Association of six single nucleotide polymorphisms with gestational diabetes mellitus in a Chinese population

Background

To investigate whether the candidate genes that confer susceptibility to type 2 diabetes mellitus are also correlated with gestational diabetes mellitus (GDM) in pregnant Chinese women.

Methodology/Principal Findings

In this study, 1764 unrelated pregnant women were recruited, of which 725 women had GDM and 1039 served as controls. Six single nucleotide polymorphisms (rs7754840 in CDKAL1, rs391300 in SRR, rs2383208 in CDKN2A/2B, rs4402960 in IGF2BP2, rs10830963 in MTNR1B, rs4607517 in GCK) were genotyped using TaqMan allelic discrimination assays. The genotype and allele distributions of each SNP between the GDM cases and controls and the combined effects of alleles for the risk of developing GDM were analyzed. We found that the rs4402960, rs2383208 and rs391300 were statistically associated with GDM (OR = 1.207, 95%CI = 1.029–1.417, p = 0.021; OR = 1.242, 95%CI = 1.077–1.432, p = 0.003; OR = 1.202, 95%CI = 1.020–1.416, P = 0.028, respectively). In addition, the effect was greater under a recessive model in rs391300 (OR = 1.820, 95%CI = 1.226–2.701, p = 0.003). Meanwhile, the joint effect of these three loci indicated an additive effect of multiple alleles on the risk of developing GDM with an OR of 1.196 per allele (p = 1.08×10⁻⁴). We also found that the risk alleles of rs2383208 (b = −0.085, p = 0.003), rs4402960 (b = −0.057, p = 0.046) and rs10830963 (b = −0.096, p = 0.001) were associated with HOMA-B, while rs7754840 was associated with decrease in insulin AUC during a 100 g OGTT given at the time of GDM diagnosis (b = −0.080, p = 0.007).

Conclusions/Significance

Several risk alleles of type 2 diabetes were associated with GDM in pregnant Chinese women. The effects of these SNPs on GDM might be through the impairment of beta cell function and these risk loci contributed additively to the disease.     

Association study of single nucleotide polymorphisms in pre-miRNA and rheumatoid arthritis in a Han Chinese population

The aim of this study was to perform an association study between two single nucleotide polymorphisms (SNPs) rs2910164 G>C and rs3746444 T>C in pre-miRNA (hsa-mir-146a and hsa-mir-499) and rheumatoid arthritis (RA) in the Han Chinese population. 208 Han Chinese patients with RA and 240 healthy controls were recruited in this study. The SNPs was genotyped by polymerase chain reaction-restriction fragment length polymorphism. Anti-cyclic citrullinated peptide (anti-CCP) antibody was measured by enzyme linked immunosorbent assay and rheumatoid factor (RF) was measured by rate nephelometry. The genotype frequencies between cases and controls were compared by χ(2) analysis. No significant association between the SNPs (rs2910164 and rs3746444) and RA was observed (P = 0.631 and 0.775, respectively), and the SNPs did not show any association with the RF-positive (P = 0.631 and 0.775, respectively). However, there was a significant difference on the level of anti-CCP antibody between different genotypes in rs3746444 (P = 0.007). The heterozygote CT had significantly higher level of anti-CCP antibody compared with homozygote CC and TT (P = 0.054 and 0.003, respectively). We first investigated the association between the SNPs (rs2910164 G>C and rs3746444 T>C) in the pre-miRNA (hsa-mir-146a and hsa-mir-499) and RA in a Han Chinese population. We did not find a significant association between the SNPs and the susceptibility to RA, while the SNP rs3746444 may affect anti-CCP antibody production.     

