Impact of genetic variants of IL-6, IL6R, LRP5, ESR1 and SP7 genes on bone mineral density in postmenopausal Mexican-Mestizo women with obesity

Background

Since obesity and osteoporosis present a high genetic predisposition and polymorphisms of IL-6, IL6R, LRP5, ESR1 and SP7 may influence the risk of both diseases, the aim of this study was to analyze the possible association of polymorphisms in these genes, as well as their haplotypes, with BMD variations in postmenopausal Mexican-Mestizo women with grade 2 or grade 3 obesity.

Methods

One hundred eighty unrelated postmenopausal women with grade 2 or grade 3 obesity were included. BMD was measured in total hip and lumbar spine by dual-energy X-ray absorptiometry. DNA was obtained from blood leukocytes. Rs1800795 of IL-6, rs2228145 of IL6R, rs3736228 of LRP5, rs9340799 (XbaI) and rs2234693 (PvuII), of ESR1, rs10876432 and rs2016266, of SP7 (and their haplotypes), were studied by real-time PCR allelic discrimination. Deviations from Hardy–Weinberg equilibrium were tested. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated by direct correlation r², and haplotype analysis was conducted.

Results

Using WHO criteria, 54.5% had grade 2 obesity, and 45.5% had grade 3 obesity. Regarding DXA results, 11.1% women had osteoporosis, 41.7% had osteopenia, and 47.2% had normal BMD. Genotype and haplotype analysis showed no significant differences with BMD variations at the lumbar spine, total hip or femoral neck.

Conclusions

We did not find a significant association between the polymorphisms analyzed or their haplotypes and BMD variations in postmenopausal women with obesity. The higher BMD observed in women with obesity could be the result of an adaptive response to the higher loading of the skeleton.     

Estrogen receptor alpha and vitamin D receptor gene polymorphisms and bone mineral density: association study of healthy pre- and postmenopausal Chinese women

In the present study, we tested the association between the estrogen receptor alpha (ER-alpha) and vitamin D receptor (VDR) genes with bone mineral density (BMD). A total of 649 healthy Chinese women, classified as pre-menopausal (N=388) and post-menopausal (N=261) groups, were genotyped at the ER-alpha PvuII, XbaI, and VDR ApaI sites. BMDs at the lumbar spine (L(1)-L(4)) and total hip were measured by dual-energy X-ray absorptiometry. For the VDR ApaI locus, AA carriers had lower spine BMD than Aa (p=0.02) and aa carriers (p<0.01) in the pre-menopausal group. For the ER-alpha gene, carriers of haplotype px had lower spine BMD than the non-carriers (p=0.03) in the pre-menopausal group. Furthermore, we observed significant interaction between the ER-alpha and VDR genes in the post-menopausal group: with AA genotype (or A allele) at the VDR ApaI locus, pX carriers had higher spine BMD than the non-carriers (p=0.02), and PX carriers had lower hip BMD than the non-carriers (p=0.04). Our data suggest that the ER-alpha and VDR genes may be associated with the BMD variation in Chinese women.     

The role of vitamin D receptor gene polymorphisms in the bone mineral density of Greek postmenopausal women with low calcium intake

The aim of this study was to investigate the effect of common vitamin D receptor (VDR) gene polymorphisms on the bone mineral density (BMD) of Greek postmenopausal women. Healthy postmenopausal women (n=578) were recruited for the study. The BMD of the lumbar spine and hip was measured using dual-energy X-ray absorptiometry with the Lunar DPX-MD device. Assessment of dietary calcium intake was performed with multiple 24-h recalls. Genotyping was performed for the BsmI, TaqI and Cdx-2 polymorphisms of the VDR gene. The selected polymorphisms were not associated with BMD, osteoporosis or osteoporotic fractures. Stratification by calcium intake revealed that in the low calcium intake group (<680 mg/day), all polymorphisms were associated with the BMD of the lumbar spine (P<.05). After adjustment for potential covariates, BsmI and TaqI polymorphisms were associated with the presence of osteoporosis (P<.05), while the presence of the minor A allele of Cdx-2 polymorphism was associated with a lower spine BMD (P=.025). In the higher calcium intake group (>680 mg/day), no significant differences were observed within the genotypes for all polymorphisms. The VDR gene is shown to affect BMD in women with low calcium intake, while its effect is masked in women with higher calcium intake. This result underlines the significance of adequate calcium intake in postmenopausal women, given that it exerts a positive effect on BMD even in the presence of negative genetic predisposition.     

