in the LEP region are linked to extreme obesity. We previously found in the 5' region of LEP a polymorphism, G-2548A, associated with a difference in BMI reduction following a low calorie diet in overweight women. Recently, this polymorphism was associated with extreme obesity in women. In this work, we genotyped a new sample from the general population including 314 normal weight (BMI < 27 kg/m²) and 109 overweight subjects (BMI ≥ 27 kg/m²). The genotype and allele frequencies were significantly different between groups, with the G-2548 allele being more frequent in the overweight subjects ( p < 0.01). In men, carriers of this allele had lower leptin concentrations adjusted for fat mass ( p = 0.05). Our results indicate that variations at the leptin locus are associated with common obesity phenotypes, and not only with extreme obesity or the rare mendelian obesity syndromes.     

Pharmacogenetic Contribution of Leptin Gene Polymorphism in Cutaneous T-Cell Lymphoma

Leptin has recently attracted more attention due to its specific effects in the pathogenesis of malignancies. The aim of this study was to investigate the possible association between variants of −2548 G/A polymorphism in leptin (LEP) gene and cutaneous T-cell lymphomas (CTCL), with respect to the treatment responsiveness. A sample of 91 patients with CTCL was compared to 198 control individuals. The CTCL men with AG and/or GG genotype were more likely to receive the topical steroids treatment (odds ratio 7.88, 95% confidential interval 1.51-41.04) when compared to AA patients. Our data supports the possible involvement of LEP-2548G/A polymorphism in CTCL treatment responsiveness and thus might provide important information for individual therapy tailoring.     

Effects of MASP2 haplotypes and MASP‐2 levels in hepatitis C‐infected patients

Mannan‐binding lectin (MBL) and MBL‐associated serine protease 2 (MASP‐2) are components of the lectin pathway, which activate the complement system after binding to the HCV structural proteins E1 and E2. We haplotyped 11 MASP2 polymorphisms in 103 HCV patients and 205 controls and measured MASP‐2 levels in 67 HCV patients and 77 controls to better understand the role of MASP‐2 in hepatitis C susceptibility and disease severity according to viral genotype and fibrosis levels. The haplotype block MASP2*ARDP was associated with protection against HCV infection (OR = 0.49, p = .044) and lower MASP‐2 levels in controls (p = .021), while haplotype block AGTDVRC was significantly increased in patients (OR = 7.58, p = .003). MASP‐2 levels were lower in patients than in controls (p < .001) and in patients with viral genotype 1 or 4 (poor responders to treatment) than genotype 3 (p = .022) and correlated inversely with the levels of alkaline phosphatase, especially in individuals with fibrosis 3 or 4 (R = ?.7, p = .005). MASP2 gene polymorphisms modulate basal gene expression, which may influence the quality of complement response against HCV. MASP‐2 levels decrease during chronic disease, independently of MASP2 genotypes, most probably due to consumption and attenuation mechanisms of viral origin and by the reduced liver function, the site of MASP‐2 production.     

A polymorphism in the leptin receptor gene at position 223 is associated with growth hormone replacement therapy responsiveness in idiopathic short stature and growth hormone deficiency patients

We hypothesized that responses to growth hormone (GH) therapy by idiopathic short stature (ISS) and growth hormone deficiency (GHD) patients were associated with single nucleotide polymorphisms (SNPs) in the leptin (LEP) and leptin receptor (LEPR) genes. We retrospectively enrolled ISS (n = 32) and GHD (n = 38) patients and forty healthy age-and gender-matched children. They were genotyped for the LEP promoter at nt.-2548, and LEPR K109R and LEPR Q223R polymorphisms. Clinical and laboratory variables were determined before and after 2 years of GH treatment. ISS patients with G/A or A/A genotypes of the LEPR Q223R SNP had a significantly higher height velocity (cm/y) than ISS patients with the G/G genotype at 2 years after GH treatment. For GHD patients, G/A or A/A genotype of the LEPR K109R SNP was associated with higher body weight, higher BMI, and higher weight velocity than patients with the G/G genotype before GH treatment, but not after GH treatment. G/A or A/A genotype of the LEPR Q223R SNP was associated with a significantly higher body weight, higher height velocity before treatment, but not after GH treatment. G/A or A/A genotype of the LEPR Q223R SNP was associated with a significantly higher weight velocity before treatment, but a significantly lower weight velocity was found at 2 years after GH treatment. These results suggest LEPR Q223R SNP (rs1137101) is associated with outcomes of GH replacement therapy in ISS and GHD patients.     

