Genetic susceptibility of opioid receptor genes polymorphism to drug addiction: A candidate-gene association study

Background Like other complex diseases including drug addiction, genetic factors can interfere with the disease. In this study, three opioid genes (OPRM1, OPRD1, and OPRK1) were examined for an association with drug addiction among Jordanian males. Methods The study involved 498 addicts, in addition to 496 healthy controls and all from Arab descent. Results The findings in this study showed that rs1799971 of the OPRM1 gene was in association with drug addiction for both alleles and genotypes with P-values = 0.002 and 0.01, respectively. In addition, a significant association between the dominant model (A/A vs G/A-G/G) of rs1799971 (OPRM1) and drug addiction (P-value = 0.003, OR = 1.59 (1.17–2.15)) was detected. Moreover, a genetic haplotype (AGGGCGACCCC) of theOPRM1 gene revealed a significant association with drug addiction (P-value = 0.01, OR = 1.56 (1.15–2.12)). We also found that the age of addicts, smoking, and marital status with genetic variants within OPRM1, OPRD1, and OPRK1 genes may be implicated in drug addiction risk. Conclusion We propose that rs1799971 of the OPRM1gene is a genetic risk factor for drug addiction among Jordanian males.

Abstract P235: The Additive Genetic Association of Beta-2 Adrenergic Receptor and Serum-and-Glucocorticoid-Inducible Kinase 1 on Salt-Sensitive Hypertension

Salt sensitivity of blood pressure (SSBP) is associated with increased cardiovascular morbidity. A diplotype on the beta 2 adrenergic receptor (β2AR) gene (rs1042713, rs1042714)—associated with increased aldosterone (ALDO)—and a polymorphism in the serum-and-glucocorticoid-inducible kinase 1 (SGK1) gene (rs2758151)—an ALDO target that increases sodium reabsorption—are each associated with SSBP. We hypothesized that SSBP will be increased in homozygotes for both β2AR and SGK1 (Combo) when compared to non-risk homozygotes and homozygotes in either gene alone. The HyperPATH database includes individuals who completed 7 days of both restricted and liberal sodium diets to determine systolic SSBP. We conducted a gene association study in 329 individuals: 42 were homozygotes for Combo; 242 were homozygotes for β2AR or SGK1; and 45 were non-carriers. Multivariate regression analyses (adjusted for age, sex, BMI, race, hypertension) found a significantly higher SSBP in the Combo homozygotes when compared to non-carriers and homozygotes for either β2AR or SGK1(p<0.001, 95% CI: 2.35, 7.56) (Figure 1). Serum ALDO levels were higher in Combo homozygotes than in the other groups (p=0.035, CI: 0.069,1.87). Additionally, analyses of either gene alone with SSBP (β2AR: p=0.056, CI: -0.038, 2.89; SGK1: p=0.003, CI: 0.87, 4.35) was less than what was observed in the Combo. In sum, Combo homozygotes for SGK1 and β2AR substantially increased the level of SSBP compared to that observed in risk allele homozygotes in each gene alone. Thus, hypertensive Combo homozygotes are likely candidates for mineralocorticoid receptor antagonist therapy—gene driven, personalized medicine. Figure 1.

Multi-omics integration of the phenome, transcriptome and genome highlights genes and pathways relevant to essential tremor

The genetic factors predisposing to essential tremor (ET), of one of the most common movement disorders, remains largely unknown. While current studies have examined the contribution of both common and rare genetic variants, very few have investigated the ET transcriptome. To understand pathways and genes relevant to ET, we used an RNA sequencing approach to interrogate the transcriptome of two cerebellar regions, the dentate nucleus and cerebellar cortex, in 16 cases and 16 age- and sex-matched controls. Additionally, a phenome-wide association study (pheWAS) of the dysregulated genes was conducted, and a genome-wide gene association study (GWGAS) was done to identify pathways overlapping with the transcriptomic data. We identified several novel dysregulated genes includingCACNA1A, a calcium voltage-gated channel implicated in ataxia. Furthermore, several pathways including axon guidance, olfactory loss, and calcium channel activity were significantly enriched. A subsequent examination of the ET GWGAS data (N=7,154) also flagged genes involved in calcium ion-regulated exocytosis of neurotransmitters to be significantly enriched. Interestingly, the pheWAS identified that the dysregulated gene,SHF, is associated with a blood pressure medication (P=9.3E-08), which is commonly used to reduce tremor in ET patients. Lastly, it is also notable that the dentate nucleus and cerebellar cortex have different transcriptomes, suggesting that different regions of the cerebellum have spatially different transcriptomes.

Non-syndromic cleft palate: Association analysis on three gene polymorphisms of the folate pathway in Asian and Italian populations

Periconceptional folic acid supplementation can reduce the risk of inborn malformations, including orofacial clefts. Polymorphisms of MTHFR, TCN2, and CBS folate-related genes seem to modulate the risk of cleft lip with or without cleft palate (CL/P) in some populations. CL/P and cleft palate only (CPO) are different malformations that share several features and possibly etiological causes. In the present investigation, we conducted a family-based, candidate gene association study of non-syndromic CPO. Three single nucleotide polymorphisms, namely, rs1801133 of MTHFR, rs1801198 of TCN2, and rs4920037 of CBS, were investigated in a sample that included 129 Italian and 65 Asian families. No evidence of association between the three genotyped polymorphisms and CPO was found in the Italian and Asian cases, indeed the transmission disequilibrium test did not detect any asymmetry of transmission of alleles. This investigation, although with some limitation, further supports that CL/P and CPO diverge in their genetic background.