Association analysis of single nucleotide polymorphisms at five loci: comparison between atopic dermatitis and asthma in the Chinese Han population

Atopic diseases, such as atopic dermatitis (AD) and asthma, are closely related to clinical phenotypes with hypersensitivity, and often share some similar genetic and pathogenic bases. Our recent GWAS identified three susceptibility gene/loci FLG (rs11204971 and rs3126085), 5q22.1 (rs10067777, rs7701890, rs13360927 and rs13361382) and 20q13.33 (rs6010620) to AD. The effect of these AD associated polymorphisms in asthma is so far unknown. To investigate whether AD relevant genetic variants is identical to asthma and reveal the differences in genetic factors between AD and asthma in Chinese Han population, seven AD associated single nucleotide polymorphisms (SNPs) as well as 3 other SNPs (rs7936562 and rs7124842 at 11q13.5 and rs4982958 at 14q11.2) from our previous AD GWAS were genotyped in 463 asthma patients and 985 controls using Sequenom MassArray system. We found rs4982958 at 14q11.2 was significantly associated with asthma (P = 3.04×10⁻⁴, OR = 0.73). We also detected one significant risk haplotype GGGA from the 4 SNPs (rs10067777, rs7701890, rs13360927 and rs13361382) at 5q22.1 in AD cases (P _correction = 3.60×10⁻¹⁰, OR = 1.26), and the haplotype was suggestive of risk in asthma cases in this study (P = 0.014, P _correction = 0.084, OR = 1.38). These SNPs (rs11204971, rs3126085, rs7936562, rs712484 and rs6010620) at AD susceptibility genes/loci FLG, 11q13.5 and 20q13.33 were not associated with asthma in this study. Our results further comfirmed that 14q11.2 was an important candidate locus for asthma and demonstrated that 5q22.1 might be shared by AD and asthma in Chinese Han population.     

Association between XPG polymorphisms and stomach cancer susceptibility in a Chinese population

Xeroderma pigmentosum group G (XPG) protein plays an important role in the DNA repair process by cutting the damaged DNA at the 3′ terminus. Previous studies have indicated some polymorphisms in the XPG gene are associated with stomach cancer susceptibility. We performed this hospital‐based case–control study to evaluate the association of four potentially functional XPG polymorphisms (rs2094258 C>T, rs751402 C>T, rs2296147 T>C and rs873601G>A) with stomach cancer susceptibility. The four single nucleotide polymorphisms (SNPs) were genotyped in 692 stomach cancer cases and 771 healthy controls. Logistic regression analysis was conducted, and odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the association of interest. Of the studied SNPs, XPG rs873601G>A polymorphism was found to significantly associate with stomach cancer susceptibility (AA versus GG/AG: OR = 1.31, 95% CI = 1.03–1.66, P = 0.027). Combined analysis of all SNPs revealed that the individuals with two of risk genotypes had a significantly increased stomach cancer risk (OR = 1.52, 95% CI = 1.13–2.06). In the stratification analysis, the association between the rs873601AA genotype and stomach cancer risk was observed in older group (>59 year), as well as patients with non‐cardia stomach cancer. Further combined analysis indicated men, smokers, or non‐drinkers more than one risk genotypes had a significantly increased stomach cancer risk. Our results indicate that XPG rs873601G>A polymorphism may be associated with the risk of stomach cancer. Further prospective studies with different ethnicities and large sample sizes are needed to validate our findings.     

Multi-locus inference of population structure: a comparison between single nucleotide polymorphisms and microsatellites

Although growing numbers of single nucleotide polymorphisms (SNPs) and microsatellites (short tandem repeat polymorphisms or STRPs) are used to infer population structure, their relative properties in this context remain poorly understood. SNPs and STRPs mutate differently, suggesting multi-locus genotypes at these loci might differ in ability to detect population structure. Here, we use coalescent simulations to measure the power of sets of SNPs and STRPs to identify population structure. To maximize the applicability of our results to empirical studies, we focus on the popular STRUCTURE analysis and evaluate the role of several biological and practical factors in the detection of population structure. We find that: (1) fewer unlinked STRPs than SNPs are needed to detect structure at recent divergence times <0.3 N_e generations; (2) accurate estimation of the number of populations requires many fewer STRPs than SNPs; (3) for both marker types, declines in power due to modest gene flow (N_em=1.0) are largely negated by increasing marker number; (4) variation in the STRP mutational model affects power modestly; (5) SNP haplotypes (θ=1, no recombination) provide power comparable with STRP loci (θ=10); (6) ascertainment schemes that select highly variable STRP or SNP loci increase power to detect structure, though ascertained data may not be suitable to other inference; and (7) when samples are drawn from an admixed population and one of its parent populations, the reduction in power to detect two populations is greater for STRPs than SNPs. These results should assist the design of multi-locus studies to detect population structure in nature.     

