Association of LIN28B with Adult Adiposity-Related Traits in Females

Context

Pubertal timing is under strong genetic control and its early onset associates with several adverse health outcomes in adulthood, including obesity, type 2 diabetes and cardiovascular disease. Recent data indicate strong association between pubertal timing and genetic variants near LIN28B, but it is currently unknown whether the gene contributes to the association between puberty and adult disease.

Objective

To elucidate the putative genetic link between early puberty and adult disease risk, we examined the association of two genetic variants near LIN28B with adult body size and metabolic profiles in randomly ascertained adult Finnish males and females.

Methods

Two single nucleotide polymorphisms (SNPs), rs7759938, the lead SNP previously associated with pubertal timing and height, and rs314279, previously also associated with menarcheal age but only partially correlated with rs7759938 (r² = 0.30), were genotyped in 26,636 study subjects participating in the Finnish population survey FINRISK. Marker associations with adult height, weight, body mass index (BMI), hip and waist circumference, blood glucose, serum insulin and lipid/lipoprotein levels were determined by linear regression analyses.

Results

Both rs7759938 and rs314279 associated with adult height in both sexes (p = 2×10⁻⁶ and p = 0.001). Furthermore, rs314279 associated with increased weight in females (p = 0.001). Conditioned analyses including both SNPs in the regression model verified that rs314279 independently associates with adult female weight, BMI and hip circumference (p<0.005). Neither SNP associated with glucose, lipid, or lipoprotein levels.

Conclusion

Genetic variants near the puberty-associated gene LIN28B associate with adult weight and body shape in females, suggesting that the gene may tag molecular pathways influencing adult adiposity-related traits.     

Fine Mapping of a Region of Chromosome 11q23.3 Reveals Independent Locus Associated with Risk of Glioma

Background

A single nucleotide polymorphism (SNP) at locus 11q23.3 (rs498872) in the near 5′-UTR of the PHLDB1 gene was recently implicated as a risk factor for gliomas in a genome-wide association study, and this involvement was confirmed in three additional studies.

Methodology/Principal Findings

To identify possible causal variants in the region, the authors genotyped 15 tagging SNPs in the 200 kb genomic region at 11q23.3 locus in a Chinese Han population-based case-control study with 983 cases and 1024 controls. We found evidence for an association between two independent loci (both the PHLDB1 and the ACRN1 genes) and a predisposition for gliomas. Among the multiple significant SNPs in the PHLDB1 gene region, the rs17749 SNP was the most significant [P = 1.31×10⁻⁶ in a recessive genetic model]. Additionally, two novel SNPs (rs2236661 and rs494560) that were independent of rs17749 were significantly associated with glioma risk in a recessive genetic model [P = 1.31×10⁻⁵ and P = 3.32×10⁻⁵, respectively]. The second novel locus was within the ARCN1 gene, and it was associated with a significantly reduced risk for glioma.

Conclusions/Significance

Our data strongly support PHLDB1 as a susceptibility gene for glioma, also shedding light on a new potentially candidate gene, ARCN1.     

A Common Variant in the SIAH2 Locus Is Associated with Estrogen Receptor-Positive Breast Cancer in the Chinese Han Population

Background

Genome-wide association studies (GWAS) have identified many loci associated with breast cancer risk. These studies have primarily been conducted in populations of European descent.

Objective

To determine whether previously reported susceptibility loci in other ethnic groups are also risk factors for breast cancer in a Chinese population.

Method

We genotyped 21 previously reported single nucleotide polymorphisms (SNPs) within a female Chinese cohort of 1203 breast cancer cases and 2525 healthy controls using the Sequenom iPlex platform. Fourteen SNPs passed the quality control test. These SNPs were subjected to statistical analysis for the entire cohort and were further analyzed for estrogen receptor (ER) status. The associations of the SNPs with disease susceptibility were assessed using logistic regression, adjusting for age. The Bonferroni correction was used to conservatively account for multiple testing, and the threshold for statistical significance was P<3.57×10⁻³ (0.05/14).

