IL1B gene polymorphisms influence the course and severity of inflammatory bowel disease

 There is evidence of a disbalance in the inflammatory regulation of patients with inflammatory bowel diseases (IBD). Interleukin-1β plays an important role in the pro-inflammatory response. Our aim was to study the influence which IL1B gene polymorphisms may have on the severity and course of these diseases. Ninety-six patients with ulcerative colitis (UC), 98 patients with Crohn's disease (CD), and 132 ethnically matched healthy individuals (HC) were typed for the polymorphic sites in the promoter region (position –511) and in exon 5 (position +3953) of the IL1B gene, using polymerase chain reaction (PCR)-based methods. In the CD group a significant association (P=0.009) was found in this pair of genes. Homozygotes for allele 1 at position +3953 were more often present (69% vs 31%) in the subgroup of patients carrying at least one copy of allele 2 at position –511. This association was significant in patients with non-perforating disease (P=0.002), but was not present in patients with perforating-fistulizing disease. The distribution of both allelic pairs in the non-fistulizing group proved to be significantly different from HC (P<0.05), UC (P<0.03), and the fistulizing group (P<0.05). There was a similar association in non-operated patients (P=0.024), whereas no such association was found in surgically treated patients. Among carriers of allele 2 at position –511, UC patients with more severe bleeding symptoms (P=0.006) were less frequently found. These results suggest that IL1B gene polymorphisms participate in determining the course and severity of inflammatory bowel disease and contribute to explain the heterogeneity of these diseases. Received: 16 July 1998 / Revised: 3 November 1998     

CTLA4 is differentially associated with autoimmune diseases in the Dutch population

Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) is an important negative regulator of T-cell response and its genetic association with type 1 diabetes (T1D) has recently been demonstrated. The frequent co-association of autoimmune diseases (AID) and the implication from multiple genome scans that the CTLA4 gene region is a general autoimmune region, led us to study the role of CTLA4 in independent cohorts of T1D, coeliac disease (CD) and rheumatoid arthritis (RA) patients. We present independent data that confirm the association of CTLA4 in Dutch patients with juvenile onset T1D and show differential association of CTLA4 with CD and RA. The CTLA4 gene polymorphisms were tested for association in 350 T1D, 310 CD, 520 RA patients and 900 controls. In addition, 218 families were tested by the transmission disequilibrium test (TDT). T1D patients showed the highest association with the MH30*G: −1147*C: +49*G: CT60*G: JO37_3*G (haplotype 2) in both a case/control cohort (P=0.002, OR=1.42) and by TDT (P=0.02, OR=1.43). In contrast, this haplotype showed no association in the RA and CD cohorts. However, we observed an increased frequency of the MH30*G: −1147*T: +49*A: CT60*G: JO37_3*A (haplotype 3) in the CD patients diagnosed at a young age (OR=1.6, P=0.026, P _c=0.052). Furthermore, when T1D and CD patients were stratified based on the HLA risk, the T1D susceptible CTLA4 haplotype 2 was over-represented in the high HLA-risk T1D and CD groups. In conclusion, we confirmed association between CTLA4 haplotype 2 and T1D in the Dutch population. Association with another CTLA4 haplotype (haplotype 3) was confirmed for CD, but only in those patients who had an early age of expression. No effect was found between RA and CTLA4. The association of the CTLA4 haplotype 2 with the high-risk HLA genotype in T1D and CD, which share DQ2 as the one of high-risk alleles, might provide a clue to understanding the common genetic background of AID.Electronic Supplementary Material Supplementary material is available for this article at An erratum to this article can be found at     

Evidence for an association between markers on chromosome 19q and non-syndromic cleft lip with or without cleft palate in two groups of multiplex families

It has been reported that BCL3 on chromosome 19q, or a nearby gene, may play a role in the etiology of non-syndromic cleft lip with or without cleft palate (NSCL/P) in some families. We tested 30 USA and 11 Mexican multiplex NSCL/P families for four markers on chromosome 19q: D19S178, APOC2/AC1, APOC2/007, and BCL3. While likelihood-based linkage analysis failed to show significant evidence of linkage, the transmission disequilibrium test indicated highly significant deviation from independent assortment of allele 3 at the BCL3 marker in both data sets (USA:P = 0.001; Mexican: P = 0.018; both combined: P < 0.001) and for allele 13 of the D19S178 marker in the Mexican data set (P = 0.004). These results support an association, possibly due to linkage disequilibrium, between chromosome 19 markers and a putative NSCL/P locus. Received: 10 May 1996 / Revised: 31 July 1996     

