Thrombophilic gene polymorphism studies in G6PD deficient individuals from Saudi population

We performed a study to evaluate the role of three single nucleotide polymorphisms (SNPs), factor V Leiden G1691A (FVL), prothrombin gene mutation G20210A (PRT or FII-G20210A) and methylenotetrahydrofolate reductase variant C677T (MTHFRC677T), as risk factors for G6PD in Saudi populations. Our results did not show any association with the three Thrombophilic genes with FVL gene, no statistical analysis have shown any association with either allele or genotype frequencies OR=0.566, p=.0.667, (95% CI=0.014-22.48) and OR=0.569, p=0.251¸ (95% CI=0.014-22.96).In PRT gene G20210A for G Vs A, p=0.774; OR=0.566 (95%CI; 0.011-29.6); AA+GA Vs GG; p=0.502; OR=0.569 (95%CI=0.010-2969). G and A allele frequencies were similar between cases and controls with no statistical significance. In the MTHFR gene none of the genotypes or allele frequency cannot show any association OR=1.281, p=.0.667, (95% CI=0.414-3.958) and OR=1.1.172, p=0.800¸ (95% CI=0.343-4.008). Similarly, the difference of T allele frequencies between patients and controls was not found any association. In conclusion, our finding indicates that the prevalence of G1691A, G20210A and C677T mutations in G6PD deficient individuals is not statistically different compared to normal subjects and G6PD is not associated with these thrombophilic mutations in Saudi population.     

Association of Histamine N-Methyltransferase Thr105Ile Polymorphism with Parkinson’s Disease and Schizophrenia in Han Chinese: A Case-Control Study

Parkinson’s disease (PD) and schizophrenia (SCZ) are frequent central nervous disorders that have unclear etiologies but that show similarities in their pathogenesis. Since elevated histamine levels in the brain have been associated with PD and SCZ, we wanted to explore whether the Thr105Ile substitution in the histamine N-methyltransferase gene (HNMT-Thr105Ile), which impairs histamine degradation, is associated with either disease. We used the ligase detection reaction to genotype a case-control cohort of Han Chinese patients with PD or SCZ and healthy controls at the HNMT-Thr105Ile locus. The Ile allele was associated with reduced risk of PD (OR 0.516, 95%CI 0.318 to 0.838, p = 0.007) and of SCZ (OR 0.499, 95%CI 0.288 to 0.865, p = 0.011). Genotype frequencies and minor allele frequencies were similar between patients and controls when we compared males with females or early-onset patients with late-onset ones. Genotype and allele frequencies were not significantly different between PD patients with dyskinesia and PD patients without dyskinesia. Our results suggest that the heterozygous Thr/Ile genotype at the HNMT-Thr105Ile locus and the minor Ile105 allele protect against PD and SCZ in Han Chinese.     

Dopamine D1 receptor gene polymorphism is associated with myocardial infarction

Dopamine D1 receptor (DRD1) gene is associated with the pathogenesis of myocardial infarction (MI) in aspects of plaque rupture, platelet aggregation, and neutrophil-mediated injury of cardiac myocytes. Thus, the study was designed to explore whether the A-48G polymorphism of the DRD1 gene was associated with MI. The genotype of the DRD1A-48G polymorphism was determined by polymerase chain reaction in the 602 Han Chinese participants, 255 MI patients and 347 controls without MI. A significant association was found between the A-48G polymorphism of DRD1 and MI (genotype model: χ(2)=13.2, unadjusted p=0.001; χ(2)=13.9, adjusted p=0.0002; dominant model: adjusted OR 2.05, 95%CI 1.40-3.00, p=0.0002; recessive model: adjusted OR 2.34, 95%CI 1.01-5.39, p=0.047). The G allele was a risk-increased allele for MI (unadjusted OR 1.83, 95%CI 1.34-2.50, p=0.0001; adjusted OR 1.94, 95%CI 1.40-2.68, p=0.00007). Thus, the study demonstrated the significant association between A-48G polymorphism of the DRD1 gene and MI.     

A Common Copy Number Variation (CNV) Polymorphism in the CNTNAP4 Gene: Association with Aging in Females

Background

Aging is a biological process strongly determined by genetics. However, only a few single nucleotide polymorphisms (SNPs) have been reported to be consistently associated with aging. While investigating whether copy number variations (CNVs) could fill this gap, we focused on CNVs that have not been studied in previous SNP-based searches via tagging SNPs.

