Human GABA, Receptor αl and α3 Subunits Genes and Alcoholism

γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. GABA effects are largely mediated by binding to the postsynaptic GABA_A receptor, causing the opening of an integral chloride-ion channel. The GABA_A antagonists picrotoxin and bicuculline reduce some ethanol-induced behaviors, such as motor impairment, sedation, and hypnosis. The role of this receptor in alcoholism is further supported by effective alleviation of alcohol withdrawal symptoms by GABA_A agonists. To determine the role of the GABA, receptor (GABR) genes in the development of alcoholism, we have used α₁ and α ₃ simple sequence repeat polymorphisms in a sample of unrelated alcoholics, alcoholic probands with both parents, and psychiatrically normal controls. For the GABRα₁ gene, the differences between allele frequencies, when all alleles were compared together, were not significant between total alcoholics, subtypes of alcoholics, and normal controls. However, for GABRα₃, the differences between total alcoholics and normal controls were significant when all alleles were compared together. The differences between subtypes of alcoholics and normal controls were not significant. The results of haplotype relative risk analysis for both genes, GABRα₁ and GABRα₃, were also negative. It is possible that the sample size in the haplotype relative risk is too small to have power to detect the differences in transmitted versus nontransmitted alleles. There is a need for a replication study in a large family sample, that will allow haplotype relative risk or affected sib-pair analysis.     

海南恶性疟原虫pfcrt等位基因多态性的单体型研究

目的 建立恶性疟原虫pfcrt（Plasmodium falciparum chloroquine resistant transporter）等位基因多态性的单体型的研究方法，比较我国海南省与东南亚及非洲地区恶性疟原虫的pfcrt等位基因多态性的单体型的特征。 方法 来自海南省19份恶性疟滤纸血样提取DNA，通过巢式PCR反应，扩增出包含第72～76、97位密码子的基因片段，根据限制性片段长度多态性（RFLP）分析结果，各选取6份突变型和野生型PCR产物进行DNA测序，检测第72～76、97位密码子序列，从而建立并分析我国海南省恶性疟pfcrt等位基因的单体型。 结果 19份滤纸血样本提取的DNA全部扩增出1条195 bp的片段，酶切消化后，有11份出现1条100 bp左右的酶切片段，为野生型pfcrt等位基因，其余8份为1条195 bp的片段，为突变型。基因序列分析发现，野生型pfcrt等位基因的第72～76位密码子单体型为CVMNK，突变型为CVIET，第97位密码子未发现突变。 结论 我国海南省氯喹抗药性恶性疟原虫pfcrt等位基因第72～76位密码子的单体型与东南亚和非洲地区抗氯喹恶性疟原虫相应单体型一致。     

Increase of HLA haplotype A9-Bw16 in familial insulin-dependent diabetes mellitus in Northern Finland

Summary Twenty-one families, each with two diabetic children, from North Finland were HLA typed. The grade of HLA identity between diabetic siblings was evaluated, and frequencies of various HLA antigens in familial cases were compared to those of non-familial cases from the same area. Ten pairs of diabetic children were HLA-identical and eleven haploidentical; two of the latter were identical for the HLA-D locus. These figures emphasize the significance of HLA-region associated genetic factors in the susceptibility to the disease, but do not support a simple dominant/recessive gene theory. There was a significant difference between familial and non-familial IDDM cases in the frequencies of B15, Bw16, B40 and Cw3 antigens. Bw16 was greatly increased and B15, B40 and Cw3 decreased among familial cases. The haplotype A9, Bw16 was common in familial cases, but, compared to healthy controls, the frequencies of the two antigens were also slightly increased among non-familial cases. Neither Dw3 nor Dw4 was associated with Bw16 antigen. The differences between familial and non-familial IDDM cases and the significance of the A9, Bw16 combination in the patients emphasize the heterogeneity of IDDM.     

Interferon Regulatory Factor 5 Gene Polymorphisms in Iranian Women with Unexplained Recurrent Pregnancy Loss

Objective: This study aimed to examine the association of three functional IRF5 rs10954213, rs3757385, and rs41298401 polymorphisms with susceptibility to unexplained recurrent pregnancy loss (RPL) among Iranian women from south of Iran.