The association of interleukin-21 polymorphisms with interleukin-21 serum levels and risk of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is one of the common autoimmune diseases, with complex genetic components. Interleukin-21 (IL-21) is the most recently discovered member of the type-I cytokine family, which has a variety of effects on the immune system, including B cell activation, plasma cell differentiation, and immunoglobulin production. Previous studies have identified that IL-21 was associated with different autoimmune and inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis and SLE. Variations in the DNA sequence in the IL-21 gene may lead to altered IL-21 production and/or activity, and thus this can modulate an individual's susceptibility to SLE. To test this hypothesis, we investigated the association of the IL-21 polymorphisms and its serum levels with the risk of SLE in a Chinese population. We analyzed three single nucleotide polymorphisms of IL-21 gene rs907715 C/T, rs2221903 T/C and rs2055979 C/A in 175 patients with SLE and 190 age- and sex-matched controls, using Snapshot SNP genotyping assays and DNA sequencing method. Soluble IL-21 (sIL-21) levels were measured by ELISA. There were significant differences in the genotype and allele frequencies of IL-21 gene rs2055979 C/A polymorphism between the group of patients with SLE and the control group (P < 0.05). sIL-21 levels were increased in patients with SLE compared with controls (P < 0.01). Moreover, genotypes carrying the IL-21 rs2055979 A variant allele were associated with increased IL-21 levels compared to the homozygous wild-type genotype in patients with SLE. The rs2055979 C/A polymorphism of IL-21 and its sIL-21 levels were associated with SLE in the Chinese population. Our data suggests that IL-21 gene may play a role in the development of SLE.     

Serum interleukin-1β as a marker for differentiation of asthma and chronic obstructive pulmonary disease

Asthma and chronic obstructive pulmonary disease (COPD) are diseases of airway inflammation with clinical and physiological similarities, making their differentiation difficult. Airway inflammatory changes are associated with systemic changes. However, no serum marker is known for their differentiation. Therefore, serum interleukin (IL)-1β levels were determined. Out of a total of 1023 patients screened, we included in the study ten patients each with atopic asthma, non-atopic asthma and COPD and ten healthy subjects. Skin prick tests with 14 inhalant allergens were performed on each patient. Blood was collected in the symptomatic and asymptomatic phases of the diseases and serum IL-1β and IgE levels were determined. Our results showed that in the symptomatic phase in asthmatics, serum IL-1β levels were higher (P<0.05) than in patients with COPD. Serum IgE levels were higher (P<0.05) in atopic asthmatics than in non-atopic asthmatics and in COPD patients. We conclude that serum IL-1β level determination during the symptomatic phase of the diseases may help to differentiate asthmatics from patients with COPD. Serum IgE levels may differentiate atopic asthmatics from non-atopic asthmatics and COPD patients.     

KCNQ1 and type 2 diabetes: study in Hubei Han Chinese and meta-analysis in East Asian populations

Recent genome-wide association studies in East Asian poulations reported the association of KCNQ1 variants with type 2 diabetes. In the present study, we first investigated the association between rs2237892 in KCNQ1 and type 2 diabetes in a Hubei Han Chinese population (223 type 2 diabetes patients and 201 controls). The frequencies of CC genotype and C allele in type 2 diabetes patients were significantly higher than those of controls group (CC: 51.6% vs 39.3%, P=0.001; C: 72.2% vs 61.2%, P=0.001). The odds ratio for the risk allele C was 1.65 (95%CI 1.23–2.2, P=0.001). Then, we systematically reviewed the association of SNPs (rs2237892, rs2237895, rs2237897, rs2074196) in KCNQ1 with type 2 diabetes risk in a meta-analysis. Significant heterogeneity between studies was found for SNPs rs2237892 and rs2237897. Combined odds ratios of the rs2237892 C, rs2237895 C, rs2237897 C, rs2074196 G allele were 1.35 (95% CI 1.29–1.41, P<0.0001), 1.27 (95%CI 1.23–1.32, P<0.0001), 1.32 (95%CI 1.21–1.43, P<0.0001), 1.30 (95%CI 1.25–1.35, P<0.0001) respectively. Our results and meta-analysis demonstrated that KCNQ1 polymorphisms were reproducibly associated with the risk of type 2 diabetes in Han Chinese and East Asian populations.     