Result

Although none of the SNPs showed an overall association with breast cancer, an analysis of the ER status of the breast cancer patients revealed that the SIAH2 locus (rs6788895; P = 5.73×10⁻⁴, odds ratio [OR] = 0.81) is associated with ER-positive breast cancer.

Conclusion

A common variant in the SIAH2 locus is associated with ER-positive breast cancer in the Chinese Han population. The replication of published GWAS results in other ethnic groups provides important information regarding the genetic etiology of breast cancer.     

Association of Genetic Variants with Primary Angle Closure Glaucoma in Two Different Populations

Purpose

A recent large genome-wide association study (GWAS) identified multiple variants associated with primary angle-closure glaucoma (PACG). The present study investigated the role of these variants in two cohorts with PACG recruited from Australia and Nepal.

Method

Patients with PACG and appropriate controls were recruited from eye clinics in Australia (n = 232 cases and n = 288 controls) and Nepal (n = 106 cases and 204 controls). Single nucleotide polymorphisms (SNPs) rs3753841 (COL11A1), rs1015213 (located between PCMTD1 and ST18), rs11024102 (PLEKHA7), and rs3788317 (TXNRD2) were selected and genotyped on the Sequenom. Analyses were conducted using PLINK and METAL.

Results

After adjustment for age and sex, SNP rs3753841 was found to be significantly associated with PACG in the Australian cohort (p = 0.017; OR = 1.34). SNPs rs1015213 (p = 0.014; OR 2.35) and rs11024102 (p = 0.039; OR 1.43) were significantly associated with the disease development in the Nepalese cohort. None of these SNPs survived Bonferroni correction (p = 0.05/4 = 0.013). However, in the combined analysis, of both cohorts, rs3753841 and rs1015213 showed significant association with p-values of 0.009 and 0.004, respectively both surviving Bonferroni correction. SNP rs11024102 showed suggestive association with PACG (p-value 0.035) and no association was found with rs3788317.

Conclusion

The present results support the initial GWAS findings, and confirm the SNP’s contribution to PACG. This is the first study to investigate these loci in both Australian Caucasian and Nepalese populations.     

Association Study of Serotonin Transporter SLC6A4 Gene with Chinese Han Irritable Bowel Syndrome

Objective

Irritable bowel syndrome (IBS) is a common clinical gastrointestinal dysfunction disorders. 5-sertonon (5-hydroxytryptamine, 5-HT) is a very important neurotransmitter, which is involved in gastrointestinal motion and sensation. Solute carrier family 6 member 4 (SLC6A4) gene encode serotonin transporter (SERT) which function is to rapidly reuptake the most of 5-HT. Therefore, it is needed to explore the association between SLC6A4 gene polymorphisms and IBS.

Methods

119 patients and 238 healthy controls were administrated to detect the SLC6A4 gene polymorphisms including 5-HT-transporter-gene-linked polymorphic region (5-HTTLPR), variable number of tandem repeats (VNTRs) and three selected tag Single Nucleotide Polymorphisms (SNPs) rs1042173, rs3794808, rs2020936 by using polymerase chain reaction (PCR) and TaqMan® SNP Genotyping.

Results

There were significant difference for 5-HTTLPR between IBS and control groups (X2 = 106.168, P<0.0001). In control group, genotypes were mainly L/L (58.4%), however, the genotypes in IBS were S/S (37.8%). The significant difference was shown in D-IBS subjects when compared to the controls (X² = 50.850, P<0.0001) for 5-HTTLPR. For STin2 VNTR, rs1042173, rs3794808, and rs2020936 polymorphisms, there were no any significant differences between IBS and control groups. There were no statistical significantly haplotypes for 5-HTTLPR, VNTRs and the three SNPs between IBS and controls.

Conclusion

The S allele in 5-HTTLPR was a susceptible allele with Chinese Han IBS, but other associations of VNTRs, three selected Tag SNPs and positive haplotype with IBS were not found. It is indicated that much research are needed to study the relationship between other polymorphisms in SLC6A4 gene and IBS.     