Combined effects of collagen type I alpha1 (COL1A1) Sp1 polymorphism and osteoporosis risk factors on bone mineral density in Turkish postmenopausal women

Identification of risk factors for osteoporosis has been essential for understanding the development of osteoporosis. The collagen type I alpha1 (COL1A1) gene is suggested to be implicated in reduced bone mineral density (BMD) in osteoporosis. In the present study, the investigation of the effects of Sp1 polymorphic variants of COL1A1 gene on BMD values, and the determination of the association between COL1A1 Sp1 gene variants and osteoporosis risk factors in the context of gene–environment interaction in Turkish postmenopausal women were aimed. For the detection of COL1A1 Sp1 polymorphism, PCR-RFLP techniques have been used. BMD for lumbar spine (L1–L4) and hip (femoral neck and total hip) was measured by DXA. This study was carried out using a sample of 254 postmenopausal women. We observed a trend decrease in BMD values in the subjects with “ss” genotype having lower BMD of lumbar spine, femoral neck and total hip than those with “SS” and “Ss” genotype, however the differences did not reach statistical significance (P > 0.05). We also found that the frequencies of the BMD under mean values at the femoral neck (57.5%) and total hip (76.2%) increased considerably in the subjects carrying “Ss/ss” genotypes in combination of having family history of osteoporosis (61.5% for femoral neck) and smoking history (90.0% for total hip). This population-based study indicates that COL1A1 Sp1 polymorphism may contribute to the development of osteoporosis in combination of osteoporosis risk factors in Turkish postmenopausal women.     

Associations study of vitamin D receptor gene polymorphisms with diabetic microvascular complications: a meta-analysis

Background

Emerging evidence from preclinical and clinical studies has shown that vitamin D plays an important role in the pathogenesis of diabetic microvascular complications (DMI). Several potentially functional polymorphisms (ApaI, BsmI, FokI and TaqI) of vitamin D receptor (VDR) gene have been implicated in DMI risk, but individually published studies showed inconclusive results. The aim of this study was to quantitatively summarize the association between VDR polymorphisms and DMI risk.

Methods

We searched all the publications about the associations mentioned as above from PubMed and ISI database updated in December 2013. Meta-analysis of the overall odds ratios (ORs) with 95% confidence intervals (CIs) was calculated with the fixed or random effect model.

Results

Eight studies involving 2734 subjects were included. Allelic and genotypic comparisons between cases and controls were evaluated. Overall analysis suggests that no significant association was observed among the ApaI, BsmI, FokI and TaqI variants and DMI risk in diabetic patients (all P values > 0.05). In the stratified analysis, significant association was observed with diabetic nephropathy (DN) for VDR gene FokI polymorphism under a dominant model (OR 1.35, 95% CI 1.05–1.74, P = 0.02) in Caucasians.

Conclusions

This meta-analysis indicated that the FokI polymorphism in VDR gene might affect individual susceptibility to DN in Caucasians. Further investigations are needed to confirm our results.     

Vitamin D status and vitamin D receptor gene polymorphisms and susceptibility to type 1 diabetes in Egyptian children

Background

Type 1 diabetes mellitus (T1DM) is recognized as a T-cell-mediated autoimmune disease. Vitamin D compounds are known to suppress T-cell activation by binding to vitamin D receptor (VDR); and thus, VDR gene polymorphisms may be related to T-cell-mediated autoimmune diseases. The aim of this study was to investigate the association between vitamin D status and VDR gene polymorphisms and T1DM.

Materials and methods

One hundred and twenty patients with T1DM and one hundred and twenty controls were enrolled in the study. VDR gene BsmI, FokI, ApaI and TaqI polymorphisms were determined using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Serum 25-hydroxyvitamin D (25(OH)D) was determined using ELISA.

