Effect of polymorphism in insulin locus and HLA on type 1 diabetes in four ethnic groups in Israel

This study examined a possible association of the insulin ( INS ) gene with type 1 diabetes (T1D) in patients and controls from four ethnic groups in Israel. We analyzed the distribution of −23 Hph I single nucleotide polymorphism (SNP) T/A alleles that correspond to INS variable number of tandem repeat short class I alleles (26–63 repeats) and class III alleles (141–209 repeats), respectively. The −23 Hph I T/T genotype was found to be positively associated with T1D in three Jewish groups (Yemenites: 93.9% patients vs 68.8% controls, P  = 0.0002; Ashkenazi: 80.6% vs 50.8%, P  < 10⁻⁴; Ethiopians: 75% vs 40.5%, P  = 0.002). The Yemenite healthy controls have the highest frequency of T allele from all Jewish groups studied (83.5% vs 68.8% in Ashkenazi and 64.3% in Ethiopians). The high frequency of a susceptibility allele in the Yemenites is in line with the high incidence of T1D in this population. No association was observed between T1D and the INS gene in Israeli Arabs studied (70.6% vs 66.7%). Variable incidence of T1D among different ethnicities in Israel is largely attributed to heterogeneous genetics. Human leukocyte antigen (HLA) results of our previous studies describing the susceptibility and protective haplotypes were used for combined analysis to determine possible interaction between the HLA and INS loci. Only in the Ashkenazi group such interaction was presented with statistical significance.     

ApoE基因多态性对毛南族人群血清apoA1、apoB水平的影响

目的 探讨载脂蛋白（apo）E基因多态性对毛南族人群血清apoA1、apoB水平的影响。 方法 收集221名贵州省黔南州毛南族人群血样品,采用免疫透射比浊法测定血清apoA1、apoB浓度;应用聚合酶链反应-限制性片段长度多态性方法（PCR-RFLP）检测apoE2、E3、E4基因多态性。 结果 与apoE2/2+E2/3+E2/4基因型亚组（ n =37）比较,apoE3/4+E4/4基因型亚组（ n =41）和apoE3/3基因型亚组（ n =143）血清apoB水平升高（ P ＜0.05）,apoA1/B比值降低（P ＜0.05）;apoE3/4+E4/4基因型亚组apoB水平高于apoE3/3亚组（ P ＜0.05）。未发现不同apoE基因型亚组间血清apoA1水平差异存在统计学意义（ P ＞0.05）。结论 毛南族人群apoE基因多态性明显影响血清apoB水平和apoA1/B比值,但未见该基因多态性与血清apoA1水平相关联。     

Variants in candidate ALS modifier genes linked to Cu/Zn superoxide dismutase do not explain divergent survival phenotypes

Familial amyotrophic lateral sclerosis (ALS) accounts for 10% of all ALS cases; approximately 25% are due to mutations in the Cu/Zn superoxide dismutase gene (SOD1). In North America, SOD1(A4V) is the most common SOD1 mutation. A4V ALS cases typically have a very short survival (1-1.5 years versus 3-5 years for other dominant SOD1 mutations). A recent study of A4V carriers identified a common haplotype around the SOD1 locus, suggesting the hypothesis that genetic variations within the haplotypic region might accelerate the course of A4V cases. By contrast, SOD1(D90A/D90A) ALS cases have a very slow progression (>10 years), raising the reciprocal hypothesis that modifier genes linked to SOD1 ameliorate the phenotype of recessively inherited SOD1(D90A/D90A) mutations. In the present study, DNA sequencing of four genes within the haplotypic region shared in A4V and D90A ALS patients revealed 15 novel variants, but none result in changes in amino acid sequences specifically associated with SOD1(D90A/D90A) or SOD1(A4V) ALS. We conclude that mutations within coding regions of genes around the SOD1 locus are not responsible for the more aggressive and more benign natures of the SOD1(A4V) and SOD1(D90A/D90A) mutations, respectively.     