A Genetic Variant rs1801274 in FCGR2A as a Potential Risk Marker for Kawasaki Disease: A Case-Control Study and Meta-Analysis

Objectives

Recent genome-wide association study found rs1801274, a functional single nucleotide polymorphism (SNP) in IgG receptor gene FCGR2A, was associated with increased risk of Kawasaki disease (KD). However, subsequent studies on the role of this SNP were limited and controversial.

Methods

A case-control study was conducted in a Chinese Han population including 428 KD patients and 493 controls to examine the association between rs1801274 and KD susceptibility. A meta-analysis was performed in combination with the relevant published studies to further clarify such an association.

Results

Our case-control study found that rs1801274 was significantly associated with increased risk of KD in the Chinese Han population, with an odds ratio (OR) of 1.58 (95% CI = 0.96–2.62) for the GA genotype and 1.93 (95% CI = 1.16–3.19) for the AA genotype compared with the GG genotype. The result of meta-analysis further demonstrated that the A allele of rs1801274 was significantly correlated with KD risk under the allelic model (OR = 1.35, 95% CI = 1.27–1.44) without heterogeneity by fixed-effects model analysis (Q = 17.30, p = 0.139). Moreover, sensitivity analysis supported the robustness of this meta-analysis.

Conclusion

These results further confirm that rs1801274 in the FCGR2A gene is significantly associated with increased risk of KD.     

A Large Scale Gene-Centric Association Study of Lung Function in Newly-Hired Female Cotton Textile Workers with Endotoxin Exposure

Background

Occupational exposure to endotoxin is associated with decrements in pulmonary function, but how much variation in this association is explained by genetic variants is not well understood.

Objective

We aimed to identify single nucleotide polymorphisms (SNPs) that are associated with the rate of forced expiratory volume in one second (FEV₁) decline by a large scale genetic association study in newly-hired healthy young female cotton textile workers.

Methods

DNA samples were genotyped using the Illumina Human CVD BeadChip. Change rate in FEV₁ was modeled as a function of each SNP genotype in linear regression model with covariate adjustment. We controlled the type 1 error in study-wide level by permutation method. The false discovery rate (FDR) and the family-wise error rate (FWER) were set to be 0.10 and 0.15 respectively.

Results

Two SNPs were found to be significant (P<6.29×10⁻⁵), including rs1910047 (P = 3.07×10⁻⁵, FDR = 0.0778) and rs9469089 (P = 6.19×10⁻⁵, FDR = 0.0967), as well as other eight suggestive (P<5×10⁻⁴) associated SNPs. Gene-gene and gene-environment interactions were also observed, such as rs1910047 and rs1049970 (P = 0.0418, FDR = 0.0895); rs9469089 and age (P = 0.0161, FDR = 0.0264). Genetic risk score analysis showed that the more risk loci the subjects carried, the larger the rate of FEV₁ decline occurred (P _trend = 3.01×10⁻¹⁸). However, the association was different among age subgroups (P = 7.11×10⁻⁶) and endotoxin subgroups (P = 1.08×10⁻²). Functional network analysis illustrates potential biological connections of all interacted genes.

Conclusions

Genetic variants together with environmental factors interact to affect the rate of FEV₁ decline in cotton textile workers.     

Four SNPs in the CHRNA3/5 Alpha-Neuronal Nicotinic Acetylcholine Receptor Subunit Locus Are Associated with COPD Risk Based on Meta-Analyses

Background

Several single nucleotide polymorphisms (SNPs) in an α-neuronal nicotinic acetylcholine receptor subunit (CHRNA3/5) were identified to be associated with chronic obstructive pulmonary disease (COPD) in a study based on a Norwegian population. However, results from subsequent studies have been controversial, particularly in studies recruiting Asians. In the present study, we conducted a comprehensive search and meta-analyses to identify susceptibility SNPs for COPD in the CHRNA3/5 locus.

Methods

A comprehensive literature search was conducted to find studies that have reported an association between SNPs in the CHRNA3/5 locus and COPD risk. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) for each SNP were calculated with the major allele or genotype as the reference group. The influence of individual studies on pooled measures was assessed, in addition to publication bias.