Result

Serum 25(OH)D levels revealed a vitamin D deficiency or insufficiency in 75% of the patients. The mean levels of vitamin D were significantly lower in patients as compared to their controls (P = < 0.001). VDR BsmI Bb and bb genotypes and VDR FokI Ff and ff genotypes were associated with increased risk of T1DM (OR = 2.3, 95% CI = 1.3–4.2, P = 0.005; OR = 2.2, 95% CI = 1.1–4.7, P = 0.04; OR = 1.8, 95% CI = 1.03–3.04, P = 0.04; OR = 4.03, 95% CI = 1.2–13.1, P = 0.01 respectively), while the VDR ApaI and TaqI polymorphisms were not.

Conclusion

Our study indicated that vitamin D deficiency and VDR BsmI and FokI polymorphisms were associated with T1DM in Egyptian children.     

Association of the CAG repeat polymorphisms in androgen receptor gene with polycystic ovary syndrome: A systemic review and meta-analysis

Background

Many studies have reported the associations of polymorphic CAG repeats in androgen receptor (AR) gene with PCOS risk, but with inconsistent results. So, the aim of present meta-analysis was to clarify such inconsistence, so as to provide more conclusive results.

Methods

PubMed was searched for the eligible reports published until February 2012 without language limitation. The studies reporting the relationship between CAG repeat length and PCOS were selected for the meta-analysis according to the inclusion criteria. Two reviewers independently extracted the data and evaluated the study quality.

Principal findings

As for the relationship between CAG repeat length and PCOS risk, the pooled results showed that the biallelic mean was not significantly different between PCOS and controls (SMD − 0.03, 95% CI − 0.16–0.10, P = 0.603), and that the ORs of PCOS were not demonstrated for the individuals with the biallelic mean less than median (OR 0.96, 95% CI 0.68–1.35, P = 0.794), with the short CAG allele (OR 0.94, 95% CI 0.80–1.10, P = 0.424), or with the X-weighted biallelic mean (OR 0.81, 95% CI 0.46–1.41, P = 0.447). Further, as for the relationship between CAG repeat length and T levels in PCOS patients, the biallelic mean was not significantly different between PCOS patients with high T and those with low T (SMD 0.79, 95% CI − 0.12–1.70, P = 0.088), while the summary correlation r indicated that the CAG biallelic mean appeared to be positively associated with T levels in PCOS (r 0.20, 95% CI 0.11–0.30, p = 0.000).

Conclusions

This meta-analysis demonstrates no evident association between the CAG length variations in AR gene and PCOS risk, while the CAG length appears to be positively associated with T levels in PCOS patients.     

Genetic association of ADIPOQ gene variants with type 2 diabetes,obesity and serum adiponectin levels in south Indian population

Objective

To investigate the genetic association of eight variants of the adiponectin gene with type 2 diabetes mellitus (T2DM), obesity and serum adiponectin level in the south Indian population.

Methods

The study comprised of 1100 normal glucose tolerant (NGT) and 1100 type 2 diabetic, unrelated subjects randomly selected from the Chennai Urban Rural Epidemiology Study (CURES), in southern India. Fasting serum adiponectin levels were measured by radioimmunoassay. The variants were screened by polymerase chain reaction-restriction fragment length polymorphism. Linkage disequilibrium was estimated from the estimates of haplotype frequencies.

Results

Of the 8 variants, four SNPs namely, + 276 G/T (rs1501299), − 4522 C/T (rs822393), − 11365 C/G (rs266729), and + 712 G/A (rs3774261) were significantly associated with T2DM in our study population. The −3971 A/G (rs822396) and − 11391 G/A (rs17300539) SNPs' association with T2DM diabetes was mediated through obesity (where the association with type 2 diabetes was lost after adjusting for BMI). There was an independent association of + 276 G/T (rs1501299) and − 3971 A/G (rs822396) SNPs with generalized obesity and + 349 A/G (rs2241767) with central obesity. Four SNPs, −3971 A/G (rs822396), + 276 G/T (rs1501299), − 4522 C/T (rs822393) and Y111H T/C (rs17366743) were significantly associated with hypoadiponectinemia. The haplotypes GCCATGAAT and AGCGTGGGT conferred lower risk of T2DM in this south Indian population.

Conclusion

The adiponectin gene variants and haplotype contribute to the genetic risk towards the development of type 2 diabetes, obesity and hypoadiponectinemia in the south Indian population.     