Short course of grass allergen peptides immunotherapy over 3 weeks reduces seasonal symptoms in allergic rhinoconjunctivitis with/without asthma: A randomized,multicenter, double‐blind,placebo‐controlled trial

Background

Immunotherapy with peptide hydrolysates from Lolium perenne (LPP) is an alternative treatment for seasonal allergic rhinitis with or without asthma. The aim of this study was to assess the clinical efficacy and safety of a cumulative dose of 170 μg LPP administered subcutaneously over 3 weeks.

Methods

In a randomized, double‐blind, placebo‐controlled trial, 554 adults with grass pollen rhinoconjunctivitis were randomized (1:2 ratio) to receive 8 subcutaneous injections of placebo or 170 μg LPP administered in increasing doses in 4 visits over 3 weeks. The primary outcome was the combined symptom and medication score (CSMS) measured over the peak pollen season. Reactivity to conjunctival provocation test (CPT) and quality of life (QOL) was assessed as secondary endpoints.

Results

The mean reduction in CSMS in the LPP vs placebo group was ?15.5% (P = .041) during the peak period and ?17.9% (P = .029) over the entire pollen season. LPP‐treated group had a reduced reactivity to CPT (P < .001) and, during the pollen season, a lower rhinoconjunctivitis QOL global score (P = .005) compared with placebo group. Mostly mild and WAO grade 1 early systemic reaction (ESR) were observed ≤30 minutes in 10.5% of LPP‐treated patients, whereas 3 patients with a medical history of asthma (<1%) experienced a serious ESR that resolved with rescue medication.

Conclusion

Lolium perenne pollen peptides administered over 3 weeks before the grass pollen season significantly reduced seasonal symptoms and was generally safe and well‐tolerated.

     

The polymorphism ‐2548 G/A in leptin and severity of Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease characterized by airway obstruction that is not fully reversible, and there is evidence of a hereditary component in COPD. We aimed to determine whether the polymorphisms ‐2548G/A of leptin (LEP) gene were associated with COPD and its severity in Chinese. A total of 456 subjects with COPD and 422 healthy controls from West China Hospital were enrolled in this study. COPD patients had been undergone a spirometry and a physical examination to refer the GOLD I–IV stages. The polymorphisms in the leptin promoter region at position ‐2548 G/A were detected by Polymerase chain reaction‐restriction fragment length polymorphism analysis. The genotypes and alleles were scored, and the frequencies of the alleles and genotypes in patients and controls were compared. A significantly higher risk for COPD was observed for carriers of the LEP ‐2548 AA genotype [odds ratio (OR) = 7.87, 95% confidence interval (CI) 4.19–14.77, P < 0.001] and carriers of the LEP ‐2548 GA genotype (OR = 2.98, 95% CI 1.57–5.66, P = 0.001). The LEP ‐2548 A allele: frequency was significantly higher in the patient group compared with the control group (OR = 2.75, 95% CI: 2.20–3.44, P < 0.001). We also found a significant relationship between leptin gene polymorphism and the severity of COPD. In the present case–control study, we found an association between the ‐2548 G/A variant of the leptin gene and pathogenesis, severity of COPD in the Chinese population. It suggests that leptin ‐2548 G/A should be used as a genetic marker of COPD severity.     