Association of three single nucleotide polymorphisms at the SIX1-SIX6 locus with primary open angle glaucoma in the Chinese population

This study investigated the genetic association of three single nucleotide polymorphisms(SNPs; rs10483727, rs33912345, and rs146737847) at the SIX1-SIX6 locus with primary open angle glaucoma(POAG) in the Chinese population. A total of 866 subjects with POAG(685 high-tension glaucoma(HTG) and 181 normal-tension glaucoma(NTG)) and 266 control individuals were included. Significant genetic association was identified for rs10483727 in HTG(P=0.02; odds ratio(OR)=1.31), NTG(P=7.41×10~(-6); OR=2.71), and POAG(i.e., HTG and NTG combined; P=0.001; OR=1.44). rs33912345 was also significantly associated with HTG(P=0.008; OR=1.36), NTG(P=2.72×10~(-6); OR=2.27), and POAG(P=3.84×10~(-4); OR=1.49). The rare SIX6 mutation, rs146737847, was not found in the subjects enrolled in this study. Stratification by patient age identified that both rs10483727 and rs33912345 were significantly associated with NTG in patients aged above 40 years(P=2.08×10~(-5); OR=2.28), whereas in patients aged between 20–40 years, rs33912345 was significantly associated with NTG(P=0.017; OR=2.06). In HTG, the genetic associations for both rs10483727 and rs33912345 were significant in patients aged between 20–40 years(P=0.006; OR=1.56) but not in those aged above 40 years(P=0.118, OR=1.21 and P=0.042, OR=1.29, respectively). This study replicated the association of POAG with two SNPs at the SIX1-SIX6 locus and demonstrated that SNPs, rs10483727 and rs33912345, are significantly associated with POAG, especially with NTG in patients aged above 40 years.     

Genetic association of single nucleotide polymorphisms in dystrobrevin binding protein 1 gene with schizophrenia in a Malaysian population

Dystrobrevin binding protein 1 (DTNBP1) gene is pivotal in regulating the glutamatergic system. Genetic variants of the DTNBP1 affect cognition and thus may be particularly relevant to schizophrenia. We therefore evaluated the association of six single nucleotide polymorphisms (SNPs) with schizophrenia in a Malaysian population (171 cases; 171 controls). Associations between these six SNPs and schizophrenia were tested in two stages. Association signals with p < 0.05 and minor allele frequency > 0.05 in stage 1 were followed by genotyping the SNPs in a replication phase (stage 2). Genotyping was performed with sequenced specific primer (PCR-SSP) and restriction fragment length polymorphism (PCR-RFLP). In our sample, we found significant associations between rs2619522 (allele p = 0.002, OR = 1.902, 95%CI = 1.266 – 2.859; genotype p = 0.002) and rs2619528 (allele p = 0.008, OR = 1.606, 95%CI = 1.130 – 2.281; genotype p = 6.18 × 10⁻⁵) and schizophrenia. Given that these two SNPs may be associated with the pathophysiology of schizophrenia, further studies on the other DTNBP1 variants are warranted.     

Association analysis of single nucleotide polymorphisms of proinflammatory cytokine and their receptors genes with rheumatoid arthritis in northwest Chinese Han population