Results

A total of 12 articles with 14 eligible studies were included in this analysis. Association between 4 SNPs in the CHRNA3/5 locus and COPD was evaluated and included rs1051730, rs8034191, rs6495309, and rs16969968. Significant associations between the 4 SNPs and COPD were identified under allele (rs1051730: OR = 1.14, 95%CI = 1.10–1.18; rs8034191: OR = 1.29, 95%CI = 1.18–1.41; rs6495309: OR = 1.26, 95%CI = 1.09–1.45; rs16969968: OR = 1.27, 95%CI = 1.17–1.39) and genotype models. Subgroup analysis conducted for rs1051730 showed a significant association between this SNP and COPD risk in non-Asians (OR = 1.14, 95%CI = 1.10–1.18), but not Asians (OR = 1.23, 95%CI = 0.91–1.67). Rs1051730 and rs6495309 were also significantly associated with COPD after adjusting for multiple variables, including age and smoking status.

Conclusion

Our results indicate that 4 SNPs in the CHRNA3/5 locus are associated with COPD risk. Rs1051730 was particularly associated with COPD in non-Asians, but its role in Asians still needs to be verified. Additional studies will be necessary to assess the effect of rs6495309 on COPD. Although rs1051730 and rs6495309 were shown to be independent risk factors for COPD, validation studies should be performed.     

Association between Single Nucleotide Polymorphisms in the ADD3 Gene and Susceptibility to Biliary Atresia

Background and Objectives

Based on the results of previous studies, the ADD3 gene, located in the 10q24.2 region, may be a susceptibility gene of biliary atresia (BA). In this study, two single nucleotide polymorphisms (SNPs) in the ADD3 gene, rs17095355 C/T and rs10509906 G/C, were selected to investigate whether there is an association between these SNPs and susceptibility to BA in a Chinese population.

Methods

A total of 752 Han Chinese (134 BA cases and 618 ethnically matched healthy controls) were included in the present study. The ADD3 gene polymorphisms were genotyped using a TaqMan genotyping assay.

Results

Positive associations were found for the SNP rs17095355 in the codominant model; specifically, the frequencies of the CT and TT genotypes and the T allele were higher in the cases than the controls, demonstrating a significant risk for BA (odds ratio [OR] = 1.62, 95% confidence interval [CI] = 1.02–2.58; OR = 2.89, 95% CI = 1.72–4.86; and OR = 1.75, 95% CI = 1.34–2.29, respectively). Regarding rs10509906, the per-C-allele conferred an OR of 0.70 (95% CI = 0.49–1.00) under the additive model. A greater risk of BA was associated with the T_a-G_b (a for rs17095355 and b for rs10509906) haplotype (OR = 1.82, 95% CI = 1.27–2.61) compared with the C_a-C_b haplotype.

Conclusion

This study suggests that the ADD3 gene plays an important role in BA pathogenesis and reveals a significant association between two SNPs, rs17095355 and rs10509906, and BA.     

Possible Single-Nucleotide Polymorphism Loci Associated with Systemic Sclerosis Susceptibility: A Genetic Association Study in a Chinese Han Population

Objective

The aim of this study was to confirm the association of RHOB and FAM167A-BLK gene polymorphisms with susceptibility to systemic sclerosis (SSc) in a Chinese Han population.

Methods

A total of 248 SSc patients and 251 healthy controls of Chinese Han ethnicity, which visited the department of dermatology of Peking Union Medical College Hospital, were included in the study. Six selected single nucleotide polymorphisms (SNPs) in the RHOB and FAM167A-BLK regions were selected as markers and were genotyped using a MassARRAY system, which is based on the matrix-assisted laser desorption/ionization time of flight mass spectrometry technique.