Genetic association between IL-17F gene polymorphisms and the pathogenesis of Graves' Disease in the Han Chinese population

Background

Graves' Disease (GD) is a common and complex disorder, with a strong hereditary component. IL-17F is a potent cytokine and a potential contributor to the etiology of various human autoimmune diseases. In the present study, we focused on the relationship between polymorphisms in the IL-17F gene and GD susceptibility through a case–control association study in two independent Chinese cohorts.

Methods

Our pilot study was performed on a cohort from Shanghai, which included 757 GD patients and 741 healthy controls. Our replication cohort was from Xiamen, consisting of 434 GD patients and 420 healthy controls. We selected four tag SNPs (rs763780, rs2397084, rs9463772 and rs761167) within the IL-17F gene to conduct a genotyping analysis.

Results

In the Shanghai cohort, the rs9463772 polymorphism showed a significant association with GD and Graves' Disease-associated Ophthalmopathy (GO) patients (P_allele = 7 × 10^− 5 and 7.4 × 10^− 3 for GD and GO patients, respectively). The rs763780 polymorphism was found to have only a difference in genotype distribution between GD individuals and healthy controls (P = 0.017). In the replication study, we confirmed the association between the rs9463772 polymorphism and GD susceptibility. Haplotype analysis showed that the haplotype of the four SNPs (GCTT) was associated with a significant risk of GD in the Shanghai cohort (P = 7.9 × 10^− 3).

Conclusion

Our results suggest that polymorphisms in the IL-17F gene increase the risk of Graves' Disease and that IL-17F is therefore a good candidate gene for Graves' Disease prediction in the Han Chinese population.     

Association between genetic polymorphisms of Toll-like receptor 2 (TLR2) and schizophrenia in the Korean population

Immunological dysregulation has been suggested to be involved in the pathogenesis of schizophrenia. Accumulating evidences further implicate that activated inflammatory processes may be particularly relevant for the precipitation of negative and cognitive symptoms of schizophrenia. Toll-like receptor 2 (TLR2) plays an important role in innate immunity by sensing a variety of pathogens and inducing an acquired immunity. In the present study, we investigated whether the coding region of single nucleotide polymorphisms (SNPs) of the TLR2 gene was associated with schizophrenia as well as with clinical symptoms in schizophrenia patients. The study population consisted of 286 Korean schizophrenia patients and 305 Korean control subjects. The assessment of the Scale for the Assessment of Negative Symptoms was used to evaluate the negative symptoms of schizophrenia; the operational criteria checklist was used to measure general psychopathology. We selected two cSNPs [rs3804099 (Asn199Asn) and rs3804100 (Ser450Ser)] considering their heterozygosity and minor allele frequency. SNP genotyping was conducted using direct sequencing. We did not find any significant associations between SNPs and schizophrenia in the genotype and allelic frequencies. On the other hand, in the analysis of cognitive symptoms, rs3804099 showed significant differences in schizophrenia patients with poor concentration in the dominant model (TC/CC vs. TT, p = 0.0099). Also, rs3804100 showed a significant association with poor concentration in the co-dominant (TC vs. TT, p = 0.014) and the dominant models (TC/CC vs. TT, p = 0.0035). We obtained no significant support for the association of the TLR2 gene with susceptibility to schizophrenia in the Korean population. However, our results provide possibility that C allele of rs3804099 and rs3804100 may be associated with poor concentration in schizophrenia patients. Further studies with larger samples are required to confirm our results.     

Genetic polymorphism of vitamin D receptor gene affects the phenotype of PCOS

Aims

Polycystic ovary syndrome (PCOS), a common female endocrine disorder, represents a wide range of clinical manifestations and disease severity. Recent studies suggest an association between gene variants involved in vitamin D metabolism and common metabolic disturbances in PCOS. We aimed to examine the association of vitamin D receptor (VDR) gene variant with PCOS susceptibility and the severity of disease phenotype.

Methods

All participants, including 260 PCOS women (cases) and 221 normoovulatory women (controls), were recruited from a reproductive endocrinology clinic. Cases were divided into the severe and mild PCOS phenotype groups, based on their clinical and paraclinical features. An adenosine to guanine single nucleotide polymorphism of VDR gene (rs757343) was genotyped using the PCR–RFLP method.

Results

Distributions of genotypes and alleles did not differ between cases and controls, indicating that this SNP is not associated with increased risk for PCOS. However, this SNP was found to be associated with the severity of the PCOS phenotype. In particular, presence of the A allele is associated with a 74% increased risk of severe phenotype development (OR, 1.74; 95% CI, 1.07–2.82).