Association between vitamin D receptor gene polymorphisms and type 1 diabetes mellitus in Iranian population

Type 1 diabetes mellitus (T1DM) is one of the T-cell mediated autoimmune diseases and vitamin D suppresses activation of T-cell and has immunomodulatory effects. In this study the association between four vitamin D receptor (VDR) gene polymorphisms, at positions FokI, BsmI, ApaI and TaqI, and susceptibility to T1DM was investigated. We assessed 87 Iranian patients with T1DM and one hundred healthy controls with no history of diabetes or other autoimmune diseases. Our results demonstrated that genotypes frequency of the TaqI VDR polymorphism differed significantly between T1DM patients and controls, TT genotype and T allele was more frequent in healthy controls compared with TIDM patients (P = 0.003; OR = 0.51, 95% CI = 0.31–0.84). Therefore, allele t is the risk-allele for developing TIDM in this study. No significant association was observed between others VDR SNPs and disease susceptibility. In conclusion, our case-control study indicated that the VDR TaqI polymorphism is associated with TIDM in Iranian population.     

Genetic variation in the apolipoprotein H (β2-glycoprotein I) gene affects plasma apolipoprotein H concentrations

Apolipoprotein H (apoH, protein; APOH, gene) is a single chain glycoprotein that exists in plasma both in a free form and in combination with lipoprotein particles. ApoH has been implicated in several physiologic pathways, including lipid metabolism, coagulation, and the production of antiphospholipid antibodies. The wide range of interindividual variation in plasma apoH levels is thought to be under genetic control, but its molecular basis is unknown. APOH displays a common structural polymorphism with the occurrence of three common alleles (APOH*1, APOH*2, and APOH*3), the APOH*2 allele being the most frequent in all populations. The relationship between the APOH polymorphism and plasma apoH levels is unknown. In this study, we have determined the impact of this APOH polymorphism on apoH levels in 455 normoglycemic non-Hispanic Whites (220 men and 235 women) from the San Luis Valley, Colorado. Mean plasma apoH levels, determined by capture enzyme-linked immunosorbent assay, were 20.0±0.2 mg/dl (range: 3.4–31.2 mg/dl) with no significant difference between men and women. In women, but not in men, age had a significant effect on plasma apoH levels explaining 3.4% of its phenotypic variance. ApoH levels also correlated positively with cholesterol (P=0.015), HDL-cholesterol (P=0.044), and triglyceride (P=0.037) in women, but not in men. An analysis of variance (ANOVA) of adjusted plasma apoH levels showed significant association with the APOH polymorphism in both men and women (P<0.0001), and the APOH polymorphism accounted for 11.4% and 13.6% of the variation in apoH levels in men and women, respectively. Compared with the APOH*1 and APOH*2 alleles, the APOH*3 allele was associated with significantly lower plasma apoH levels. At the molecular level, APOH*3 can be further subdivided into two distinct forms, called APOH*3 ^W and APOH*3 ^B . The APOH*3 ^W form is more common in US Whites and is the result of a missense mutation at codon 316. An ANOVA for the codon 316 polymorphism revealed that this polymorphism is a major determinant of plasma apoH variation (P<0.0001). This study indicates that common genetic variation in the APOH gene is a significant determinant of plasma apoH levels in non-Hispanics Whites and should be useful in evaluating the role of the APOH genetic variation in various metabolic pathways in which apoH has been implicated. Electronic Publication     

Association of the polymorphisms of the <Emphasis Type="Italic">ERBB3</Emphasis> and <Emphasis Type="Italic">SH2B3</Emphasis> genes with type 1 diabetes