Methods

TaqMan qPCR assays were developed to quantify 20 common CNVs in 222 senior American Caucasians in order to reveal possible association with longevity. The replication study was comprised of 1283 community-dwelling senior European Caucasians. Replicated CNVs were further investigated for association with healthy aging and aging-related diseases, while association with longevity was additionally tested in Caenorhabditis elegans.

Results

In the discovery study of ≥80 vs.<80 years old seniors, a homozygous intronic CNV deletion in the CNTNAP4 gene was inversely associated with survival to the age of 80 (OR=0.51, 95%CI 0.29-0.87, p=0.015 before correction for multiple testing). After stratification by sex, association remained significant in females (OR=0.41, 95%CI 0.21-0.77, p=0.007), but not in males (OR=0.97, 95%CI 0.33-2.79, p=1). The finding was validated in a replication study (OR=0.66, 95%CI 0.48-0.90, p=0.011 for females). CNTNAP4 association with longevity was supported by a marked 25% lifespan change in C. elegans after knocking down the ortholog gene. An inverse association of the CNV del/del variant with female healthy aging was observed (OR=0.39, 95%CI 0.19-0.76, p=0.006). A corresponding positive association with aging-related diseases was revealed for cognitive impairment (OR=2.17, 95%CI 1.11-4.22, p=0.024) and, in independent studies, for Alzheimer’s (OR=4.07, 95%CI 1.17-14.14, p=0.036) and Parkinson’s (OR=1.59, 95%CI 1.03-2.42, p=0.041) diseases.

Conclusion

This is the first demonstration for association of the CNTNAP4 gene and one of its intronic CNV polymorphisms with aging. Association with particular aging-related diseases awaits replication and independent validation.     

Analysis of <Emphasis Type="Italic">COQ2</Emphasis>gene in multiple system atrophy

Background

Loss of function COQ2 mutations results in primary CoQ10 deficiency. Recently, recessive mutations of the COQ2 gene have been identified in two unrelated Japanese families with multiple system atrophy (MSA). It has also been proposed that specific heterozygous variants in the COQ2 gene may confer susceptibility to sporadic MSA. To assess the frequency of COQ2 variants in patients with MSA, we sequenced the entire coding region and investigated all exonic copy number variants of the COQ2 gene in 97 pathologically-confirmed and 58 clinically-diagnosed MSA patients from the United States.

Results

We did not find any homozygous or compound heterozygous pathogenic COQ2 mutations including deletion or multiplication within our series of MSA patients. In two patients, we identified two heterozygous COQ2 variants (p.S54W and c.403?+?10G?>?T) of unknown significance, which were not observed in 360 control subjects. We also identified one heterozygous carrier of a known loss of function p.S146N substitution in a severe MSA-C pathologically-confirmed patient.

Conclusions

The COQ2 p.S146N substitution has been previously reported as a pathogenic mutation in primary CoQ10 deficiency (including infantile multisystem disorder) in a recessive manner. This variant is the third primary CoQ10 deficiency mutation observed in an MSA case (p.R387X and p.R197H). Therefore it is possible that in the heterozygous state it may increase susceptibility to MSA. Further studies, including reassessing family history in patients of primary CoQ10 deficiency for the possible occurrence of MSA, are now warranted to resolve the role of COQ2 variation in MSA.

     

Methylenetetrahydrofolate reductase gene polymorphisms in patients with nonalcoholic steatohepatitis (NASH)

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of abnormal hepatic steatosis in the absence of a history of alcohol use. Nonalcoholic steatohepatitis (NASH) is the progressive form of NAFLD. Hyperhomocysteinemia causes steatosis, and the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms result in hyperhomocysteinemia. To examine whether the C677T and A1298C polymorphisms of the MTHFR gene were associated with NASH, we analysed the allele and genotype distribution of the MTHFR C677T and A1298C polymorphisms in 57 well-diagnosed NASH patients, 324 healthy controls in a case-control study of Turkish subjects of Caucasian origin. The diagnosis of the NASH patients was based on liver biopsy. The method used in the analysis of genotypes was PCR-RFLP. The MTHFR A1298C polymorphism was significantly associated with NASH (chi(2) = 8.439; p = 0.015) in the total NASH patients compared with healthy controls. The MTHFR 1298C allele (odds ratio (OR) = 2.480; 95%CI = 1.286-4.782; chi(2) = 7.703; df = 1; p = 0.006) was significantly associated with NASH in the total NASH patients. The MTHFR C677C/A1298C compound genotype (OR = 2.218; 95%CI = 1.003-4.906; chi(2) = 3.998; df = 1; p = 0.046) in men patients was also significantly associated with NASH. Likewise the MTHFR C1298C genotype was significantly associated with NASH in women patients with NASH (OR = 2.979; 95%CI = 1.027-8.641; chi(2) = 4.343; df = 1; p = 0.037). In conclusion, the MTHFR 1298C allele in all NASH patients, C1298C genotype, C677C/C1298C compound genotype in women NASH patients and C677C/A1298C compound genotype in men NASH patients were genetic risk factors for NASH.     

