Genetics in liver diseases

In recent years, few fields in medicine have witnessed discoveries as momentous as those pertaining to the liver. Dramatic advances have been made, particularly in the areas of molecular biology and genetics. A joint EASL/AASLD Monothematic Conference was held on June 23rd-24th, 2006, in Modena, Italy, to bring the latest breakthroughs in different fields of genetics to hepatologists. This article reports the highlights of the conference and summarizes the main conclusions and implications for clinical and experimental hepatology.     

Mitochondrial haplogroups and hypervariable region polymorphisms in schizophrenia: A case-control study

Previous studies have detected associations between mitochondrial haplogroups and schizophrenia (SZ). However, no study has examined the relationship between major mitochondrial DNA (mtDNA) haplogroups and SZ in the Chinese population. The aim of this study was to assess the association between mtDNA haplogroups and SZ genesis in the Chinese Han population. We used a case-control study and sequenced the mtDNA hypervariable regions (HVR1, HVR2, and HVR3) in the Han population. We analyzed mtDNA haplogroups and HVR polymorphisms in 298 SZ patients and 298 controls. The haplotypes were classified into 10 major haplogroups: A, B, CZ, D, F, G, M, N, N9a, and R. Statistical analysis revealed that only N9a showed a nominally significant association with protection from SZ [1.68% vs. 6.38%, p=0.004, OR=0.251 (0.092–0.680); after adjustment for age and sex: p=0.006, OR=0.246 (0.090–0.669)]. Three HVR polymorphisms were found to be nominally significantly different between subjects with SZ and controls, and all except one (m.204T>C) are linked to the N9a haplogroup. Our results indicate that mtDNA haplogroup N9a might be a protective factor for SZ.     

Bowel Ultrasound in Crohn Disease: Current Role and Future Applications

Background: The majority of hemochromatosis patients are homozygous for the HFE-C282Y mutation. However, less than half of C282Y homozygous subjects identified by population screening studies actually develop the disease. The cytokine TNF- &;#33 is implicated in the regulation of iron metabolism at different levels. Our aim was to study the role of TNF- &;#33 and its promoter polymorphisms in the phenotypic expression of hemochromatosis in individuals with and without the C282Y mutation. Methods: We studied 4 groups of 10 subjects each: ( 1 ) C282Y homozygotes without clinical hemochromatosis; ( 2 ) C282Y homozygotes with hemochromatosis; ( 3 ) secondary hemochromatosis (without C282Y mutation); and ( 4 ) controls. Groups were age-matched and sex-matched. Peripheral blood mononuclear cells (PBMC) were stimulated with lipopolysaccharide (LPS) and the release of TNF- &;#33 was measured. Additionally, the G/A polymorphisms at position -238 and -308 of the TNF- &;#33 gene were determined by PCR and RFLP analysis in 178 hemochromatosis patients and 41 controls. Results: TNF- &;#33 production from PBMC at 8 and 24 &;#114 h after increasing concentrations of LPS stimulation were similar in the four groups. The prevalence of TNF- &;#33 polymorphisms was similar in patients and controls. The prevalences of cirrhosis, siderosis, median s-ferritin and median ALT values were similar in patients with and without the TNF- &;#33 polymorphisms. Conclusions: Neither TNF- &;#33 released from PBMC nor the presence of TNF- &;#33 polymorphisms seem to be associated with disease manifestation in hemochromatosis.     

2型糖尿病肥胖患者CXCL5基因多态性的研究

探讨CXCL5启动子-156G/C基因多态性与肥胖2型糖尿病的关系.结果显示该基因多态性在2型糖尿病组与对照组的分布差异无统计学意义(P＞0.05),而肥胖者C等位基因频率高于非肥胖者,差异有统计学意义(P＜0.05).提示趋化因子CXCL5-156G/C基因变异不是糖尿病发病的危险因素,有可能是引起肥胖的重要遗传因素.     

JAG1 and COL1A1 polymorphisms and haplotypes in relation to bone mineral density variations in postmenopausal Mexican-Mestizo Women

Osteoporosis is characterized by low bone mineral density (BMD). One of the most important factors that influence BMD is the genetic contribution. The collagen type 1 alpha 1 (COL1A1) and the JAGGED (JAG1) have been investigated in relation to BMD. The aim of this study was to investigate the possible association between two single-nucleotide polymorphisms (SNPs) of COL1A1, their haplotypes, and one SNP of JAG1 with BMD in postmenopausal Mexican-Mestizo women. Seven hundred and fifty unrelated postmenopausal women were included. Risk factors were recorded and BMD was measured in lumbar spine, total hip, and femoral neck by dual-energy X-ray absorptiometry. DNA was obtained from blood leukocytes. Two SNPs in COL1A1 (rs1800012 and rs1107946) and one in JAG1 (rs2273061) were studied. Real-time PCR allelic discrimination was used for genotyping. The differences between the means of the BMDs according to genotype were analyzed with covariance. Deviations from Hardy–Weinberg equilibrium were tested. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated by direct correlation r², and haplotype analysis of COL1A1 was conducted. Under a dominant model, the rs1800012 polymorphism of the COL1A1 showed an association with BMD of the lumbar spine (P = 0.021). In addition, analysis of the haplotype of COL1A1 showed that the G–G haplotype presented a higher BMD in lumbar spine. We did not find an association between the s1107946 and rs2273061 polymorphisms of the COL1A1 and JAG1, respectively. Our results suggest that the rs1800012 polymorphism of the COL1A1, in addition to one haplotype, were significantly associated with BMD variation in Mexican-Mestizo postmenopausal women.     