Results

Three SNPs in the coding regions of the RHOB and FAM167A-BLK genes displayed an association with SSc: (1) rs1062292T, which is a newly discovered SNP in the RHOB gene (P = 0.03, odds ratio [OR] = 1.62, 95% confidence interval (CI) = 1.05–2.50), (2) rs2736340T (P = 0.03, OR = 1.39, 95%CI = 1.03–1.85), and (3) rs13277113A (P = 0.04, OR = 1.34, 95%CI = 1.01–1.76), both in the FAM167A-BLK gene. Our results support previous findings that vaiants in the RHOB and FAM167A-BLK genes may be associated with susceptibility to SSc. However, the loci of the SNPs in RHOB region that displayed an association with SSc are quite different from the loci which were identified in studies of Caucasian populations.

Conclusion

Our results confirm that RHOB and FAM167A-BLK polymorphisms exist in Chinese Han SSc patients. Therefore, variants of the RHOB and FAM167A-BLK genes are promising genetic markers for SSc.     

Liver X Receptor Gene Polymorphisms in Tuberculosis: Effect on Susceptibility

Objectives

The Liver X receptors (LXRs), Liver X receptor A (LXRA) and Liver X receptor B (LXRB), regulate lipid metabolism and antimicrobial response. LXRs have a crucial role in the control of Mycobacterium tuberculosis (M.tb). Lacking LXRs mice is more susceptibility to infection M.tb, developing higher bacterial burdens and an increase in the size and number of granulomatous lesions. We aimed to assess the associations between single nucleotide polymorphisms (SNPs) in LXRs and risk of tuberculosis.

Methods

We sequenced the LXRs genes to detect SNPs and to examine genotypic frequencies in 600 patients and 620 healthy controls to investigate for associations with tuberculosis (TB) in the Chinese Han population. DNA re-sequencing revealed eight common variants in the LXRs genes.

Results

The G allele of rs1449627 and the T allele of rs1405655 demonstrated an increased risk of developing TB (p<0.001, p = 0.002), and the T allele of rs3758673, the T allele of rs2279238, and the C allele of rs1449626 in LXRA and the C allele of rs17373080, the G allele of rs2248949, and the C allele of rs1052677 in LXRB were protective against TB patients compared to healthy controls (p = 0.0002, p = 0.006, p<0.001, p = 0.004, p = 0.008, p = 0.003, respectively). All SNP genotypes were significantly associated with TB. An estimation of the frequencies of haplotypes revealed two potential risk haplotypes,GGCG in LXRB (p = 0.004,) and TTCG in LXRA (p<0.001, p = 0.004). Moreover, three protective haplotypes, TTAT and CCAT in LXRA and CATC in LXRB, were significantly “protective” (p = 0.008, p<0.001, p = 0.031) for TB. Furthermore, we determined that the LXRs SNPs were nominally associated with the clinical pattern of disease.

Conclusions

Our study data supported that LXRs play a fundamental role in the genetic susceptibility to TB and to different clinical patterns of disease. Thus, further investigation is required in larger populations and in additional areas.     

miR-485-5p Binding Site SNP rs8752 in HPGD Gene Is Associated with Breast Cancer Risk

Background

Single nucleotide polymorphisms (SNPs) that reside in microRNA target sites may play an important role in breast cancer development and progression. To reveal the association between microRNA target site SNPs and breast cancer risk, we performed a large case-control study in China.

Methods

We performed a two-stage case-control study including 2744 breast cancer cases and 3125 controls. In Stage I, we genotyped 192 SNPs within microRNA binding sites identified from the “Patrocles” database using custom Illumina GoldenGate VeraCode assays on the Illumina BeadXpress platform. In Stage II, genotyping was performed on SNPs potentially associated with breast cancer risk using the TaqMan platform in an independent replication set.

Results

In stage I, 15 SNPs were identified to be significantly associated with breast cancer risk (P<0.05). In stage II, one SNP rs8752 was replicated at P<0.05. This SNP is located in the 3’ untranslated region (UTR) of the 15-hydroxyprostaglandin dehydrogenase (HPGD) gene at 4q34-35, a miR-485-5p binding site. Compared with the GG genotype, the combined GA+AA genotypes has a significantly higher risk of breast cancer (OR = 1.18; 95% CI: 1.06-1.31, P = 0.002). Specifically, this SNP was associated with estrogen receptor (ER) positive breast cancer (P = 0.0007), but not with ER negative breast cancer (P = 0.23), though p for heterogeneity not significant.