Association of rs11801299 and rs1380576 polymorphisms at MDM4 with risk,clinicopathological features and prognosis in patients with retinoblastoma

Backgroundrs11801299 and rs1380576, two novel polymorphisms in MDM4 gene, have been investigated in several different cancer types. However, the role of these two polymorphisms in retinoblastoma (RB) remains unclear.MethodsA total of 126 patients with primary RB and 148 age-/gender-matched controls were included in this retrospective study. The frequency of rs11801299 and rs1380576 were determined between RB patients and controls. The association of these two polymorphisms with clinicopathological characteristics, prognosis were further evaluated.ResultsAA genotype at rs11801299 was significantly associated with an increased risk of developing RB (OR = 2.06, 95%CI 1.09–3.90). The possibility of developing RB was also significantly increased in individuals with A allele at rs11801299 (OR = 1.49, 95%CI 1.06–2.08). RB patients carrying AA genotype and A allele at rs11801299 were more likely to have tumor invasion and poor differentiation. As for rs1380576, a significantly lower risk of developing RB was observed in patients with G allele (CG + GG) compared with wild-type CC genotype (OR = 0.59, 95%CI 0.36–3.95). RB patients with GG genotype or G allele had a lower risk of developing highly aggressive cancer. Kaplan-Meier curves and log-rank results revealed that RB patients carrying AA genotype or A allele (AA + GA) at rs11801299 had significantly poorer prognosis. Multivariate COX analysis showed that the rs11801299 G allele was associated with decreased survival but was not an independent prognostic factor.Conclusionrs11801299 was significantly associated with RB risk, pathological differentiation, tumor aggressiveness and poor prognosis.     

Combined test for UGT1A1 -3279T-->G and A(TA)nTAA polymorphisms best predicts Gilbert's syndrome in Italian pediatric patients

Gilbert's syndrome is a common hereditary chronic or recurrent, mild unconjugated hyperbilirubinemia. Polymorphisms in the bilirubin uridine diphosphate glucuronosyl transferase gene (UGT1A1) causing a decreased enzyme activity are associated with susceptibility to the syndrome. Homozygosity for TA(7) allele of the A(TA)(n)TAA promoter polymorphism is found in the majority of Caucasian patients. We sought to investigate the role of three UGT1A1 polymorphisms (A[TA](n)TAA, -3279T-->G, and G71R) in the susceptibility to Gilbert's syndrome in 53 Italian pediatric subjects compared to 83 unaffected controls. Carriage of two TA(n) risk alleles (TA(7) and TA(8)) and -3279G homozygosity were similarly associated with hyperbilirubinemia (odds ratio [OR] = 11.59, 95% confidence interval [CI] = 4.80-27.98; p < 0.001, and OR = 11.51, 95% CI = 5.06-26.19; p < 0.001, respectively). Homozygosity for both TA7 and -3279G was associated with the highest relative risk estimate (OR = 19.23, 95% CI = 7.34-50.4; p < 0.001), but a significant association was found also for TA7 heterozygosity combined with -3279G/G genotype (OR = 7.98, 95% CI = 2.54-25.06; p < 0.001). The G71R variant was found only in two controls. Our results demonstrate that genotyping of both UGT1A1 A(TA)(n)TAA and -3279T-->G polymorphisms best defines genetic susceptibility to Gilbert's syndrome in Caucasian pediatric patients, and the TA7 heterozygous genotype combined with homozygosity for the -3279G allele can also be associated with pediatric mild hyperbilirubinemia.     