To study the association with diabetes mellitus type 1, we analyzed the distribution of allele and genotype frequencies of polymorphic marker rs2292239 of ERBB3 gene, encoding epidermal growth factor receptor type 3 and polymorphic marker rs3184504 of SH2B3 gene, encoding adaptor protein LNK. The study included groups of T1DM patients and unrelated controls of Russian origin. Genotyping was performed using RFLP and real-time amplification methods. No statistically significant association with type 1 diabetes was found for the polymorphic marker rs2292239 of ERBB3, while the analysis of the distribution of allele and genotype frequencies of the polymorphic marker rs3184504 of SH2B3 gene revealed the association with T1DM in the Russian population.     

Association of tumor necrosis factor alpha, interferon gamma and interleukin 10 gene polymorphisms with peripheral neuropathy in South Indian patients with type 2 diabetes

Diabetic peripheral neuropathy (DPN) is a major global health threat and a common complication of diabetes. Peripheral nerve complications due to irregular cytokine production are eminent factors in many inflammatory diseases. The present study focused on gene polymorphisms of pro and anti-inflammatory cytokines that may be responsible for nerve damage in diabetic neuropathy. We examined three common functional SNPs primarily at the positions on genes of tumor necrosis alpha (TNFα) −308G/A, interferon gamma (IFNγ) +874A/T and interleukin (IL) 10 −1082G/A in order to establish their association with peripheral neuropathy in type 2 diabetes. Results: Genotypic frequencies obtained from TNFα −308G/A gene analysis in DPN group comprised 86.4% of G/A, 10.6% of G/G and 3% of A/A genotype, where as the control group had 94% of G/A, 2% of G/G and 4% of A/A which could not reach the statistical significance with the disease after Bonferroni correction. The IFNγ +874 A/T polymorphism in patient group revealed 33.3% of A/A, 47.5% of A/T and 19.2% of T/T genotype. The A/A genotype had attained statistical significance of P = 0.04 (P corrected); OR 2; 95% CI 1.14–3.64 when compared to controls. The IL10 −1082 G/A polymorphism in the patient group has showed 62.6% of A/A, 21.2% of G/A, 16.2% of G/G genotype, revealing significant association with G/G genotype (P < 0.01, OR 2.9; 95% CI 1.47–5.84) when compared to controls. Conclusion: Our findings indicate that the tested markers within the IFNγ and IL-10 genes, but not the TNFα gene, are significantly associated with peripheral neuropathy in South Indian type 2 diabetic patients. The study shows that the ‘high-producer’ IL-10 −1082 G/G genotype and the ‘low-producer’ IFNγ +874 A/A genotype may be responsible for the down regulation of immune response leading to inflammation in this setting.     

Allelic variation adjacent to the human insulin and apolipoprotein C-II genes in different ethnic groups

Summary We have used DNA probes for the human insulin gene and apolipoprotein C-II (apo C-II) gene to determine the extent of allelic variation in different ethnic groups. The distribution of an apo C-II DNA polymorphism revealed by the restriction endonuclease Taq I showed no significant variation amongst racial groups; in contrast, an insulin gene-related DNA polymorphism showed marked variability. In Japanese, Chinese, and Asian Indian groups there was an increased frequency of homozygosity for the class 1 allele compared to Caucasian groups (P<0.001, P<0.01, and P<0.05, respectively). In Caucasian, Japanese, Chinese, and Asian Indian groups no class 2 allele was observed; but in the Negroid populations (African and West Indian) the class 2 allele frequencies were 0.23 and 0.25 respectively. Possible reasons for this variation in allele distribution are considered in relation to disease associations.     

Prognostic value of interleukin-1 receptor antagonist gene polymorphism and cytomegalovirus seroprevalence in patients with coronary artery disease

Background

Chronic inflammatory stimuli such as cytomegalovirus (CMV) infection and various genetic polymorphisms determining the inflammatory response are assumed to be important risk factors in atherosclerosis. We investigated whether patients with stable coronary artery disease (CAD) and homozygous for allele 2 of the interleukin 1 receptor antagonist (IL-1RA) gene and seropositive for CMV represent a group particular susceptible for recurrent cardiovascular events.