Methods: 176 women with unexplained RPL and 173 healthy postmenopausal controls were enrolled in this case-control study. Genotyping of the polymorphisms rs10954213 and rs3757385 was carried out using touchdown tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS PCR), and polymorphism rs41298401 was typed using PCR-restriction fragment length polymorphism (PCR-RFLP).

Results: Genotype frequencies were significantly different between RPL cases and controls regarding AG heterozygote genotype of rs10954213, GT genotype of rs3757385, and GG genotype of rs41298401. In addition, allele variants (G for rs10954213, T for rs3757385, and G for rs41298401) showed protective role against RPL, while GG haplotype of two first variants was shown to be a susceptibility factor for the disease.

Conclusion: These data provide the first evidence, to our knowledge, of the protective role of the studied IRF5 gene polymorphisms against unexplained RPL among Iranian women from south of Iran.     

Possible Association between Serotonin Transporter Gene Polymorphism and Suicide Behavior in Major Depressive Disorder

Objective

The serotonin transporter (5-HTT) genes are major candidate genes for modulating the suicidal behavior. We investigated the association between serotonin transporter polymorphisms and suicidal behavior in patients with major depressive disorder (MDD).

Methods

Serotonin transporter intron 2 VNTR polymorphism (5-HTTVNTR) and serotonin transporter linked polymorphic region polymorphism (5-HTTLPR) were analyzed in 132 depressed patients with suicidal attempt as well as in 122 normal controls. Hamilton''s 17-item Depression Rating Scale (HDRS), the Risk-Rescue rating system (RRR) and the Lethality Suicide Attempt Rating Scale updated (LSARS-II) were assessed for the depressed patients.

Results

Although not statistically significant, a trend was found such that the 10/10 and 10/12 alleles of 5-HTTVNTR were more common in suicidal subjects than in control subjects. Comparing allele frequency, those with a 10 allele or 10 allele carriers were higher in suicidal subjects than in control subjects. No difference was noted in 5-HTTLPR genotypes and haplotype distribution between the suicidal subjects and control subjects. The RRR scores in subjects with the 10/10 5-HTTVNTR genotype or 10 5-HTTVNTR allele were significantly lower than those in subjects with other genotypes.

Conclusion

These results show the possibility that 10 allele of 5-HTTVNTR is related to suicidal behavior in the suicidal subjects with MDD and suggest that 12 allele of 5-HTTVNTR might be related to more lethality in the suicidal subjects with MDD.     

母亲MTHFD1及MTHFD2基因多态性与子代先天性心脏病的关联北大核心CSCD

目的探讨母亲亚甲基四氢叶酸脱氢酶(methylenetetrahydrofolate dehydrogenase,MTHFD)1、2(MTHFD1、MTHFD2)基因多态性与子代先天性心脏病(congenital heart disease,CHD)的关联。方法采用以医院为基础的病例对照研究,选取2017年11月至2020年3月在湖南省儿童医院就诊的683例单纯CHD患儿的母亲作为病例组,选取同时间段内就诊于同一家医院并排除任何先天畸形的740例儿童的母亲作为对照组。通过问卷调查,收集研究对象的相关暴露信息。完成调查问卷后,采集母亲5 mL静脉血,用于MTHFD1、MTHFD2基因多态性的检测。采用多因素logistic回归模型分析MTHFD1、MTHFD2基因多态性与CHD的关联;采用Haploview 4.2软件的四配子检验法构建单倍型,评估单倍型与CHD的关联;并采用广义多因子降维法和logistic回归法分析基因-基因交互作用与CHD的关联。结果多因素logistic回归分析显示,母亲MTHFD1基因rs11849530位点(GA vs AA:OR=1.49;GG vs AA:OR=2.04)和rs1256142位点(GA vs GG:OR=2.34;AA vs GG:OR=3.25)显著增加子代CHD的发生风险(P<0.05),而母亲MTHFD1基因rs1950902位点(AA vs GG:OR=0.57)和MTHFD2基因rs1095966位点(CA vs CC:OR=0.68)显著降低子代CHD的发生风险(P<0.05)。母亲携带单倍型G-G-G(OR=1.86)、G-A-G(OR=1.35)显著增加子代CHD的发生风险(P<0.05)。交互作用分析显示,母亲MTHFD基因2个位点(MTHFD1 rs1950902、MTHFD1 rs2236222)的一阶交互作用及3个位点(MTHFD1 rs1950902、MTHFD1 rs1256142、MTHFD2 rs1095966)的二阶交互作用可能与CHD的发生风险存在关联(P<0.05)。结论母亲MTHFD1、MTHFD2基因多态性及其单倍型,以及2个位点(MTHFD1 rs1950902、MTHFD1 rs2236222)和3个位点(MTHFD1 rs1950902、MTHFD1 rs1256142、MTHFD2 rs1095966)的交互作用与子代CHD的发生相关。     