Overrepresentation of rare variants in a specific ethnic group may confuse interpretation of association analyses

Rare sequence variants may be important in understanding the biology of common diseases, but clearly establishing their association with disease is often difficult. Association studies of such variants are becoming increasingly common as large-scale sequence analysis of candidate genes has become feasible. A recent report suggested SLITRK1 (Slit and Trk-like 1) as a candidate gene for Tourette Syndrome (TS). The statistical evidence for this suggestion came from association analyses of a rare 3'-UTR variant, var321, which was observed in two patients but not observed in more than 2000 controls. We genotyped 307 Costa Rican and 515 Ashkenazi individuals (TS probands and their parents) and observed var321 in five independent Ashkenazi parents, two of whom did not transmit this variant to their affected child. Furthermore, we identified var321 in one subject from an Ashkenazi control sample. Our findings do not support the previously reported association and suggest that var321 is overrepresented among Ashkenazi Jews compared with other populations of European origin. The results further suggest that overrepresentation of rare variants in a specific ethnic group may complicate the interpretation of association analyses of such variants, highlighting the particular importance of precisely matching case and control populations for association analyses of rare variants.     

Insulin-like growth factor 1 promoter polymorphism influences insulin gene variable number of tandem repeat-associated risk for juvenile onset type 1 diabetes

Insulin-like growth factor 1 (IGF1) plays an important role in the development and function of pancreatic beta-cells and contributes to infant growth, which we recently reported to be associated with type 1 diabetes (T1D). Here, we studied an IGF1 microsatellite in 206 families with T1D and its interaction with the polymorphism near the insulin (INS) gene variable number of tandem repeats. The IGF1 microsatellite was associated with T1D (P = 0.045), which was mainly caused by a protective effect of the 194 bp allele (36% transmission to affected offspring). Interestingly, co-segregation of this IGF1 194 bp allele affected the risk of INS alleles. These results provide the first evidence for an association of IGF1 with T1D and imply that co-inheritance of these functional genetic variants of IGF1 and insulin predispose to T1D.     

Vitamin D insufficiency: A risk factor to vertebral fractures in community-dwelling elderly women

Objective

To determine the risk factors for the presence of moderate/severe vertebral fracture, specifically 25-hydroxyvitamin D (25-OHD).

Study design

Cross-sectional study conducted for 2 years in the city of São Paulo, Brazil including community-dwelling elderly women.

Methods

Bone mineral density (BMD), serum 25-OHD, intact parathyroid hormone (iPTH), calcium and estimated glomerular filtration rate (eGFR) were examined in 226 women without vertebral fractures (NO FRACTURE group) and 189 women with at least one moderate/severe vertebral fracture (FRACTURE group). Vertebral fracture assessment (VFA) was evaluated using both the Genant semiquantitative (SQ) approach and morphometry.

Results

Patients in the NO FRACTURE group had lower age, increased height, higher calcium intake, and higher BMD compared to those patients in the FRACTURE group (p < 0.05). Of interest, serum levels of 25-OHD in the NO FRACTURE group were higher than those observed in the FRACTURE group (51.73 nmol/L vs. 42.31 nmol/L, p < 0.001). Reinforcing this finding, vitamin D insufficiency (25-OHD < 75 nmol/L) was observed less in the NO FRACTURE group (82.3% vs. 93.65%, p = 0.001). After adjustment for significant variables within the patient population (age, height, race, calcium intake, 25-OHD, eGFR and sites BMD), the logistic-regression analyses revealed that age (OR = 1.09, 95% CI 1.04–1.14, p < 0.001) femoral neck BMD (OR = 0.7, 95% CI 0.6–0.82, p < 0.001) and 25-OHD <75 nmol/L (OR = 2.38, 95% CI 1.17–4.8, p = 0.016) remains a significant factor for vertebral fracture.

Conclusion

Vitamin D insufficiency is a contributing factor for moderate/severe vertebral fractures. This result emphasizes the importance of including this modifiable risk factor in the evaluation of elderly women.     

Ethnic Manifestations of Gene Polymorphisms of Vitamin D Receptor (VDR) in Adolescents of Western Kazakhstan Region

Background (Objectives)

The objective of the article is studying the connection of VDR gene polymorphisms with bone tissue mineral density and biochemical marker of 25-PO vitamin D in adolescents of both ethnic groups, living in Western Kazakhstan Region.

