Aim: Heroin addiction is a chronic, relapsing disease that has genetic and environmental, including drug-induced, contributions. Stress influences the development of addictions. This study was conducted to determine if variants in stress-related genes are associated with opioid dependence (OD). Patients & methods: One hundred and twenty variants in 26 genes were analyzed in 597 Dutch subjects. Patients included 281 OD in methadone maintenance with or without heroin-assisted treatment and 316 controls. Results: Twelve SNPs in seven genes showed a nominally significant association with OD. Experiment-wise significant associations (p < 0.05) were found for three SNP pairs, through an interaction effect: NPY1R/GAL rs4691910/rs1893679, NPY1R/GAL rs4691910/rs3136541 and GALR1/GAL rs9807208/rs3136541. Conclusion: This study lends more evidence to previous reports of association of stress-related variants with heroin dependence.

OBJECTIVE: To evaluate the association between high myopia (HM) and single nucleotide polymorphisms (SNPs) in collagen, type XI, alpha 1 (COL11A1) and collagen, type XVIII, alpha 1 (COL18A1) genes in a Han Chinese population.
METHODS: A total of 869 patients with HM and 804 controls were recruited for this study. The genotyping of five SNPs in COL11A1 and COL18A1 was performed using the SNaPshot method. The genotyping data were analyzed using the χ2 test, and the linkage disequilibrium block structure was calculated and examined by Haploview software.
RESULTS: No statistically significant differences (p > 0.05) were identified between HM cases and controls after a Bonferroni correction for multiple tests in the allele frequencies of COL11A1 and COL18A1 SNPs. However, the G allele of rs2236475 showed a susceptible effect for HM (p = 0.016, corrected p = 0.08, odds ratio [OR] = 1.26). Moreover, the carriers of rs2236475GG genotype displayed an increased risk of HM compared with the rs2236475AA and rs2236475AG+AA genotypes (p = 0.008, OR = 1.79, confidence interval [95% CI] = 1.18-2.64, uncorrected; p = 0.012, OR = 1.74, 95% CI = 1.12-2.57, corrected, respectively).
CONCLUSIONS: Our results suggested that common polymorphisms in these two candidate genes were unlikely to play major roles in the genetic susceptibility to HM. Nevertheless, to avoid filtering real myopia genes, the role of COL11A1 and COL18A1 in the pathogenesis of myopia requires more refinement in both animal models and human genetic epidemiological studies.

Over the past decades, the prevalence of type 2 diabetes mellitus (T2D) has been steadily increasing around the world. Despite large efforts devoted to better understand the genetic basis of the disease, the identified susceptibility loci can only account for a small portion of the T2D heritability. Some of the existing approaches proposed for the high dimensional genetic data from the T2D case-control study are limited by analyzing a few number of SNPs at a time from a large pool of SNPs, by ignoring the correlations among SNPs and by adopting inefficient selection techniques.
We propose a network constrained regularization method to select important SNPs by taking the linkage disequilibrium into account. To accomodate the case control study, an iteratively reweighted least square algorithm has been developed within the coordinate descent framework where optimization of the regularized logistic loss function is performed with respect to one parameter at a time and iteratively cycle through all the parameters until convergence.
In this article, a novel approach is developed to identify important SNPs more effectively through incorporating the interconnections among them in the regularized selection. A coordinate descent based iteratively reweighed least squares (IRLS) algorithm has been proposed.
Both the simulation study and the analysis of the Nurses\'s Health Study, a case-control study of type 2 diabetes data with high dimensional SNP measurements, demonstrate the advantage of the network based approach over the competing alternatives.

Differentiated thyroid carcinoma (DTC) results from complex interactions between genetic and environmental factors. Known etiological factors include exposure to ionizing radiations, previous thyroid diseases, and hormone factors. It has been speculated that dietary acrylamide (AA) formed in diverse foods following the Maillard\'s reaction could be a contributing factor for DTC in humans. Upon absorption, AA is biotransformed mainly by cytochrome P450 2E1 (CYP2E1) to glycidamide (GA). Considering that polymorphisms within CYP2E1 were found associated with endogenous levels of AA-Valine and GA-Valine hemoglobin adducts in humans, we raised the hypothesis that specific CYP2E1 genotypes could be associated with the risk of DTC. Analysis of four haplotype tagging SNPs (ht-SNPs) within the locus in a discovery case-control study (N = 350/350) indicated an association between rs2480258 and DTC risk. This ht-SNP resides within a linkage disequilibrium block spanning intron VIII and the 3\'-untranslated region. Extended analysis in a large replication set (2429 controls and 767 cases) confirmed the association, with odds ratios for GA and AA genotypes of 1.24 (95 % confidence interval (CI) 1.03-1.48) and 1.56 (95 % CI, 1.06-2.30), respectively. Functionally, the minor allele was associated with low levels of CYP2E1 mRNA and protein expression as well as lower enzymatic activity in a series of 149 human liver samples. Our data support the hypothesis that inter-individual differences in CYP2E1 activity could modulate the risk of developing DTC suggesting that the exposure to specific xenobiotics, such as AA, could play a role in this process.