ObjectiveTo analyze the relationship of genetic polymorphisms in IL1β, IL6, TNF-α genes and their receptors genes with rheumatoid arthritis (RA) for northwest Han Chinese. This study also explores whether there are gene–gene interactions among these genetic polymorphisms.MethodsA total of 452 patients with RA and 373 matched healthy controls were enrolled to carry out a case-control study for 16 SNPs of IL1B-511 C > T, IL1B-31 T > C, IL1B+3954 C > T, IL1RN T > C, IL6-597 G > A, IL6-572 G > C, IL6-174 G > C, IL6R-183 G > A, IL6R exon2 T > A, IL6R exon1 A > C, TNFA-863 C > A, TNFA-857 C > T, TNFA-308 G > A, TNFA-238 G > A, TNFR1-383 A > C and TNFR2 T676G T > G from seven genes. Genotyping for the SNPs was conducted on the RotorGene 6000 PCR platform using in-house high resolution melting (HRM) approaches. Detection correctness was validated through direct sequencing. Generalized multifactor dimensionality reduction (GMDR) analysis was applied to discover likely gene–gene interaction model among the SNPs.ResultsThe results showed that the genotype distributions of TNFA-308, TNFA-857 and TNFA-863 are significantly different between case and control groups (P = 0.016, P = 0.048 and P = 0.016, respectively). Carriers of TNFA-857 mutant allele conferred risk to RA (OR = 1.525, 95% CI = 1.157–2.009) while those of TNFA-308 and TNFA-863 mutant alleles conferred protection to RA (OR = 0.459, 95% CI = 0.286–0.739; OR = 0.490, 95% CI = 0.329–0.732). GMDR analysis for the SNPs indicated that gene–gene interaction existed among IL1B-31, IL1RN, IL6-572, IL6R-183, IL6R-exon1 and TNFA-857. Thirteen of all genotypes of the six SNPs combination were discovered to have significant distribution difference between RA group and the control.ConclusionsThis study demonstrated that PCR-HRM assay is a highly efficient SNP genotyping method especially for the detection of large-scale samples. The SNPs of TNFA-308 and TNFA-863 are closely associated with RA susceptibility and that gene–gene interactions may occur among the six SNPs of IL1B-31, IL1RN, IL6-572, IL6R-183, IL6R-exon1 and TNFA-857 in RA patients from northwest Chinese Han population, especially these SNPs’ combination genotypes CT/TT/CC/GG/AC/CC, CT/TT/GC/AA/AC/CT and CT/CT/CC/GA/AC/CC to show high risk of RA susceptibility in our study.     

Association of single nucleotide polymorphisms in the microRNA miR‐1596 locus with residual feed intake in chickens

MicroRNAs are an abundant class of small non‐coding RNAs that regulate gene expression. Genetic variations in microRNA sequences may be associated with phenotype differences by influencing the expression of microRNAs and/or their targets. This study identified two single nucleotide polymorphisms (SNPs) in the genomic region of the microRNA miR‐1596 locus of chicken. Of the two SNPs, one was 95 bp upstream of miR‐1596 (g.5678784A>T) and the other was in the middle of the sequence producing the mature microRNA gga‐miR‐1596‐3p (g.5678944A>G). Genotypic distribution of the two SNPs had large differences among 12 chicken breeds (lines), especially between the fast‐growing commercial lines and the slow‐growing Chinese indigenous breeds for the g.5678784A>T SNP. Only the g.5678784A>T SNP was significantly associated with residual feed intake (RFI) in the F₂ population derived from a fast‐growing and a slow‐growing broiler as well as in the pure Huiyang bearded chicken. The birds with the AA genotype of the g.5678784A>T SNP had lower RFI and higher expression of the mature gga‐miR‐1596‐3p microRNA of miR‐1596 than did those with the other genotypes of the same SNP. We also found that the expression of the mature gga‐miR‐1596‐3p microRNA of miR‐1596 was significantly associated with RFI. These findings suggest that miR‐1596 can become a candidate gene related to RFI, and its genetic variation may contribute to changes in RFI by altering expression levels of the mature gga‐miR‐1596‐3p microRNA in chicken.     

Association study of microRNA polymorphisms with hepatocellular carcinoma in Korean population

Background

Recent studies have suggested that common genetic polymorphisms alter the processing of microRNA (miRNA) and may be associated with the development and progression of cancer.

Patients and methods

The association of miRNA polymorphisms with HCC survival was analyzed in 159 HCC patients and 201 controls by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.

Results

The risk of HCC was significantly lower for the miR-499A>G, AG + GG in HCC patients (AOR = 0.603, 95% CI = 0.370–0.984) and hepatitis B virus (HBV)-related HCC patients (AOR = 0.561, 95% CI 0.331–0.950). In addition, the risk of HCC was significantly lower for the miR-149C>T, CT and CT + CC in HCC patients (CT; AOR = 0.542, 95% CI = 0.332–0.886, CT + CC; AOR = 0.536, 95% CI = 0.335–0.858) and HBV-related HCC patients (CT: AOR = 0.510, 95% CI 0.305–0.854, CT + CC: AOR = 0.496, 95% CI 0.302–0.813). The miR-149C>T polymorphism was also associated with survival rate of HCC patients in OKUDA II stage.