Alpha2-macroglobulin exon 24 (Val-1000-Ile) polymorphism is not associated with late-onset sporadic Alzheimer's dementia in the Hungarian population

Several lines of biochemical evidence support a role of alpha2-macroglobulin (A2M) in the pathogenesis of Alzheimer's dementia (AD). A2M participates in the general defence mechanism against proteinases and it is supposed to be involved in the degradation of beta-amyloid peptide (betaAP). Furthermore, A2M has been shown to reduce betaAP fibril formation, and it is upregulated in the acute-phase inflammatory response like the process occurring in the AD brain. The exon 18 splice acceptor deletion polymorphism and the exon 24 (Val-1000-Ile) GG genotype were reported to be associated with AD, but the results are contradictory. Since the Hungarian population is genetically distinct from the other European ethnic groups, we examined whether the risk for developing AD is increased in the A2M GG carriers. The interaction of apolipoprotein E (apoE) and A2M polymorphisms was also examined. The distribution of A2M genotypes and alleles in the entire data set was consistent with the previous negative observations in which A and G allelic frequencies were comparable in both groups (72% and 28% in the AD population, and 72% and 28% in the control population, respectively). The GG genotype was over-represented (14%) only in the apoE epsilon4 non-carrier subgroup of AD probands (7% in the control group), but the difference was not significant. Our data suggest that, although A2M has an important role in the AD-specific neurodegenerative process, its exon 24 Val-1000-Ile polymorphism is not likely to be associated with late-onset sporadic AD in the Hungarian population.     

载脂蛋白E-CI-CII基因多态性与冠状动脉粥样硬化性心脏病易感性的关系

目的　探讨载脂蛋白E- CI- CII基因簇多态性与冠状动脉粥样硬化性心脏病(冠心病)的关系。方法　采用多重扩增突变系统(multiplex amplification refractory mutation system ,multi- ARMS)和聚合酶链反应-限制性片段长度多态性法检测了2 0 3例患者和36 5名对照的apo E、CI、CII基因多态性;L INKAGE程序计算连锁不平衡系数D和D′。结果　病例组apo E基因E3/4基因型频率为0 .2 5 9、ε4等位基因型频率为0 .139,均高于对照组,差异有统计学意义(P<0 .0 5 ) ;apo C 基因H2等位基因型频率在病例组为0 .2 0 5 ,高于对照组的0 .113,差异有统计学意义(P<0 .0 5 ) ;apo CII基因多态性分布在两组间差异无统计学意义(P>0 .0 5 ) ;apo E、CI基因存在显著的连锁不平衡(D′=0 .6 72 ,P<0 .0 1) ,病例组ε4 - H2 - T1单倍型频率为5 .4 %高于对照组的0 .5 % ,差异有统计学意义(P<0 .0 5 )。调整混杂因素后,ε4、H2等位基因同时携带者吸烟呈显著的相乘交互作用,危险度(odds ratio,OR)及其95 %可信限(95 % confidenceinterval,95 % CI)为18. 3(2 .35～15 0 .81,P<0 .0 5 ) ,交互作用归因比(attributable proportions ofinteraction,API)为5 7.3% ;ε4、H2和多量饮酒三者间呈超相加作用,OR(95 % CI)为12 .7(2 .75 7～5 8.5 5     

Ethnic differences in expression of the dysregulated proteins in uterine leiomyomata

BACKGROUND: Black ethnicity is one of the risk factors for uterine leiomyomata (ULM). Little is known about the ethnic differences in leiomyoma-associated gene products in women with uterine leiomyomata. METHODS: A total of 120 hysterectomies with ULM were collected from black, Asian, Hispanic and white women (30 cases from each group). Twenty-two gene products were selected for the study. The expressions of the selected dysregulated gene products were measured by the semiquantification and the immunoscores were normalized by matched myometrium. RESULTS: The relative expressions of progesterone receptor A (PR-A) (up-regulation), retinoid acid receptor alpha (down-regulation), and retinoid X receptor alpha (RXRalpha) (no change) in leiomyomata compared to normal myometrium in black women were significantly different compared to other ethnic groups (P < 0.05). About one-third of ULM from black women subclustered together in association with a group of up-regulated gene products. Many other gene products, including local growth factors, insulin-like growth factor (IGF)-signalling proteins, and cell proliferation markers, were dysregulated in ULM but showed non-significant differences between the ethnic groups. CONCLUSIONS: There are substantial differences of the sex steroid receptors and other nuclear receptors between black women and other ethnic groups. Based on tissue microarray data, there are at least two broad groups of leiomyomata presented by the dysregulation of different groups of gene products. One is dominated by up-regulation of amplified in breast cancer 1, CD24, hamartin, human mobility group gene 2, IGF2, PR-A and RXR, and the other is characterized by up-regulation of epithelial growth factor receptor, down-regulation of hamartin, PR-A and tuberin.     