OBJECTIVE: Are the four candidate loci (rs7867029, rs7174015, rs12870438 and rs724078) for human male fertility traits, identified in a genome-wide association study (GWAS) of a Hutterite population in the USA, associated with male infertility in a Japanese population?
CONCLUSIONS: rs7867029, rs7174015 and rs12870438 are significantly associated with the risk of male infertility in a Japanese population.
BACKGROUND: Recently, a GWAS of a Hutterite population in the USA revealed that 41 single-nucleotide polymorphisms (SNPs) were significantly correlated with family size or birth rate. Of these, four SNPs (rs7867029, rs7174015, rs12870438 and rs724078) were found to be associated with semen parameters in ethnically diverse men from Chicago.
METHODS: This is a case-control association study in a total of 917 Japanese subjects, including 791 fertile men, 76 patients with azoospermia and 50 patients with oligozoospermia.
METHODS: Azoospermia was diagnosed on the basis of semen analysis (the absence of sperm in ejaculate), serum hormone levels and physical examinations. Oligozoospermia was defined as a sperm concentration of <20 × 10(6)/ml. We excluded patients with any known cause of infertility (i.e. obstructive azoospermia, varicocele, cryptorchidism, hypogonadotropic hypogonadism, karyotype abnormalities or complete deletion of AZF a, b or c). The SNPs rs7867029, rs7174015, rs12870438 and rs724078 were genotyped using DNA from peripheral blood samples and either restriction fragment length polymorphism PCR or TaqMan probes. Genetic associations between the four SNPs and male infertility were assessed using a logistic regression analysis under three different comparative models (additive, recessive or dominant).
RESULTS: The genotypes of all four SNPs were in Hardy-Weinberg equilibrium in the fertile controls. The SNPs rs7867029 and rs7174015 are associated with oligozoospermia [rs7867029: odds ratio (OR) = 1.70, 95% confidence interval (CI) = 1.07-2.68, P = 0.024 (log-additive); rs7174015: OR = 6.52, 95% CI = 1.57-27.10, P = 0.0099 (dominant)] and rs12870438 is associated with azoospermia (OR = 10.90, 95% CI = 2.67-44.60, P = 0.00087 (recessive)] and oligozoospermia [OR = 8.54, 95% CI = 1.52-47.90, P = 0.015 (recessive)]. The association between rs7174015 and oligozoospermia under a dominant model and between rs12870438 and azoospermia under additive and recessive models remained after correction for multiple testing. There were no associations between rs724078 and azoospermia or oligozoospermia.
CONCLUSIONS: Even though the sample size of case subjects was not very large, we found that three SNPs were associated with the risk of male infertility in a Japanese population.
CONCLUSIONS: The three infertility-associated SNPs may be contributing to a quantitative reduction in spermatogenesis.
BACKGROUND: This study was supported in part by the Ministry of Health and Welfare of Japan (1013201) (to T.I.), Grant-in-Aids for Scientific Research (C) (23510242) (to A.Ta.) from the Japan Society for the Promotion of Science, the European Union (BMH4-CT96-0314) (to T. I.) and the Takeda Science Foundation (to A.Ta.). None of the authors has any competing interests to declare.

The aim of this study was to examine the individual and interactive associations of five non-synonymous variants of four DNA repair relevant genes (XRCC1, XRCC3, hOGG1, NQO1) with hypertension in a large northeastern Han Chinese population. This was a hospital-based study involving 1009 hypertensive patients and 756 normotensive controls. All five variants satisfied the Hardy-Weinberg equilibrium. With a Bonferroni corrected alpha of 0.05/5, significance was only attained in the genotype (P=0.007) and allele (P=0.006) distributions of rs25487 in XRCC1 gene between patients and controls, with its mutant allele conferring 29% (95% CI: 1.09-1.53; P=0.003), 31% (95% CI: 1.05-1.62; P=0.015) and 66% (95%CI: 1.10-2.52; P=0.016) increased risks of hypertension under the additive, dominant and recessive models, respectively after adjusting for confounders. The frequency of allele combination C-A-C-G-C (alleles in order of rs1799782, rs25487, rs861539, rs1052133 and rs1800566) was significantly higher in patients than in controls (P=0.003), while that of C-G-C-C-C was significantly lower (P=0.001). Interaction analysis failed to identify any suggestive evidence of synergism across five examined variants. Our findings provide evidence for a contributory role of XRCC1 gene rs25487 variant in the development of hypertension, and this variant possibly acted in a recessive pattern.

OBJECTIVE: To investigate whether genetic variants in inflammation-related genes are associated with increased risk of childhood-onset febrile seizures.
METHODS: Tagging single nucleotide polymorphisms (SNPs) from 19 inflammation-related candidate genes were identified and genotyped on the Sequenom platform in a sample of Caucasian childhood-onset febrile seizures cases (n=98) compared to ethnicity, age and gender matched febrile controls presenting without seizures (n=123). Tests for allelic association were carried out using PLINK. SNPs generating empirical P-values (P<0.05) were analysed in an expanded Caucasian control sample (n=2692) from the 1958 Birth Cohort.
RESULTS: Six SNPs generated empirical pointwise significance values P<0.05 in the febrile seizures case-control analysis in the P2X7R (purinergic receptor P2X7), TLR4 (toll-like receptor 4), IL6R (interleukin 6 receptor) and PTGER3 (prostaglandin E receptor 3, subtype EP3) genes. The most significant result was for missense SNP rs208294 in P2X7R (P=0.009); this novel association was supported in the expanded case-control analysis using the 1958 Birth Cohort (pointwise P=0.009, OR=0.63, familywise P=0.039).
CONCLUSIONS: Genetic variants in inflammation-related genes, specifically purinergic receptor P2X7, may be involved in susceptibility to childhood-onset febrile seizures.