Methods

In a series of 300 consecutive patients with angiographically defined CAD a prospective follow-up was conducted (mean age 57.9 years, median follow-up time 38.2 months).

Results

No statistically significant relationship was found between CMV serostatus and IL-1RN*2 (alone or in combination) and risk for future cardiovascular events (CVE). The hazard ratio (HR) for a CVE given positive CMV-serology and IL-1RN*2 was 1.07 (95% confidence interval (CI) 0.32–3.72) in the fully adjusted model compared to seronegative CMV patients not carrying the IL-1RN*2 allele. In this prospective cohort study involving 300 patients with angiographically defined CAD at baseline, homozygousity for allele 2 of the IL-1 RA and seropositivity to CMV alone and in combination were not associated with an increased risk for cardiovascular events during follow-up; in addition, combination of the CMV-seropositivity and IL-1RN*2 allele were not associated with a proinflammatory response

Conclusion

Our study suggests that seropositivity to CMV and IL-1RA*2 genotype alone or in combination might not be a strong risk factor for recurrent cardiovascular events in patients with manifest CAD, and is not associated with levels of established inflammatory markers.     

Pericardial Fat Volume Correlates With Inflammatory Markers: The Framingham Heart Study

The objective of this study was to determine whether systemic inflammatory and oxidative stress marker concentrations correlate with pericardial and intrathoracic fat volumes. Participants of the Framingham Offspring Study (n = 1,175, 53% women, mean age 59 ± 9 years) had pericardial and intrathoracic fat volumes assessed by multidetector computed tomography (MDCT) scans, and provided fasting blood and urine samples to measure concentrations of 14 inflammatory markers: C‐reactive protein (CRP), interleukin‐6, monocyte chemoattractant protein‐1 (MCP‐1), CD40 ligand, fibrinogen, intracellular adhesion molecule‐1, lipoprotein‐associated phospholipase A₂ activity and mass, myeloperoxidase, osteoprotegerin, P‐selectin, tumor necrosis factor‐α, tumor necrosis factor receptor‐2, and urinary isoprostanes. Multivariable linear regression models were used to determine the association of log‐transformed inflammatory marker concentrations with fat volumes, using fat volume as the dependent variable. Due to smaller sample sizes, models were rerun after adding urinary isoprostanes (n = 961) and tumor necrosis factor‐α (n = 813) to the marker panel. Upon backward elimination, four of the biomarkers correlated positively with each fat depot: CRP (P < 0.0001 for each fat depot), interleukin‐6 (P < 0.05 for each fat depot), MCP‐1 (P < 0.01 for each fat depot), and urinary isoprostanes (P < 0.01 for pericardial fat; P < 0.001 for intrathoracic fat). Even after adjusting for BMI, waist circumference (WC), and abdominal visceral fat, CRP (P = 0.0001) and urinary isoprostanes (P = 0.02) demonstrated significant positive associations with intrathoracic fat, but not with pericardial fat. Multiple markers of inflammation and oxidative stress correlated with pericardial and intrathoracic fat volumes, extending the known association between regional adiposity and inflammation and oxidative stress.     

Genetic influences on Alzheimer's disease: evidence of interactions between the genes APOE, APOC1 and ACE in a sample population from the South of Brazil

Alzheimer’s disease is a complex neurodegenerative disorder. Several genes have been suggested as Alzheimer’s susceptibility factors, the apolipoprotein E (APOE) gene being an established susceptibility gene and the genes coding angiotensin-converting enzyme (ACE) and apolipoprotein C1 (APOC1) being considered possible candidate genes for the disease. The objective of this study was to investigate the association of ACE and APOC1 gene polymorphisms with susceptibility to Alzheimer’s disease and dementia in general, both alone and combined with the APOE gene. Forty-seven patients with dementia in general (35 of them with Alzheimer’s disease) and 85 controls were investigated. The haplotypes E*3/−317*ins and E*4/−317*ins of APOE/APOC1 genes were significantly more frequent in the groups with Alzheimer′s disease and dementia in general (P < 0.001). The frequency of the ACE*ins allele was also greater in the groups with Alzheimer’s disease and dementia in general (P = 0.022; P = 0.045), but genotype frequencies were only different in groups without the E*4/−317*ins haplotype (P = 0.012 for Alzheimer’s disease; P = 0.04 for dementia). Our data point to important genetic interactions involved in these diseases.     