Association of Helicobacter pylori infection with Toll‐like receptor‐4 Thr399Ile polymorphism increased the risk of peptic ulcer development in North of Iran

Toll‐like receptor‐4 (TLR4) polymorphisms may influence host immune response against Helicobacter pylori (H. pylori). This study aimed to investigate whether TLR4 polymorphisms are associated with H. pylori susceptibility and risk of peptic ulcer development or not. The TLR4 + 3725 G/C polymorphism was studied using polymerase chain reaction with confronting two‐pair primers (PCR–CTPP). In addition, TLR4 Asp299Gly and Thr399Ile polymorphisms were evaluated by PCR‐restriction fragment length polymorphism (RFLP). There was no significant difference in TLR4 + 3725 G/C and Asp299Gly genotype frequencies between non‐peptic ulcer (NPUD) and peptic ulcer (PUD) individuals in the context of peptic ulcer development and susceptibility to infection with H. pylori. Nevertheless, a significant association with increased risk for PUD development was observed for polymorphism TLR4 Thr399Ile [odds ratio (OR) = 4.2; 95% confidence interval (CI) = 1.35–13.26; p = 0.01]. Correspondingly, TLR4 Thr399Ile polymorphism was associated with H. pylori susceptibility (OR = 0.27; 95% CI = 0.08–0.88; p = 0.04). In addition, TLR4 Thr399Ile polymorphism increased 4.2‐fold, the risk of peptic ulcer development in individuals infected by H. pylori carrying CT + TT genotype. Our results showed that TLR4 Thr399Ile polymorphism along with H. pylori infection may play critical roles in peptic ulcer development in North of Iran.     

Association study of a SNAP‐25 microsatellite and attention deficit hyperactivity disorder

Several lines of evidence implicate synaptosomal‐associated protein of 25 kDa (SNAP‐25) in the etiology of attention deficit hyperactivity disorder (ADHD). Most notably, the coloboma mouse mutant, considered to be a good animal model of hyperactivity, has a deletion spanning this gene. Introducing a SNAP‐25 transgene into these animals alleviates hyperlocomotion. We have identified a novel microsatellite repeat in SNAP‐25 located between the 5′UTR and the first coding exon, and tested for association with ADHD. Case‐control analyses suggest there may be a role of this polymorphism in ADHD, with one allele over‐represented in controls and another over‐represented in probands. Within‐family tests of linkage and association confirmed these findings. Further work is needed to ascertain the role of SNAP‐25 in ADHD and assess the functional significance of this polymorphism. © 2002 Wiley‐Liss, Inc.     

Occurrence of class 1 integrons in uropathogenic fluoroquinolone‐resistant clinical Escherichia coli isolates from Jamaica

Quinolone resistance is generally caused by chromosomal mutations, but has been more recently found associated with the plasmid‐mediated qnr genes. The objective of this study was to screen and analyse polymorphisms of integrons in clinical isolates of Escherichia coli in Jamaica. Previous studies in Jamaica identified fluoroquinolone resistance in predominantly uropathogenic E. coli clinical isolates: 45% harbouring qnrA, qnrB and/or qnrS, and 17% were (Extended‐spectrum beta‐lactamase) ESBL‐producers. These isolates were analysed for the presence and variation of class 1 and 2 integrase genes, 5′‐ and 3′‐ conserved segments and the Orf513 recombinase gene by primer‐specific polymerase chain reaction (PCR) and restriction fragment‐length polymorphism (RFLP). Results indicated integron‐encoded integrases in 93% of isolates primarily harbouring class 1 integrase genes; four of 58 isolates carried both classes. The Orf513 and 5′‐ and 3′‐conserved segment (CS) regions were identified in 83% and 55% of the isolates respectively. RFLP evaluation of the 5′‐ and 3′‐CS regions in int1‐positive strains yielded two main types. The reduced diversity, but wide dispersion of class 1 integrons harbouring qnr genes may give rise to the conservation of the mobile genetic elements in which they are carried.     

Respiratory sinus arrhythmia and serotonin transporter promoter gene polymorphisms: Taking a triallelic approach makes a difference

It has been recently reported in Psychophysiology that carriers of the short allele of an insertion/deletion (ins/del) functional polymorphism in the promoter region (5‐HTTLPR) of the serotonin transporter gene may display decreased resting respiratory sinus arrhythmia (RSA). However, this region hosts another functionally connected single‐nucleotide polymorphism (rs25531), which should also be genotyped in order to correctly categorize the low‐ and high‐expressing alleles of 5‐HTTLPR. The present study investigated resting RSA in an ethnically homogenous sample (N = 143) of participants genotyped for both the ins/del and rs25531 polymorphisms in 5‐HTTLPR. In contrast with the biallelic genotypes, based only on the ins/del alleles, the triallelic 5‐HTTLPR genotypes (i.e., including rs25531) showed no association with resting RSA. Taking a triallelic approach to 5‐HTTLPR is thus necessary in order to avoid false positive results.     