Genetic association of single nucleotide polymorphisms in dystrobrevin binding protein 1 gene with schizophrenia in a Malaysian population

Dystrobrevin binding protein 1 (DTNBP1) gene is pivotal in regulating the glutamatergic system. Genetic variants of the DTNBP1 affect cognition and thus may be particularly relevant to schizophrenia. We therefore evaluated the association of six single nucleotide polymorphisms (SNPs) with schizophrenia in a Malaysian population (171 cases; 171 controls). Associations between these six SNPs and schizophrenia were tested in two stages. Association signals with p < 0.05 and minor allele frequency > 0.05 in stage 1 were followed by genotyping the SNPs in a replication phase (stage 2). Genotyping was performed with sequenced specific primer (PCR-SSP) and restriction fragment length polymorphism (PCR-RFLP). In our sample, we found significant associations between rs2619522 (allele p = 0.002, OR = 1.902, 95%CI = 1.266 – 2.859; genotype p = 0.002) and rs2619528 (allele p = 0.008, OR = 1.606, 95%CI = 1.130 – 2.281; genotype p = 6.18 × 10⁻⁵) and schizophrenia. Given that these two SNPs may be associated with the pathophysiology of schizophrenia, further studies on the other DTNBP1 variants are warranted.     

Nicotinic acetylcholine receptor variants associated with susceptibility to chronic obstructive pulmonary disease: a meta-analysis

Background

Only 10-15% of smokers develop chronic obstructive pulmonary disease (COPD) which indicates genetic susceptibility to the disease. Recent studies suggested an association between COPD and polymorphisms in CHRNA coding subunits of nicotinic acetylcholine receptor. Herein, we performed a meta-analysis to clarify the impact of CHRNA variants on COPD.

Methods

We searched Web of Knowledge and Medline from 1990 through June 2011 for COPD gene studies reporting variants on CHRNA. Pooled odds ratios (ORs) were calculated using the major allele or genotype as reference group.

Results

Among seven reported variants in CHRNA, rs1051730 was finally analyzed with sufficient studies. Totally 3460 COPD and 11437 controls from 7 individual studies were pooled-analyzed. A-allele of rs1051730 was associated with an increased risk of COPD regardless of smoking exposure (pooled OR = 1.26, 95% CI 1.18-1.34, p < 10^-5). At the genotypic level, the ORs gradually increased per A-allele (OR = 1.27 and 1.50 for GA and AA respectively, p < 10^-5). Besides, AA genotype exhibited an association with reduced FEV1% predicted (mean difference 3.51%, 95%CI 0.87-6.16%, p = 0.009) and increased risk of emphysema (OR 1.93, 95%CI 1.29-2.90, p = 0.001).

Conclusions

Our findings suggest that rs1051730 in CHRNA is a susceptibility variant for COPD, in terms of both airway obstruction and parenchyma destruction.     

Joint effect of G1691A factor V point mutation and factor VII Arg/Gln(353) gene polymorphism on the risk of premature coronary artery disease

The study sought an association between the G1691A factor V point mutation and factor VII Arg/Gln(353) gene polymorphism and premature coronary artery disease (CAD), and the interactive effect on CAD risk between the G1691A factor V point mutation and factor VII Arg/Gln(353) gene polymorphism as well as between tested polymorphisms and traditional risk factors. 167 patients with CAD younger than 55 years were compared with 132 healthy subjects. The frequency of factor V point mutation was 7.8 % among Slovene patients with premature CAD, and 4.5 % among controls. No association was found between either the factor V point mutation (AG genotype) or M1M1 genotype of factor VII Arg/Gln(353) gene polymorphism and the risk of CAD in Slovenia using univariate analysis (factor V point mutation: OR = 1.8, 95% CI = 0.7-4.9; p = 0.25; factor VII Arg/Gln(353) gene polymorphism: OR = 1, 95 % CI = 0.6-1.7; p = 0.9). However, a joint effect on the risk of CAD was found between factor V point mutation (AG genotype) and M1M1 genotype (OR = 3.6, 95 % CI = 1-12.9; p = 0.03). Additionally, an interactive effect on CAD risk was found between AG genotype and metabolic risk factors (OR = 3.8, 95% CI = 1.1-13.6; p = 0.03). In conclusion, we provide evidence for a joint effect on CAD risk between G1691A factor V point mutation and factor VII Arg/Gln(353) gene polymorphism as well as between factor V point mutation and metabolic risk factors.     