No association between two candidate markers of prenatal sex hormones: Digit ratios (2D:4D and other) and finger‐ridge counts

The second‐to‐fourth digit ratio (2D:4D), putatively indexing prenatal androgen levels retrospectively, has become increasingly popular as an easily applied measure in research into the prenatal sex‐hormonal bases of behavior, health, and disease. However, its validity has not yet been conclusively demonstrated and in fact is currently debated, because validation tests of 2D:4D with other, prenatally established, presumed markers for prenatal sex‐hormone action have yielded mixed evidence or still are unavailable. Hence, the associations of 2D:4D with finger‐ridge counts, one such further under‐researched marker, were examined in this study. In a sample of 75 male and 75 female normal healthy adults, the six possible finger‐length ratios of the human hand (from 2D:3D to 4D:5D, including the classic 2D:4D ratio) were ascertained with two commonly used measurement methods (imaged‐based vs. fingers measured directly), along with two traditional dermatoglyphic traits (total and absolute finger‐ridge counts). Sex differences in finger‐length ratios (lower in men) generally were of moderate size (about .5 SD units), whereas those in finger‐ridge counts (higher in men) were small to negligible (about .2 SD units). Within‐sex analysis did not indicate theory compliant (i.e., negative) correlations between these two sets of traits that were consistent, noteworthy, or reliable. Finger‐length ratios and finger‐ridge counts are ontogenetically overlapping in their prenatal formation and anatomically adjacent. Hence, possible temporal and localized sex‐hormonal effects in prenatal life are unlikely to account for their nonassociation. The current findings cast some doubt on the validity of these retrospective pointers to prenatal androgen levels. © 2010 Wiley Periodicals, Inc. Dev Psychobiol 53: 69–78, 2011.     

CYP gene polymorphisms and early menarche.

Early age at menarche is a risk factor for breast cancer. A previous study reported a significant positive association between the CYP3A4*1B variant allele and early puberty. We investigated whether polymorphisms of the CYP3A4, CYP17, CYP1B1, and CYP1A2 genes predict the age at onset of menarche. Five hundred eighty-three nulliparous women between ages 17 and 35, of various ethnic backgrounds, completed a questionnaire that included information about menstrual history. Samples of DNA were provided and used to genotype these women for polymorphic variants in the four genes. There was no significant difference in mean age at menarche between women who carried two variant CYP17 A2 alleles (12.5 years) and women who carried one or no variant allele (12.5 years) (P = 0.8, adjusted for ethnic group and year of birth). Similar results were found for the CYP1B1*3 variant allele and for the CYP1A2*1F variant allele. Women who carried two variant CYP3A4*1B alleles had an earlier mean age at menarche (12.0 years) than women who carried one or no variant allele (12.6 years) (P = 0.02). However, after adjusting for ethnic group and year of birth, no significant differences in mean age at menarche were found. The polymorphic variants of the CYP3A4, CYP17, CYP1B1, and CYP1A2 genes are unlikely to influence age of menarche.     

Association of genomic instability, and the methylation status of imprinted genes and mismatch-repair genes, with neural tube defects

We studied the genomic instability and methylation status of the mismatch-repair (MMR) genes hMLH1 and hMSH2, and the imprinted genes H19/IGF2, in fetuses with neural tube defects (NTDs) to explore the pathogenesis of the disease. Microsatellite instability (MSI) was observed in 23 of 50 NTD patients. Five NTD patients showed high-degree MSI (MSI-H) and 18 showed low-degree MSI (MSI-L). The frequencies of mutated microsatellite loci were 3/50 (6%) for BatT-25, 10/50 (20%) for Bat-26, 3/50 (6%) for Bat34C4, 6/50 (12%) for D2S123, 4/50 (8%) for D2S119, and 3/50 (6%) for D3S1611. The promoter regions of the hMLH1 and hMSH2 genes were unmethylated in NTD patients, as determined by methylation-specific PCR. The hMLH1 and hMSH2 promoter methylation patterns, the methylation levels of H19 DMR1, and IGF2 DMR0 were detected by bisulfite sequencing PCR, sub-cloning, and sequencing. The hMSH2 promoter sequence was unmethylated, and the hMLH1 promoter showed a specific methylation pattern at two CpG sites. The methylation levels of H19 DMR1 in the NTD and control groups are 73.3% ± 15.9 and 58.3% ± 11.2, respectively. The methylation level of the NTD group was higher than that of the control group (Student's t-test, P<0.05). There is no significant difference in IGF2 DMR0 methylation level between the two groups. All of the results presented here suggest that genomic instability, the MMR system, and hyper-methylation of the H19 DMR1 may be correlated with the occurrence of NTDs.     