Association between Type 2 Diabetes and CDKN2A/B: a meta-analysis study

Cyclin-dependent kinase inhibitor-2A/B (CDKN2A/B) has been reported as a candidate gene of type 2 diabetes (T2D) based on its chromosomal position and its important role in β-cell function and regeneration. However, studies to date have reported inconsistent findings regarding the association between T2D and CDKN2A/B. To clarify this inconsistence, we conducted a meta-analysis based on alleles and genotypes prevalence of rs10811661 and rs564398 in CDKN2A/B. The PubMed, EMBASE, and Medline databases were systematically reviewed for studies published between January, 2006, and November, 2010. A total of 35 reports were collected, among of them only 16 studies (including 24,407 cases and 33,937 controls) match the inclusion criteria and were selected for the statistical test. In the meta-analysis of published data, our results suggest that the rs10811661 T allele (OR 1.28, 95% CI 1.21–1.36, P < 1 × 10⁻⁵) and TT genotype (OR 1.32, 95% CI 1.22–1.43, P < 1 × 10⁻⁵) of CDKN2A/B were associated with type 2 diabetes respectively, but rs564398 was not (for allele only: OR 0.96, 95% CI 0.88–1.05, P = 0.35). The association between rs10811661 T allele and T2D was observed both in Asia (P < 1 × 10⁻⁴) and Europe ethnicity groups (P = 0.002). This meta-analysis yielded evidence that rs10811661 of CDKN2A/B confers risk for T2D. Larger studies with mixed ethnicity subjects are required to validate our findings.     

Maternal inflammatory diet and adverse pregnancy outcomes: Circulating cytokines and genomic imprinting as potential regulators?

Excessive inflammation during pregnancy alters homeostatic mechanisms of the developing fetus and has been linked to adverse pregnancy outcomes. An anti-inflammatory diet could be a promising avenue to combat the pro-inflammatory state of pregnancy, particularly in obese women, but we lack mechanistic data linking this dietary pattern during pregnancy to inflammation and birth outcomes. In an ethnically diverse cohort of 1057 mother-child pairs, we estimated the relationships between dietary inflammatory potential [measured via the energy-adjusted dietary inflammatory index (E-DII?)] and birth outcomes overall, as well as by offspring sex and maternal pre-pregnancy body mass index (BMI). In a subset of women, we also explored associations between E-DII, circulating cytokines (n = 105), and offspring methylation (n = 338) as potential modulators of these relationships using linear regression. Adjusted regression models revealed that women with pro-inflammatory diets had elevated rates of preterm birth among female offspring [β = ?0.22, standard error (SE) = 0.07, P<0.01], but not male offspring (β=0.09, SE = 0.06, P<0.12) (P_interaction = 0.003). Similarly, we observed pro-inflammatory diets were associated with higher rates of caesarean delivery among obese women (β = 0.17, SE = 0.08, P = 0.03), but not among women with BMI <25 kg/m² (P_interaction = 0.02). We observed consistent inverse associations between maternal inflammatory cytokine concentrations (IL-12, IL-17, IL-4, IL-6, and TNFα) and lower methylation at the MEG3 regulatory sequence (P<0.05); however, results did not support the link between maternal E-DII and circulating cytokines. We replicate work by others on the association between maternal inflammatory diet and adverse pregnancy outcomes and provide the first empirical evidence supporting the inverse association between circulating cytokine concentrations and offspring methylation.     