Association of GRM7 Variants with Different Phenotype Patterns of Age-Related Hearing Impairment in an Elderly Male Han Chinese Population

Several single nucleotide polymorphisms (SNPs) of the Glutamate metabotrophic receptor 7 gene (GRM7) have recently been identified by the genome-wide association study (GWAS) as potentially playing a role in susceptibility to age-related hearing impairment (ARHI), however this has not been validated in the Han Chinese population. The aim of this study was to determine if these SNPs are also associated with ARHI in an elderly male Han Chinese population. In this case-control candidate genes association study, a total of 982 men with ARHI and 324 normal-hearing controls subjects were studied. Using K-means cluster analysis, four audiogram shape subtypes of ARHI were identified in the case group: ‘‘flat shape (FL)’’, ‘‘sloping shape (SL)’’, ‘‘2-4 kHz abrupt loss (AL) shape’’ and ‘‘8 kHz dip (8D) shape’’. Results suggested that the SNP rs11928865 (A>T) of GRM7 was significantly associated with ARHI after adjusting for non-genetic factors (p= 0.000472, OR= 1.599, 95%CI= 1.229~2.081). Furthermore, frequency of TT genotype (rs11928865) were significant higher in the SL subgroup and AL subgroup with compared to controls group (p= 9.41E-05, OR= 1.945, 95%CI= 1.393~2.715; p= 0.000109, OR= 1.915, 95%CI= 1.378~2.661 adjusted, respectively) after Bonferroni correction. However, there wasn’t significant difference in the frequency of the TT genotype between cases in the FL subgroup or the 8D subgroup with when compared with controls. Results of the current study suggest that, in an elderly male Han Chinese population, GRM7 SNP rs11928865 (TT) occurs more frequently in ARHI patients with SL and AL phenotype patterns.     

Association of common variation in the <Emphasis Type="Italic">PPARA</Emphasis>gene with incident myocardial infarction in individuals with type 2 diabetes: A Go-DARTS study

Background

Common variants of the PPARA gene have been found to associate with ischaemic heart disease in non diabetic men. The L162V variant was found to be protective while the C2528G variant increased risk. L162V has also been associated with altered lipid measures. We therefore sought to determine the effect of PPARA gene variation on susceptibility to myocardial infarction in patients with type 2 diabetes. 1810 subjects with type 2 diabetes from the prospective Go-DARTS study were genotyped for the L162V and C2528G variants in the PPARA gene and the association of the variants with incident non-fatal myocardial infarction was examined. Cox's proportional hazards was used to interrogate time to event from recruitment, and linear regression for analysing association of genotype with quantitative clinical traits.

Results

The V162 allele was associated with decreased risk of non-fatal myocardial infarction (HR = 0.31, 95%CI 0.10–0.93 p = 0.037) whereas the C2528 allele was associated with increased risk (HR = 2.77 95%CI 1.34–5.75 p = 0.006). Similarly V162 was associated with a later mean age of diagnosis with type 2 diabetes and C2582 an earlier age of diagnosis. C2528 was also associated with increased total cholesterol and LDL cholesterol, which did not account for the observed increased risk. Haplotype analysis demonstrated that when both rare variants occurred on the same haplotype the effect of each was abrogated.

Conclusion

Genetic variation at the PPARA locus is important in determining cardiovascular risk in both male and female patients with diabetes. This genotype associated risk appears to be independent of the effect of these genotypes on lipid profiles and age of diagnosis with diabetes.

     

Association of Ficolin-2 Serum Levels and FCN2 Genetic Variants with Indian Visceral Leishmaniasis

BackgroundVisceral leishmaniasis (VL), one of the neglected tropical diseases, is endemic in the Indian subcontinent. Ficolins are circulating serum proteins of the lectin complement system and involved in innate immunity.MethodsWe have estimated ficolin-2 serum levels and analyzed the functional variants of the encoding gene FCN2 in 218 cases of VL and in 225 controls from an endemic region of India.ResultsElevated levels of serum ficolin-2 were observed in VL cases compared to the controls (adjusted P<0.0001). The genetic analysis revealed that the FCN2 structural variant +6359 C>T (p.T236M) was associated with VL (OR=2.2, 95% CI=1.23-7.25, P=0.008) and with high ficolin-2 serum levels. We also found that the FCN2*AAAC haplotype occurred more frequently among healthy controls when compared to cases (OR=0.59, 95%CI=0.37-0.94, P=0.023).ConclusionsOur findings indicate that the FCN2 variant +6359C>T is associated with the occurrence of VL and that ficolin-2 serum levels are elevated in Leishmania infections.     