Conclusion

Through a systematic case-control study of microRNA binding site SNPs, we identified a new breast cancer risk variant rs8752 in HPGD in Chinese women. Further studies are warranted to investigate the underling mechanism for this association.     

The SNP rs3128965 of HLA-DPB1 as a Genetic Marker of the AERD Phenotype

Background

Two common clinical syndromes of acetylsalicylic acid (aspirin) hypersensitivity, aspirin-exacerbated respiratory disease (AERD) and aspirin-exacerbated cutaneous disease (AECD), were subjected to a genome-wide association study to identify strong genetic markers for aspirin hypersensitivity in a Korean population.

Methods

A comparison of SNP genotype frequencies on an Affymetrix Genome-Wide Human SNP array of 179 AERD patients and 1989 healthy normal control subjects (NC) revealed SNPs on chromosome 6 that were associated with AERD, but not AECD. To validate the association, we enrolled a second cohort comprising AERD (n = 264), NC (n = 238) and disease-control (aspirin tolerant asthma; ATA, n = 387) groups.

Results

The minor genotype frequency (AG or AA) of a particular SNP, rs3128965, in the HLA-DPB1 region was higher in the AERD group compared to the ATA or NC group (P = 0.001, P = 0.002, in a co-dominant analysis model, respectively). Comparison of rs3128965 alleles with the clinical features of asthmatics revealed that patients harboring the A allele had increased bronchial hyperresponsiveness to inhaled aspirin and methacholine, and higher 15-HETE levels, than those without the A allele (P = 0.039, 0.037, and 0.004, respectively).

Conclusions

This implies the potential of rs3128965 as a genetic marker for diagnosis and prediction of the AERD phenotype.     

Causal Relationship between Adiponectin and Metabolic Traits: A Mendelian Randomization Study in a Multiethnic Population

Background

Adiponectin, a secretagogue exclusively produced by adipocytes, has been associated with metabolic features, but its role in the development of the metabolic syndrome remains unclear.

Objectives

We investigated the association between serum adiponectin level and metabolic traits, using both observational and genetic epidemiologic approaches in a multiethnic population assembled in Canada.

Methods

Clinical data and serum adiponectin level were collected in 1,157 participants of the SHARE/SHARE-AP studies. Participants were genotyped for the functional rs266729 and rs1260326 SNPs in ADIPOQ and GCKR genes.

Results

Adiponectin level was positively associated with HDL cholesterol and negatively associated with body mass index, waist-to-hip ratio, triglycerides, fasting glucose, fasting insulin, systolic and diastolic pressure (all P<0.002). The rs266729 minor G allele was associated with lower adiponectin and higher HOMA-IR (P = 0.004 and 0.003, respectively). The association between rs266729 SNP and HOMA-IR was no longer significant after adjustment for adiponectin concentration (P = 0.10). The rs266729 SNP was associated with HOMA-IR to an extent that exceeded its effect on adiponectin level (0.15 SD 95% C.I. [0.06, 0.24], P<0.001). There was no significant interaction between rs266729 SNP and ethnicity on adiponectin or HOMA-IR. In contrast, the SNP rs1260326 in GCKR was associated with HOMA-IR (P<0.001), but not with adiponectin level (P = 0.67).

Conclusion

The association of the functional promoter polymorphism rs266729 with lower serum adiponectin and increased insulin resistance in diverse ethnic groups may suggest a causal relationship between adiponectin level and insulin resistance.     

Hepatocyte Growth Factor Genetic Variations and Primary Angle-Closure Glaucoma in the Han Chinese Population

Purpose

The aim of this study is to examine whether or not hepatocyte growth factor (HGF) genetic variations are associated with susceptibility to primary angle-closure glaucoma (PACG) in the Han Chinese population.

Methods

Three single-nucleotide polymorphisms (SNPs)–rs5745718, rs17427817, and rs3735520–in the HGF gene were genotyped in 238 adult patients with PACG and 287 age-, sex-, and ethnically matched healthy controls by using a polymerase chain reaction restriction fragment length polymorphism assay. Data was analyzed by χ² analysis.