Conclusion

The genetic variant of the VDR was found to have an association with severity of clinical features of PCOS, but none with disease risk.     

Association of HHIP polymorphisms with COPD and COPD-related phenotypes in a Chinese Han population

The hedgehog signaling pathway plays an important role in lung morphogenesis and cellular responses to lung injury. Genome-wide association studies (GWAS) and integrative genomics approaches have demonstrated the associations between HHIP polymorphisms and chronic obstructive pulmonary disease (COPD) and in non-Asian populations. Here we investigated whether HHIP polymorphisms would also be associated with COPD susceptibility and COPD-related phenotypes in a Chinese Han population. In the present case–control study a total of 680 COPD patients and 687 healthy control subjects were recruited. Six single nucleotide polymorphisms (SNPs) (rs1828591, rs13118928, rs6817273, rs10519717, rs12504628, rs13147758) were selected for genotyping. Allele frequencies and genotype distributions were compared between patients and controls. To estimate the strength of association, odds ratios (OR) (with 95% CI) were calculated and potential confounding variables were tested by using logistic regression analysis. Association between haplotypes and COPD outcome was also assessed. We identified that SNP rs12504628 was associated with FEV1/FVC ratio among cases (P = 0.0460). Moreover, the HHIP SNP rs10519717 was associated with the severity of disease (adjusted P-value = 0.0300). The six SNPs showed strong linkage disequilibrium (r² ≥ 0.9). Three major haplotypes were observed but showed no significant difference between case and control groups (P = 0.4532, 0.0875, and 0.3484, respectively). In conclusion, our study suggests that the HHIP gene may be involved in COPD susceptibility in Chinese Han population.     

Association study of polymorphisms in the receptor for advanced glycation end-products (RAGE) gene with susceptibility and prognosis of heart failure

Background

Functional polymorphisms in the receptor for advanced glycation end-products (RAGE) gene have been implicated in several vascular diseases. However, to date, no study investigated the association of RAGE polymorphisms with heart failure (HF).

Objective

In this study we tested the hypothesis that the 63-bp insertion/deletion, the − 374T > A (rs1800624) and the − 429T > C (rs1800625) polymorphisms in the RAGE gene might be associated with susceptibility to HF and could predict all-cause mortality in Brazilian outpatients with left ventricular systolic dysfunction.

Methods

A total of 273 consecutive HF patients (196 Caucasian- and 77 African-Brazilians) and 334 healthy blood donors (260 Caucasian- and 74 African-Brazilians) were enrolled in a tertiary care university hospital. Genotyping of RAGE polymorphisms was done by polymerase chain reaction (PCR) or PCR followed by enzyme restriction analysis.

Results

The allele, genotype and haplotype frequencies of − 374T > A and − 429T > C polymorphisms were not significantly different between HF patients and healthy blood donors in both ethnic groups. However, among African-Brazilians, the frequency of carriership of the del allele was lower in HF patients than in blood donors (2.6% vs 12.2%, respectively, p = 0.008). Patients were followed-up for a median of 38 months and the survival analysis did not reveal a consistent association between RAGE polymorphisms and all-cause death in both ethnic groups.

Conclusion

The − 374T > A and − 429T > C polymorphisms in the RAGE gene were not associated with the susceptibility and prognosis of HF. Notwithstanding, the 63-bp ins/del polymorphism might be involved in the susceptibility to HF in African-Brazilians.     

Association of BANK1 and cytokine gene polymorphisms with type 1 diabetes in Tunisia

Type 1 diabetes (T1D) is an autoimmune disease (AID) with both genetic and environmental components. We aimed to investigate the genetic association of polymorphisms in genes previously linked with other AIDs, namely BANK1, IL15 and IL2/IL21 region.     