p53 Codon 72 arginine/proline polymorphism and cancer in Sudan

The aim of this report is to determine frequencies and associations of p53 codon 72 arg/pro polymorphism with different types of cancer in Sudan. p53 codon72 arg/pro polymorphism distribution and allele frequencies in 264 samples of different types of cancers were investigated using PCR. The results were compared to 235 normal controls. The results indicated significant differences in frequency and genotype association between different types of cancers. Breast carcinoma patients most prominently showed excess of homozygous arg genotype as compared to controls with an Odd ratio (OR) of 19.44, 95?%CI: 6.6–78.3, P?<?0.0001. Less prominently cervical cancer showed genotype effect of 2.4 OR, 95?%CI: 1.12–5.33, P?=?0.015, while esophageal cancer had an OR of 0.57, 95?%CI: 0.23–1.42, P?=?0.1. In Burkitt’s lymphoma, however, in contrast the homozygous arg accounted for only 6.9?%, (OR 0.18, 95?%CI: 0.02–0.89, P?=?0.018). We concluded that p53 arg/pro polymorphism has different pattern of frequency in different types of cancer among Sudanese patients, indicating perhaps different etiology and biology of these tumours.     

Association analysis of <Emphasis Type="Italic">C242T</Emphasis> and <Emphasis Type="Italic">A640G</Emphasis> polymorphisms in the gene for p22<Superscript>phox</Superscript> subunit of NADPH oxidase with the risk of bronchial asthma: A pilot study

Genetic control of free radical oxidation, generation of reactive oxygen species, as well as of preoxidant and antioxidant balance in airway diseases, including bronchial asthma, is an important issue of the research in pulmonology. The present study is the first investigation of association between two common polymorphisms, C242T (exon 4) and A640G (3′ untranslated region), within the NADPH oxidase gene (CYBA) and the risk of bronchial asthma. Samples of asthma patients (n = 209) and healthy controls (n = 210) of Russian nationality were examined. Genotyping of the CYBA C242T and A640G polymorphisms was performed using polymerase chain reaction and restriction fragment length polymorphism. It was demonstrated that the frequency of heterozygous CYBA genotype A640G in bronchial asthma patient group was lower than that in control group (OR = 0.66; 95%CI, 0.45–0.97; P = 0.04). Separate analysis of different clinical pathogenetic variants of the disease showed that homozygous wild-type CYBA genotype 640AA was associated with the increased risk of allergic bronchial asthma (OR = 1.76; 95%CI, 1.07–2.90; P = 0.03), while heterozygous CYBA genotype A640G was associated with the decreased risk of this form of the disease (OR = 0.63; 95%CI, 0.41–0.96; P = 0.03). Thus, a new candidate gene for allergic bronchial asthma was discovered. Possible mechanisms of the involvement of CYBA in the development of asthmatic phenotype are discussed.     

Association of HDL-Related Loci with Age-Related Macular Degeneration and Plasma Lutein and Zeaxanthin: the Alienor Study

Background

Several genes implicated in high-density lipoprotein (HDL) metabolism have been reported to be associated with age-related macular degeneration (AMD). Furthermore, HDL transport the two carotenoids, lutein and zeaxanthin, which are highly suspected to play a key-role in the protection against AMD. The objective is to confirm the associations of HDL-related loci with AMD and to assess their associations with plasma lutein and zeaxanthin concentrations.

Methods

Alienor study is a prospective population-based study on nutrition and age-related eye diseases performed in 963 elderly residents of Bordeaux, France. AMD was graded according to the international classification, from non-mydriatic colour retinal photographs. Plasma lutein and zeaxanthin were determined by normal-phase high-performance liquid chromatography. The following polymorphisms were studied: rs493258 and rs10468017 (LIPC), rs3764261 (CETP), rs12678919 (LPL) and rs1883025 (ABCA1).

Results

After multivariate adjustment, the TT genotype of the LIPC rs493258 variant was significantly associated with a reduced risk for early and late AMD (OR=0.64, 95%CI: 0.41-0.99; p=0.049 and OR=0.26, 95%CI: 0.08-0.85; p=0.03, respectively), and with higher plasma zeaxanthin concentrations (p=0.03), while plasma lipids were not significantly different according to this SNP. Besides, the LPL variant was associated with early AMD (OR=0.67, 95%CI: 0.45-1.00; p=0.05) and both with plasma lipids and plasma lutein (p=0.047). Associations of LIPC rs10468017, CETP and ABCA1 polymorphisms with AMD did not reach statistical significance.