Conclusions

miR-149C>T and miR-499A>G were associated with HBV-related HCC. Further studies on larger populations will need to be conducted to confirm these results.     

Association between promoter variants of interleukin-18 and schizophrenia in a Han Chinese population

An increasing amount of evidence suggests that interleukin-18 (IL-18) plays a pivotal role in the pathophysiology of schizophrenia. However, association between single nucleotide polymorphism of IL-18 and the risk of schizophrenia has not been clarified. This study examined whether two promoter polymorphisms -137 G/C (rs187238) and -607 C/A (rs1946518) of IL-18 were associated with schizophrenia and six clinical symptoms (disorder of perception, thought disorder, disturbance of emotion, disorder of behavior and volition, suicide action, and aggressive action) to provide data for screening high-risk Han Chinese individuals. Three hundred seventy-two schizophrenic patients and 353 healthy controls from a Han Chinese population were examined to assess their genotype and allele frequencies of the two promoter polymorphisms of IL-18. The genotype distributions in both patients and controls were within Hardy-Weinberg equilibrium. No significant differences were observed in the genotype or the allele frequencies of the two single-nucleotide polymorphisms between patients and controls. However, genotype frequencies of -607 C/A showed significant differences between patients and controls in the appearance of perception disorder (χ2 = 6.153, p = 0.046). A significant difference was detected in -137 G/C between patients and controls in the appearance of aggressive action (χ2 = 3.909, p = 0.048). In conclusion, IL-18 gene promoter polymorphisms may not contribute to the susceptibility of schizophrenia in a Han Chinese population, but two single-nucleotide polymorphisms, -137 G/C and -607 C/A, may play a role in the development of perception disorder and aggressive action, respectively.     

Association between single-nucleotide polymorphisms in pre-miRNAs and the risk of asthma in a Chinese population

Single-nucleotide polymorphisms (SNPs) in pre-miRNAs may alter microRNA (miRNA) expression levels or processing and contribute to susceptibility to a wide range of diseases. We investigated the correlation between four SNPs (rs11614913, rs3746444, rs2910164, and rs229283) in pre-miRNAs and the risk of asthma in 220 asthma patients and 540 controls using polymerase chain reaction-restriction fragment length polymorphism methodology and DNA-sequencing. There were significant differences in the genotype and allelic distribution of rs2910164G/C and rs2292832C/T polymorphisms among cases and controls. The CC genotype and C allele of rs2910164G/C were significantly associated with a decreased risk of asthma (CC vs. GG, odds ratio [OR]?= 0.51, 95% confidence interval [CI]: 0.31-0.82; C vs. G, OR = 0.74, 95% CI: 0.59-0.93). Similarly, the TT genotype and T allele of rs2292832C/T were significantly associated with a decreased risk of asthma (TT vs. CC, OR = 0.56, 95% CI: 0.33-0.95; T vs. C, OR = 0.71, 95% CI: 0.53-0.95). However, no significant association between the other two polymorphisms (i.e., rs11614913C/T and rs3746444C/T) and the risk of asthma was observed. Our data indicate that rs2910164G/C and rs2292832C/T may play a role in the development of asthma.     

Eye color prediction using single nucleotide polymorphisms in Saudi population

BackgroundDNA prediction of eye color represent one application of the externally visible characteristics (EVC), which attained growing interest in the field of DNA forensic phenotyping. This is mainly due to its ability to narrow the pool of suspects without the need to compare any retrieved DNA material from the crime scene to a reference DNA. Several methods and multiplex genetic panel were proposed with variable prediction accuracy between different populations. However, such panel was not previously tested in the Saudi population, nor any populations of the Middle East and North Africa origin.MethodA panel of eleven single nucleotide polymorphisms (SNPs) was tested for their association with three eye colors (brown, hazel, and intermediate) in 80 volunteer Saudi individuals. SNPs and haplotype association test with eye colors were performed to identify the top significant SNPs with the three eye colors. Also, multinomial logistic regression was used to construct the prediction model using a training set of 60 subjects, and a validation set of 20 subjects. The goodness of fit parameter of the model to correctly predicts each eye color as compared to the other was performed.ResultsEye color was significantly associated with rs12913832, rs7170852, and rs916977 that are located within HERC2. SNP rs12913832 was the top significant SNP (p-value = 1.78E?15) that accounted for the association in this region, as the other SNPs were not significant after adjusting for rs12913832. A prediction model containing five SNPs showed high prediction accuracy with Area Under the receiver operating characteristic Curves (AUC) equals to 0.95 and 0.83 for brown and intermediate eye colors, respectively. However, the model’s performance was very low for predicting the hazel eye color with AUC equals 0.75.DiscussionDespite the small sample size of our study, we reported very significant SNP associations with eye color. Our model to predict eye colors based on DNA material showed high accuracy for brown and intermediate eye colors. The eye color prediction-model underperformed for the hazel eye colors, suggesting that larger sample size, as well as more comprehensive set of SNPs, could improve the model-prediction accuracy.     