BsmI polymorphisms in vitamin D receptor gene are associated with diabetic nephropathy in type 2 diabetes in the Han Chinese population

We investigated the relationship between BsmI/ApaI polymorphisms in vitamin D receptor gene and diabetic nephropathy in a Han Chinese population. PCR-restriction fragment length polymorphism was used to test the genotype and allele frequency of BsmI and ApaI polymorphisms in 304 patients with type 2 diabetes mellitus (DM group) and 100 control individuals (ND group). The DM group was further divided into DN0 (no diabetic nephropathy), DN1 (diabetes with small amount of albuminuria), DN2 (diabetes with large amount of albuminuria), L/NDN (late-onset DN after 5 years/no DN over the whole follow-up period of 5 years) and EDN (early-onset diabetic nephropathy occurring within first year) subgroup. We found that (1) genotype and allele frequency of BsmI polymorphism had significant difference between DM and ND group; BB+Bb genotype and B allele frequency were significantly higher in DN2 group than in ND and DN0 group; the ApaI polymorphism and allele frequency did not show any difference between DM and ND group; (2) BsmI BB+Bb genotype and B allele frequency were significantly higher in EDN group than in L/NDN group; (3) among patients with nephropathy, albumin excretion rate (AER) in 24-hour urine was significantly higher in those with BB+Bb phenotype than in those with bb phenotype (P<0.01), (4) unconditional logistic regression analysis showed that BsmI BB+Bb genotype was not only correlated with type 2 diabetic nephropathy, but also correlated with early-onset type 2 diabetic nephropathy. We conclude that the allele B (BB or Bb genotype) in vitamin D receptor gene is correlated with large amount albuminuria in the Han Chinese population with type 2 diabetes, and is probably a risk factor for early-onset diabetic nephropathy.     

Association of TLR and TREM-1 gene polymorphisms with risk of coronary artery disease in a Russian population

Atherosclerosis, manifesting itself as acute coronary syndrome, stroke, and peripheral arterial diseases, is a chronic progressive inflammatory disease which is driven by responses of both innate and adaptive immunity. Toll-like receptors (TLRs) and Triggering Receptor Expressed on Myeloid Cells-1 (TREM-1) are important effectors of the innate immune system, and polymorphisms within genes encoding them may increase risk of occurrence of various pathologies including cardiovascular disorders. Thus, we carried out a genetic association study on the sample of 702 consecutive Caucasian (Russian) patients with coronary artery disease (CAD) and 300 age-, sex-, and ethnicity-matched healthy controls. We revealed that the C/C genotype of the TLR1 rs5743551 polymorphism was significantly associated with a reduced risk of CAD according to the recessive model (OR = 0.41, 95% CI = 0.20–0.84, P = 0.017, adjusted by age and gender). Concerning TREM-1 gene polymorphisms, we found that A/A genotype of the rs2234237 polymorphism, the G/G genotype of the rs6910730 polymorphism, the C/C genotype of the rs9471535 polymorphism, and the T/T genotype of the rs4711668 polymorphism were significantly associated with elevated CAD risk according to the recessive model (OR = 5.52, 95% CI = 1.17–25.98, P = 0.011; OR = 4.28, 95% CI = 1.09–16.81, P = 0.021; OR = 5.55, 95% CI = 1.18–26.09, P = 0.011, and OR = 1.66, 95% CI = 1.10–2.52, P = 0.014, respectively, adjusted by age and gender). Conversely, the G allele of the rs1817537 polymorphism, the T allele of the rs2234246 polymorphism, and the T allele of the rs3804277 polymorphism significantly correlated with similarly decreased risk of CAD according to the dominant model (OR = 0.57, 95% CI = 0.40–0.81, P = 0.0013; OR = 0.59, 95% CI = 0.42–0.84, P = 0.003, and OR = 0.58, 95% CI = 0.41–0.81, P = 0.0014, respectively, adjusted by age and gender). We conclude that certain TLR and TREM-1 gene polymorphisms may be associated with CAD in Russian population; however, their significance as predictive and pathogenic markers of CAD should be interpreted with caution in other populations.     

Association between the ghrelin Leu72Met polymorphism and type 2 diabetes risk: A meta-analysis

Aims

Data on the association between the ghrelin Leu72Met polymorphism and type 2 diabetes are conflicting. A meta-analysis was performed on this topic.

Methods

We searched for case–control studies using electronic databases (Medline and PubMed) and reference lists of studies. Odds ratios (OR) and 95% confidence intervals (CI) assuming dominant, recessive and homozygote comparison genetic models were calculated.