Conclusion

These findings suggest that LIPC and LPL genes could both modify the risk for AMD and the metabolism of lutein and zeaxanthin.     

A Haplotype of Two Novel Polymorphisms in δ-Sarcoglycan Gene Increases Risk of Dilated Cardiomyopathy in Mongoloid Population

The role of genetic abnormality of δ-sarcoglycan (δ-SG) gene in dilated (DCM) and hypertrophied (HCM) cardiomyopathy patients is still unfolding. In this study we first defined the promoter region and then searched for polymorphisms/mutations among the promoter, 5''-untranslated region, and the encoding exons in δ-SG gene in 104 Chinese patients with DCM, 145 with HCM, and 790 normal controls. Two novel polymorphisms were found, an 11 base-pair (bp) deletion (c._-100~-110; -) in the promoter region and a missense polymorphism of A848G resulting in p.Q283R in the highly conserved C-terminus. The prevalence of homozygous genotype -/- of c._-100~-110 was slightly higher in DCM (14.42%) and HCM patients (14.48%), as compared with normal controls (11.01%). The prevalence of genotype of 848A/G was significantly higher in DCM (6.73%; OR = 9.43; p = 0.0002), but not in HCM patients (1.38%; OR = 1.37; p = 0.62), as compared with controls (0.76%). Haplotype -_G consisting c._-100~-110 and A848G was associated with increased risk of DCM (OR = 17.27; 95%CI = 3.19–93.56; p = 0.001) but not associated with HCM (OR = 1.90; 95%CI = 0.38–9.55; p = 0.44). Co-occurrence of the genotypes -/- of c._-100~-110 and 848A/G was found in 5 patients with DCM (4.81%; OR = 39.85; p = 0.0001), none of HCM patients, and only 1 of the controls (0.13%). Both polymorphisms were also found in the Japanese population, but not in the Africans and Caucasians. C._-100~-110 resulted in a decrease of δ-SG promoter activity to 64±3% of the control level (p<0.01). Both co-immunoprecipitation and in vitro protein pull-down assays demonstrated that δ-SG-283R interacts normally to β- and γ-SG, but significantly decreased localization of β/δ/γ-SG on the plasma membrane. In conclusion, haplotype -_G composed of c._-100~-110 and A848G confers higher susceptibility to DCM in the Mongoloid population.     

PUNISHER rs12318065 C>A transversion: a putative somatic driver mutation for poor prognosis in colon cancer

Objective: Colon cancer (CC) remains one of the leading causes of cancer death worldwide. Several mutations/polymorphisms have been implicated in CC development and/or progression. The role of the recently identified variants related to the long non-coding RNAs (lncRNAs) family has not yet been fully uncovered. In this sense, we aimed to explore the association between the lncRNA PUNISHER rs12318065 variant and the CC risk and/or prognosis. Methods: A total of 408 CC (paired 204 cancer/non-cancer) tissues were genotyped using the TaqMan allelic discrimination assay. Results: “A” variant was associated with higher susceptibility to develop CC under heterozygote (A/C vs. C/C: OR = 1.39, 95%CI = 1.09–2.17, P=0.002), homozygote (A/A vs. C/C: OR = 2.63, 95%CI = 1.51–4.58, P=0.001), dominant (A/C-A/A vs. C/C: OR = 1.72, 95%CI = 1.15–02.57, P=0.008), and recessive (A/A vs. C/C-A/C: OR = 2.23, 95%CI = 1.34–3.72, P=0.001) models. Patients with metastasis were more likely to harbor A/A and A/C genotypes (16.7% and 14.1%) than 11% with the C/C genotype (P=0.027). Patients harboring C>A somatic mutation were more likely to develop relapse (52.6% vs. 26.5%, P=0.003), have poor survival (57.9% vs. 27.7%, P=0.001), and have shorter disease-free survival (43.2 ± 2.6 months vs. 56.8 ± 1.29 months, P<0.001) and overall survival (49.6 ± 2.4 months vs. 56.6 ± 0.99 months, P<0.001). Multivariate Cox regression analysis showed that patients with distal metastasis and C>A somatic mutation were three times more likely to die. Conclusions: To our knowledge, the present study is the first to identify that the PUNISHER rs12318065 variant could be a novel putative driver of colon cancer and is associated with poor prognosis.