APP and BACE1 miRNA genetic variability has no major role in risk for Alzheimer disease

Expression levels of the amyloid precursor protein (APP) and β‐site amyloid (Aβ) cleaving enzyme 1 (BACE1) have been implicated in Alzheimer disease (AD) progression. In a well‐characterized Belgian group of 358 AD patients and 462 controls, we examined whether genetic variability in microRNA (miRNA) binding sites of APP and BACE1 or in associated miRNAs influenced risk for AD. Direct sequencing identified six variants in the 3′ untranslated region (UTR) of APP and 29 variants in the 3′ UTR of BACE1, of which few variants were restricted to patients: in APP; 4 variants in 6 patients (～2%) and in BACE1; 7 variants in 11 patients (～3.5%). Further genetic screening of the miR‐29 cluster encoding the miR‐29a/b‐1 genes showed 10 variants in close proximity of this cluster. Association studies using all common variants detected in the 3′ UTR of BACE1 and the miR‐29 gene cluster did not identify an association with AD risk. However, we did observe statistical interaction between rs535860 (BACE1 3′ UTR) and rs34772568 (near miR29a; odds ratio [OR]_interaction, 0.4; 95% confidence interval [CI], 0.17–0.96; P=0.033). While the exact role of the patient‐specific miRNA variants within the 3′ UTR region of APP and BACE1 demands further analyses, this study does not support a major contribution of miRNA genetic variability to AD pathogenesis. Hum Mutat 30:1–7, 2009. © 2009 Wiley‐Liss, Inc.     

Pro‐ and anti‐inflammatory cytokine gene single‐nucleotide polymorphisms in inflammatory bowel disease

Anti‐inflammatory cytokines have an important role in disease, tumour and transplant processes. Alterations in the regulation of several cytokines have been implicated in a variety of inflammatory disorders, including IBD (inflammatory bowel disease) [Crohn′s disease (CD) and ulcerative colitis (UC)]. Cytokine polymorphisms are also known to affect the level of gene expression. Thus, the aim of this study was to determine the relationship between cytokine polymorphisms and the IBD pathologies in a Spanish population. Polymorphisms analysis was performed using PCR‐SSOP using a microbeads luminex assay. The following polymorphisms were determined: TNFα [?238G/A (rs361525) and ?308G/A (rs1800629)], IFNγ [+874A/T (rs62559044)], TGFβ [+869C/T (rs1982073) and +915G/C (rs1800471)], IL10 [?1082A/A (rs1800896), ?592A/C (rs1800872), ?819C/T (rs1800871)], IL6 [?174C/G (rs1800795)], IL12p40 [3′UTR ?1188A/C (rs3212227)], IL1α [?889C/T (rs1800587)], IL1β [?511C/T (rs1143634) and +3962C/T (rs1143633)], IL1R [Pst‐1 1970C/T] and IL1RA [Mspa‐1 11100C/T]. No statistical differences in TNFα, IFNγ, TGFβ, IL10, IL6, IL1α, IL1β, IL1R and IL1Ra genotypes and allele distributions between the IBD groups and healthy controls were found. However, we observed significant differences in the 3′UTR ?1188A/C polymorphism of IL12p40. So ?1188A allele was increased in patients with UC and the ?1188C allele (high IL12p40 production) was increased in patients with CD with respect to controls. These data are in concordance with the fact that CD has been shown to be associated with a Th1 T‐cell‐mediated inflammation model and high IL12/IFNγ production at histological affected sites. These data suggest that cytokine polymorphisms in TNFα, IFNγ, TGFβ, IL10, IL6 and IL1α, IL1β, IL1R and IL1Ra cytokine gene do not seem to be relevant in IBD susceptibility and IL12p40 3′UTR ?1188A/C polymorphism seems to be associated with a differential IBD development.