Results

Six case–control studies involving a total of 3417 cases and 3081 controls were included in this meta-analysis. No association was found between the ghrelin Leu72Met polymorphism and type 2 diabetes risk in the overall population in dominant, recessive and homozygote comparison models. However, in subgroup analyses stratified by ethnicity, we found that the risk for type 2 diabetes was decreased in subjects with Met72 + genotypes in Caucasians (OR = 0.79, 95% CI: 0.64–0.98, P_z = 0.030).

Conclusion

The ghrelin Leu72Met polymorphism was protective against type 2 diabetes in Caucasians. Future studies performed in larger sample size are needed to allow a more definitive conclusion.     

Genetic polymorphisms of IFNG and IFNGR1 in association with the risk of pulmonary tuberculosis

Objective

Genetic host factors play an important role in controlling individual's susceptibility to the pathogen. This study aims to explore the single and joint effect of genetic polymorphisms of interferon-gamma (IFNG) and its receptor (IFNGR1) in association with the pulmonary tuberculosis in a Chinese Han population.

Methods

This population-based case control study consisted of 1434 pulmonary tuberculosis patients and 1412 healthy controls. Six tag SNPs in IFNG/IFNGR1 were genotyped using TaqMan allelic discrimination technology. The logistic regression model was carried out to analyze the associations between the genotypes and haplotypes and the risk of tuberculosis by calculating the odds ratio (OR) and 95% confidence interval (CI).

Results

After the Bonferroni correction for multiple comparisons, three SNPs (rs2234711, rs1327475 and rs7749390) in IFNGR1 gene were observed to be significantly associated with the altered risks of tuberculosis. For the SNP rs2234711, individuals carrying C allele (vs. T) showed a decreased risk, with the adjusted OR(95% CI) of 0.82(0.76–0.91). The additive model revealed that each additional allele contributed about 14% decreased risk (OR: 0.86, 95% CI: 0.77–0.95). Moreover, we observed a strong linkage disequilibrium between rs2234711 and rs3799488. Compared with the common rs2234711C–rs3799488C haplotype, the haplotype rs2234711T–rs3799488C contributed to a significant increase in the risk of tuberculosis (adjusted OR: 1.24, 95% CI: 1.09–1.41).

Conclusions

Our results suggest that genetic polymorphisms in IFNGR1 gene are involved in the risk of tuberculosis in the Chinese population. Future studies should include a comprehensive sequencing analysis to identify the specific causative sequence variants underlying the observed associations.     

Diagnostic utility of HFE variants in Spanish patients: Association with HLA alleles and role in susceptibility to acute lymphoblastic leukemia

Two single nucleotide polymorphisms (SNPs) in the Human Hemochromatosis (HFE) gene, C282Y and H63D, are the major variants associated to altered iron status and it is well known that these mutations are in linkage disequilibrium with certain Human Leukocyte Antigen (HLA)-A alleles. In addition, the C282Y SNP has been previously suggested to confer susceptibility to acute lymphoblastic leukemia (ALL). We have aimed to assess the diagnosis utility of these polymorphisms in a population of Spanish subjects with suspicion of hereditary iron overload and to evaluate the effect of their associations with HLA-A alleles on the susceptibility to ALL. Both the 63DD [OR = 4.31 (1.7–11.2)] and 282YY (p for trend = 0.02) genotypes were more frequently found among subjects with suspicion of iron overload than among controls. 282YY carriers displayed significantly higher transferrin saturation index (TSI) values (p < 0.001) as well as serum iron (p = 0.01) and ferritin (p = 0.01) levels. In addition, transferrin levels were lower in these subjects (p = 0.01). Likewise, patients who were carriers of the compound heterozygous diplotype (282CY/63HD) showed significantly higher TSI and serum iron and ferritin concentrations. The H63D SNP did not significantly affect the analytical parameters measured. All 282YY carriers and 69.2% of compound heterozygotes showed an altered biochemical index. The frequencies of the HFE SNPs in ALL pediatric patients were lower than those found in controls, whereas the HLA-A*24 allele was significantly overrepresented in the patients group [OR = 3.76 (1.9–7.3)]. No HFE-HLA-A associations were found to modulate the ALL risk. These results suggest that it may be useful to test for both HFE H63D and C282Y polymorphisms in patients with iron overload, as opposed to just genotyping for the C282Y SNP, which is customary in some healthcare centers. These HFE variants and their associations with HLA-A alleles were not observed to be relevant for the susceptibility to ALL in our population.