The PECAM-1 gene polymorphism — a genetic marker of myocardial infarction

We investigated a possible association between the C373G (Leu125Val) polymorphism in the platelet endothelial cell adhesion molecule-1 (PECAM-1) and myocardial infarction (MI) among patients with type 2 diabetes (T2DM) in the Slovene population (Caucasians). The study population of this cross-sectional analysis consisted of 452 subjects with T2DM lasting more than 10 years: 142 patients with MI (MI group) and 310 patients (control group) with no history of coronary diseases. There were significant differences of PECAM-1 genotype distribution in patients with MI (CC=28.2%, CG=47.2% and GG=24.6%) compared with subjects in the control group (CC=17.1%, CG=53.5% and GG=29.4%). The multivariate model showed that the CC genotype of the PECAM-1 gene polymorphism (C373G) (OR=1.9, 95% CI 1.2–3.0, P=0.007) was an independent risk factor for MI. The C allele frequency was also significantly higher (P=0.005) in MI (51.8%) than in control subjects (41%). In addition, our study revealed the connection between smoking habits, the duration of diabetes and the total and LDL cholesterol serum levels and MI in Slovene T2DM patients. We suggest that the tested polymorphism of PECAM-1 (C373G) is associated with MI. Therefore, it might be used as genetic marker of MI in T2DM.     

Interleukin IL-1B gene polymorphism in Tunisian patients with chronic hepatitis B infection: Association with replication levels

Approaches based on association studies have proven useful in identifying genetic predictors for many diseases, including susceptibility to chronic hepatitis B. In this study we were interested by the IL-1B genetic variants that have been involved in the immune response and we analyzed their role in the susceptibility to develop chronic hepatitis B in the Tunisian population. IL - 1B is a potent proinflammatory cytokine that plays an important role in inflammation of the liver. Polymorphic gene IL-1 ( − 511, +3954) was analyzed in a total of 476 individuals: 236 patients with chronic hepatitis B from different cities of Tunisia recruited in Pasteur Institute between January 2017 and December 2018 and 240 controls. Genomic DNA was obtained using the standard salting-out method and genotyping was performed by polymerase chain reaction (PCR)-restriction fragment length polymorphism. For − 511C>T polymorphism a significant association was found between patients and controls when comparing the genotypic (P = 0.007; χ² = 9.74 and odds ratio [OR] = 0.60; confidence interval [CI] = 0.41–0.89) and allelic (P = 0.001; χ² = 10.60) frequencies. When the viral load was taken into account a highly significant difference was found (P = 9 × 10⁻⁴; χ² = 10.89). For +3954C>T polymorphism a significant association was found between patients and controls when comparing genotypic (P = 0.0058; χ² = 7.60 and OR = 1.67; CI = 1.14–2.46) and allelic (P = 0.0029; χ² = 8.81) frequencies. T allele can be used as a strong marker for hepatitis B virus disease for both polymorphisms.     

New genomic region for Wegener’s granulomatosis as revealed by an extended association screen with 202 apoptosis-related genes

Wegeners granulomatosis (WG) is a systemic disease with complex genetic background. It is characterized by necrotizing granulomatous inflammation of the upper and lower respiratory tract, glomerulonephritis, vasculitis and the presence of antineutrophil cytoplasmatic autoantibodies (C-ANCAs) in sera of patients. Here, we report on an extended association screen (EAS) with 202 microsatellite markers, representing apoptosis-related genes and further genes down-regulated in apoptotic neutrophils, using pooled DNA of 150 Northern German patients suffering from WG and 100 healthy Northern German controls. Six microsatellite allele patterns were found significantly associated with WG, three of which could be confirmed by individual genotyping. One marker remained significantly associated after multiple corrections. This marker representing the retinoid X receptor ß gene (RXRB, P=7.60×10^–6, distance to gene: ~5.3 kb) is localised in the major histocompatibility complex (MHC) region between the HLA-DPB1 and DAXX genes. HLA-DPB1 typing and fine mapping of the region with additional microsatellites and single-nucleotide polymorphisms (SNPs) revealed a strong association of WG with the significantly over-represented DPB1*0401 (P=1.51×10^–10, OR=3.91) allele compared with the control cohort. In addition, an extended haplotype DPB1*0401/RXRB03 was identified showing an even stronger association with WG (P=7.13×10^–17, OR=6.41). These results represent the strongest association of a genomic region with WG, suggesting a major genetic contribution in the aetiology of the disease. Thus, our data demonstrate that EAS may be a valuable alternative approach for determining genetic predisposition factors in multifactorial diseases.P. Jagiello and M. Gencik contributed equally to this work