延边朝鲜族和汉族脂联素启动子SNPs与原发性高血压的相关性

为了探讨延边朝鲜族和汉族脂联素基因启动子单核苷酸多态性(SNPs)与原发性高血压(EH)的关系, 文章采用PCR产物直接测序方法检测了220例EH患者和268例对照个体的脂联素启动子5个SNPs位点: -11426A>G(rs16861194)、-11391G>A(rs17300539)、-11377C>G(rs62620185)、-11156insCA(rs60806105)、-11043C>T(rs76786086), 氧化酶法测定空腹血糖、甘油三酯、总胆固醇、低密度脂蛋白、高密度脂蛋白, 酶联免疫吸附法(ELISA)测定血浆脂联素和胰岛素。结果显示: (1) -11426A>G、-11377C>G 和-11156insCA 3个位点具有多态性, 且它们的基因型频率分布符合Hardy-Weinberg平衡定律(P>0.05), -11391G>A和-11043C>T位点无多态性; (2) -11426A>G和-11156insCA呈完全连锁不平衡(D’=1; r2=1); (3) -11426G基因频率比较, 朝鲜族(21.10%)高于汉族(12.05%), 汉族EH组高于对照组; -11377C>G的基因型和基因频率在朝鲜族和汉族间及同一民族内EH组和对照组间比较均无统计学意义(P>0.05); (4)单倍型?11426G -11377C的频率, 汉族EH组高于对照组(P<0.05), 朝鲜族EH组和对照组比较无统计学意义(P>0.05); (5)EH组的血浆脂联素水平明显低于对照组(P<0.001)。据此得出结论: (1)首次发现?11426A>G和?11156insCA呈完全连锁不平衡, -11426 A>G的多态性在朝鲜族和汉族中存在民族差异; (2) -11426 G和-11426G -11377C是延边汉族EH的危险因子和危险单倍型, 但不是朝鲜族的; (3)低血浆脂联素是延边朝鲜族和汉族EH的重要危险因素; (4)血浆脂联素水平与-11426A>G基因型无关。     

Association between lncRNA-H19 polymorphisms and hepatoblastoma risk in an ethic Chinese population

H19 polymorphisms are associated with increased susceptibility to several cancers; however, their role in hepatoblastoma remains unclear. In this study, we investigated the association between three H19 polymorphisms (rs2839698 G>A, rs3024270 C>G, rs217727 G>A) and hepatoblastoma susceptibility in 213 hepatoblastoma patients. The rs2839698 and rs3024270 polymorphisms were associated with significantly increased hepatoblastoma risk, with the GG genotype associated with a higher risk of hepatoblastoma than the CC genotype at the rs3024270 locus. The rs217727 polymorphism was associated with significantly decreased hepatoblastoma risk, with the AG genotype associated with a lower risk of hepatoblastoma than the GG genotype. These findings were confirmed by combined analysis, and stratification analysis revealed that age, gender and clinical stage were associated with increased hepatoblastoma susceptibility. The GGG and AGG haplotypes were significantly associated with increased hepatoblastoma risk compared with the GCA reference (rs2839698, rs3024270, rs217727). The rs2839698 and rs3024270 polymorphisms correlated with decreased MRPL23-AS1 expression, whereas the rs217727 polymorphism was associated with increased MRPL23-AS1 expression. Overall, the H19 rs2839698, rs3024270 and rs217727 polymorphisms were associated with hepatoblastoma susceptibility in a Chinese Han population.     