Contribution of TIMP3 polymorphisms to the development of preeclampsia in Han Chinese women

Purpose

The aim of this study was to investigate whether polymorphisms in the tissue inhibitor of metalloproteinase 3 gene (TIMP3) are associated with the risk of preeclampsia (PE) in Han Chinese women.

Methods

Nine single TIMP3 tag-single nucleotide polymorphisms were selected by Haploview and genotyped using the Sequenom method in 181 preeclamptic and 203 healthy pregnant women from eastern China.

Results

The allele frequencies of the tag-single nucleotide polymorphisms were not significantly different between groups (P > 0.05). However, the genotype distribution of rs135025 was shown to differ between the multigravidity PE subgroup (>3) and controls under additive (P = 0.018) and recessive models (P = 0.008), while the genotype distribution of rs80272 differed significantly between the severe PE subgroup and controls under additive (P = 0.014) and dominant models (P = 0.041). Moreover, the H2 haplotype (A-C-G-T-A-A-G-C-G) was found to be associated with the risk of PE (P = 0.035).

Conclusions

Genotypes of rs135025 and rs80272 in TIMP3 may therefore influence susceptibility to PE, and pregnant women carrying the H2 haplotype might be more prone to developing PE.

Electronic supplementary material

The online version of this article (doi:10.1007/s10815-015-0529-8) contains supplementary material, which is available to authorized users.     

Analysis of IL10 haplotypes in primary Sjögren’s syndrome patients from Western Mexico: Relationship with mRNA expression,IL-10 soluble levels,and autoantibodies

Primary Sjögren’s syndrome (pSS) is an autoimmune disease characterized by lymphocytic infiltration of salivary and lacrimal glands. Interleukin-10 (IL-10) plays a role in autoimmune diseases by promoting B-cell activation and autoantibodies production. IL10-1082A > G, -819C > T, -592C > A polymorphisms and their haplotypes have been associated with IL-10 production. The aim of this study was to associate IL10 haplotypes with mRNA expression and soluble IL-10 levels with susceptibility to pSS in 111 Mexican patients and 111 healthy subjects (HS). Primary Sjögren’s syndrome patients showed high levels of sIL-10 (p = 0.0001 vs HS) correlating with anti-Ro and anti-La antibodies (p < 0.05). In addition, IL10 mRNA expression in pSS was higher than HS (0.8 vs 0.1, p = 0.1537). However, no difference was observed in sIL-10 levels between haplotypes. Patients carriers of GCC haplotype showed higher mRNA expression than ACC + ATA (1.4 vs 0.6, p = 0.2424) and high foci number (p = 0.04 vs ACC). Our results suggest a strong relationship of IL10 with pSS which is demonstrated by the increased mRNA expression and also high sIL-10 levels positively correlated with autoantibodies. Besides that, the GCC haplotype carriers expressed high mRNA. However, IL10 haplotypes were not associated with sIL-10 in pSS from Western Mexico which suggest that diverse biological factors may regulate the IL10 expression in pSS.