Results

The three tested analyzed polymorphisms in the HGF gene were in Hardy-Weinberg equilibrium, in all the subjects. The frequencies of the genotype and allele of rs5745718 and rs1742817 in the HGF gene were significantly different between the PACG patients and the controls. On one hand, the frequencies of the CC genotype and C allele of rs5745718 were significantly decreased in PACG patients compared with controls (P_c = 1.40×10⁻³; P_c = 3.21×10⁻⁴, respectively); however, on the other hand, significantly decreased frequencies of the GG genotype and the G allele of rs17427817 were observed in PACG patients compared with the controls (P_c = 0.006,; P_c = 6.06×10⁻⁴, respectively). A comparison of the distributions of the genotypes and alleles of rs3735520 showed no statistically significant differences between the PACG patients and the controls (p_c>0.05). The haplotype analysis results showed that the CGC haplotype frequency was significantly decreased in the patients with PACG compared with the controls (p_c<0.001). No difference was detected between the patients and the controls with regard to the other haplotypes.

Conclusions

Our study suggests that rs5745718 and rs17427817 are associated with a decreased risk of PACG in the Chinese Han population. The CGC haplotype was demonstrated to possibly play a protective role against PACG in this population.     

Association of Genetic Markers with CSF Oligoclonal Bands in Multiple Sclerosis Patients

Objective

to explore the association between genetic markers and Oligoclonal Bands (OCB) in the Cerebro Spinal Fluid (CSF) of Italian Multiple Sclerosis patients.

Methods

We genotyped 1115 Italian patients for HLA-DRB1*15 and HLA-A*02. In a subset of 925 patients we tested association with 52 non-HLA SNPs associated with MS susceptibility and we calculated a weighted Genetic Risk Score. Finally, we performed a Genome Wide Association Study (GWAS) with OCB status on a subset of 562 patients. The best associated SNPs of the Italian GWAS were replicated in silico in Scandinavian and Belgian populations, and meta-analyzed.

Results

HLA-DRB1*15 is associated with OCB+: p = 0.03, Odds Ratio (OR) = 1.6, 95% Confidence Limits (CL) = 1.1–2.4. None of the 52 non-HLA MS susceptibility loci was associated with OCB, except one SNP (rs2546890) near IL12B gene (OR: 1.45; 1.09–1.92). The weighted Genetic Risk Score mean was significantly (p = 0.0008) higher in OCB+ (7.668) than in OCB− (7.412) patients. After meta-analysis on the three datasets (Italian, Scandinavian and Belgian) for the best associated signals resulted from the Italian GWAS, the strongest signal was a SNP (rs9320598) on chromosome 6q (p = 9.4×10⁻⁷) outside the HLA region (65 Mb).

Discussion

genetic factors predispose to the development of OCB.     

The Common Variant rs11646213 Is Associated with Preeclampsia in Han Chinese Women

Background

Preeclampsia, characterized by hypertension and proteinuria, is a multifactorial disease caused by complex interactions between environmental and genetic factors. A recent genome-wide association study of blood pressure reported an association between hypertension and rs11646213. This study evaluated the association between preeclampsia and rs11646213.

Methods

A total of 454 cases and 460 controls were recruited to participate in this study. The single nucleotide polymorphism (SNP) rs11646213 was genotyped by polymerase chain reaction (PCR) and direct sequencing.

Results

The allele frequency of rs11646213 was significantly different between the preeclampsia and control groups (P = 0.017, OR = 1.36, 95% CI = 1.06–1.76). Differences were particularly significant in the severe preeclampsia subgroup (P = 0.002, OR = 1.54, 95% CI = 1.17–2.03) and the early-onset preeclampsia subgroup (P = 0.004, OR = 1.57, 95% CI = 1.16–2.13). Genotyping analysis showed that the T allele of rs11646213 could confer a risk for preeclampsia, severe preeclampsia and early-onset preeclampsia.

Conclusions

Rs11646213 upstream of the CDH13 gene is associated with preeclampsia in Han Chinese women.