An unaffected individual from a breast/ovarian cancer family with germline mutations in both BRCA1 and BRCA2

Currently many centers offer testing for three specific mutations, 185delAG, 5382insC, and 6174delT, in the BRCA1 and BRCA2 genes to Ashkenazi Jewish individuals at high risk for breast and ovarian cancer. We recently tested members of a family with multiple cases of breast and ovarian cancer (Family R014). The proband in this family tested positive for the 185delAG mutation. The unaffected sister of the proband tested positive for both the 185delAG and the 6174delT mutations. Further testing and review of the family history suggest that both mutations may have come from a maternal grandfather and passed down for two generations. Counseling of the unaffected double heterozygote individual in this family is complicated by lack of information on the risk of breast, ovarian, and other cancers in such individuals. A better understanding of these risks will depend on the identification and study of more individuals carrying mutations in both the BRCA1 and BRCA2 genes. Our study emphasizes the importance of testing Ashkenazi Jewish individuals from high-risk breast and ovarian cancer families for all three common BRCA1 and BRCA2 mutations identified in this ethnic group.     

Apolipoprotein E alleles in nonagenarian subjects in the Belfast Elderly Longitudinal Free-living Ageing Study (BELFAST)

The ApoE gene has three alleles coding for the proteins apoE2, apoE3 and apoE4. E4 has been reported to be associated with hypercholesteraemia, ischaemic heart disease, age-related cognitive decline and Alzheimer's disease. Conversely, the E2 allele has been associated with longevity in French centenarians and their siblings. In this study, we have assessed any shift in the ApoE genotypes in nonagenarian subjects from Belfast where there is a high intrinsic incidence of cardiovascular disease. ApoE phenotypes were determined by electrofocusing and immunoblotting in 114 Senieur-approximated subjects >90 years old and compared with 2071 subjects, 30--65 years of age, recruited from the same geographical area by the MONItoring of CArdiovascular trends study group in Belfast (MONICA). The E4 allele was reduced in the nonagenarian group (X(2)=11.1; P=0.0006), the E3 unchanged and E2 frequency was increased (X(2)=4.0; P=0.047). These results suggest that longevity is negatively associated with the E4 allele and may be associated with carriage of E2.     

DNA sequence analysis of the conserved region around the SOD1 gene locus in recessively inherited ALS

Familial amyotrophic lateral sclerosis (ALS) accounts for 10% of all ALS cases; 12–23% are associated with mutations in the Cu/Zn superoxide dismutase gene (SOD1). All ALS-linked SOD1 mutations present with a dominant pattern of inheritance apart from the aspartate to alanine mutation in exon 4 (D90A). This mutation has been observed in dominant, recessive and apparently sporadically cases. SOD1^D90A/D90A ALS cases have a very slow disease progression (>10 years), raising the hypothesis that modifier genes linked to SOD1 ameliorate the phenotype of recessively inherited SOD1^D90A/D90A mutations. Previous sequence analysis of a conserved haplotype region around the SOD1 gene did not reveal any functional polymorphisms within known coding or putative regulatory regions. In the current study we expanded the previous analyses by sequencing the entire SOD1 conserved haplotypic region. Although many polymorphisms were identified, none of these variants explain the slowly progressive phenotype observed in patients with recessive SOD1^D90A mutations. This study disproves the hypothesis that there is a tightly linked genetic protective factor specifically located close to the SOD1 gene in SOD1^D90A mediated ALS.     

Age-dependent changes in the expression of superoxide dismutases and catalase are associated with ultrastructural modifications in human granulosa cells

Limited knowledge exists about changes in follicle quality associated with age. The aim of this work was to investigate whether ageing may cause oxidative stress-mediated alterations in human granulosa cells (GCs) from periovulatory follicles. GCs employed in this study were obtained from follicular aspirates of 20 younger women (range 27-32 years) and 20 older women (range 38-41 years) undergoing an IVF treatment. Results obtained from comparative RT-PCR analysis revealed that the mean relative levels of mRNAs coding for superoxide dismutases, Cu, ZnSOD (SOD1), MnSOD (SOD2) and catalase were significantly decreased in women > or =38 years (P < 0.05, Student's t-test). These changes were associated with a reduced expression of SOD1, SOD2 and catalase at the protein level. When examined at an ultrastructural level, most of the GCs from this group showed defective mitochondria and fewer lipid droplets than those observed in the younger group. These results indicate that GCs from older patients suffer from age-dependent oxidative stress injury and are taken as an evidence for reduced defence against reactive oxygen species (ROS) in GCs during reproductive ageing.