Estimation of population parameters and recombination rates from single nucleotide polymorphisms

Some general likelihood and Bayesian methods for analyzing single nucleotide polymorphisms (SNPs) are presented. First, an efficient method for estimating demographic parameters from SNPs in linkage equilibrium is derived. The method is applied in the estimation of growth rates of a human population based on 37 SNP loci. It is demonstrated how ascertainment biases, due to biased sampling of loci, can be avoided, at least in some cases, by appropriate conditioning when calculating the likelihood function. Second, a Markov chain Monte Carlo (MCMC) method for analyzing linked SNPs is developed. This method can be used for Bayesian and likelihood inference on linked SNPs. The utility of the method is illustrated by estimating recombination rates in a human data set containing 17 SNPs and 60 individuals. Both methods are based on assumptions of low mutation rates.     

Association study of CD36 single nucleotide polymorphisms with essential hypertension in the Northeastern Han Chinese

We found that cluster determinant 36 (CD36) gene is up-regulated in essential hypertension (EH) patients in our former research, but the association between CD36 gene variations and EH has not yet been clearly demonstrated. The relationship between CD36 gene single nucleotide polymorphisms (SNPs) and EH in the northeastern Han Chinese was examined in the present study through direct sequencing and genotype-detection. A total of 589 unrelated northeastern Han Chinese including 276 with EH and 313 controls were studied. SNPs in exon 7, exon 13 and intron 4 were detected using PCR-sequencing. The genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). + 216T/C, + 273A/G, + 132C/T, + 217T/C, + 212T/G and + 233T/C polymorphisms were identified. Distributions of genotypes AA, GA and GG of + 273A/G polymorphism were significantly different between EH group and the control group (χ²: 9.056, p = 0.011) and G allelic frequency was higher in EH (p = 0.006, OR = 1.629, 95% CI [1.224–2.168]). Logistic regression analysis showed that + 273A/G polymorphism was closely associated with blood pressure (BP) after adjusting for ages. When subclassified by sex, the genotype distribution of + 273A/G (p = 0.011) and allelic frequency of G allele (p = 0.006) were significantly different between EH participants and controls in males, but not in females. Subgroup analysis performed by body mass index (BMI) suggested that the genotype distribution of + 273A/G and allelic frequency were significantly different in non-obese group and non-obese men, but the associations were not significant (non-obese group: p = 0.016, OR = 1.664, 95% CI [1.459–2.409]; non-obese men: p = 0.073, OR = 1.898, 95% CI [1.033–3.487]). + 273A/G polymorphism in CD36 gene was associated with EH, and + 273G could be an independent predictor.     

Frequencies of single nucleotide polymorphisms in genes regulating inflammatory responses in a community-based population

Background

Researchers may embark on a genome-wide association study before fully investigating candidate regions which have been reported to produce evidence to suggest that they harbour susceptibility loci. If the genome wide study had not been carried out then results which demonstrated only modest statistical significance from candidate regions would be judged to be of interest and would stimulate further investigation. However if hundreds of thousands of markers are typed then inevitably very large numbers of such results will occur by chance and those from candidate regions may attract no special attention.

Results

An approach is proposed in which differential treatment is afforded to markers from candidate regions and from those that are routinely typed in the context of a genome wide scan. Different prior probabilities are assigned to the two types of marker. A likelihood ratio is derived from the reported p value for each marker, calculated as LR = e^{chiinv(1,p)/2}, and the posterior odds in favour of a true positive association are obtained. These odds can be used to rank the markers with a view to suggesting the regions in which further genotyping is indicated. We suggest that prior probabilities be specified such that a candidate marker significant at p = 0.01 and a routine marker significant at p = 0.00001 will yield similar values for the posterior odds. We show that this can be achieved by setting a value for prior probability of association to 0.1 for candidate markers and to 0.00018 for routine markers.

Conclusion

It is essential that formal procedures be adopted in order to avoid modestly positively results from candidate regions being swamped by the huge number of nominally significant results which will be obtained when very many markers are genotyped. Software to carry out the conversion from p values to posterior odds is available from http://www.mds.qmul.ac.uk/statgen/grpsoft.html.