Association Between NR3C1 Gene Polymorphisms and Toxicity Induced by Glucocorticoids Therapy in Saudi Children with Acute Lymphoblastic Leukemia

Background: Glucocorticoids (GCs) are key hormones used for the treatment of acute lymphoblastic leukemia(ALL) in children, but their cytotoxic effects are not well defined. The aim of this study was to evaluate the associationbetween polymorphisms in NR3C1 encoding for protein involved in the GCs metabolism and its role in the developmentof ALL and the toxicity outcome, in terms of liver toxicity, glucose abnormality and infections, in ALL Saudi children.Methods: The following polymorphisms BCII rs41423247, ER22/23 EK rs6189 and rs6190 and N363S rs6195 inNR3C1 were analyzed in 70 children with ALL treated according to the ALL 2000 study protocol in comparison to60 control subjects. Treatment toxicities and their association with genotypes were evaluated according to CommonToxicity Criteria (NCI-CTC). Results: This study demonstrated that the NR3C1 did not contribute to the developmentof childhood ALL. Homozygous ER22/23EK polymorphism was not found in both ALL patients and in control groupwhereas the heterozygous polymorphism was only observed in the control group (6.66%). The toxicology data inthis study showed a significant difference between ALL patients carrying N363S polymorphism and wild type (40%and 6.51% respectively, P= 0.009) and a high-risk factor in the toxicity of glucose abnormality (OR=10.167; 1.302-79.339).BCII shows increased risk factors towards the liver toxicity (OR=2.667; 0.526-7.330) as well as the glucoseabnormality (OR=7.5; 1.039-54.116). Conclusion: This study suggested that the polymorphisms in NR3C1 were notassociated with the development of ALL in children. N363S polymorphism was sensitive to glucocorticoids and it maycontribute to the glucose abnormality for these patients.     

Impact of DNA repair,folate and glutathione gene polymorphisms on risk of non small cell lung cancer

Lung cancer, particularly non-small cell lung cancer (NSCLC) subtype, is the leading cause of cancer-related death related worldwide. Numerous gene polymorphisms in DNA repair, folate and glutathione pathways have been associated with susceptibility of NSCLC. We conducted this study to evaluate the effects of ERCC1, ERCC2, ERCC5, XRCC1, XRCC3, MTHFR, MTR, MTHFD1, SLC19A1 and GSTP1 gene polymorphisms on risk of NSCLC.No association between these gene polymorphisms and susceptibility of NSCLC were found in our patients, suggesting that genetic variations in genes involved in DNA repair, folate and glutathione metabolism pathways may not influence the risk of NSCLC.     

DNA sequence polymorphisms of the pfmdr1 gene and association of mutations with the pfcrt gene in Indian Plasmodium falciparum isolates

Mutations in the Plasmodium falciparum multidrug resistance (pfmdr1) gene are known to provide compensatory fitness benefits to the chloroquine (CQ)-resistant malaria parasites and are often associated with specific mutations in the P. falciparum CQ resistant transporter (pfcrt) gene. Prevalence of the specific mutations in these two genes across different malaria endemic regions was mostly studies. However, reports on mutations in the pfmdr1 gene and their genetic associations with mutations in the pfcrt gene in Indian P. falciparum field isolates are scarce. We have sequenced a 560 bp region of pfmdr1 coding sequence in 64 P. falciparum isolates collected from different malaria endemic populations in India. Twenty out of these 64 isolates were laboratory cultured with known in vitro CQ sensitiveness (10 sensitive and 10 resistant). Three low frequency mutations (two non-synonymous and one synonymous) in the pfmdr1 gene were segregating in Indian isolates in addition to the predominant Y₈₆ and Y₁₈₄ ones, with high haplotype and nucleotide diversity in the field isolates in comparison to the cultured ones. No statistically significant genetic association between the mutations in the pfmdr1 and pfcrt gene could be detected; almost all observed associations were intragenic in nature. The results on the genetic diversity of the pfmdr1 gene were discussed in term of evolutionary perspectives in Indian P. falciparum, with possible future potential of gaining further insights on this gene in view of evolving malaria parasites resistant to artemisinin partner drugs.     

Body adiposity but not insulin resistance is associated with -675 4G/5G polymorphism in the PAI-1 gene in a sample of Mexican children

ObjectiveTo assess whether the -675 4G/5G polymorphism in the plasminogen activator inhibitor-1 gene is associated with obesity and insulin resistance in Mexican children.MethodsA cross-sectional study was performed in 174 children, 89 with normal-weight and 85 with obesity, aged from 6 to 13 years. All children were from state of Guerrero, and recruited from three primary schools in the city of Chilpancingo, state of Guerrero, Mexico. Insulin levels were determined by immunoenzymatic assay. The homeostasis model assessment was used to determine insulin resistance. The -675 4G/5G polymorphism in PAI-1 gene was analyzed by polymerase chain reaction-restriction fragment length polymorphism.ResultsThe prevalence of insulin resistance in the obese group was higher (49.41%) than in the normal-weight group (16.85%). The 4G/5G PAI-1 polymorphism was found in Hardy Weinberg equilibrium. The 4G/5G genotype contributed to a significant increase in waist-hip ratio (β = 0.02, p = 0.006), waist circumference (β = 4.42, p = 0.009), and subscapular skinfold thickness (β = 1.79, p = 0.04); however, it was not related with insulin resistance.ConclusionThe -675 4G/5G genotype of PAI-1 gene was associated with increase of body adiposity in Mexican children.