Characterization of genome-wide association-identified variants for atrial fibrillation in African Americans

Background

Despite a greater burden of risk factors, atrial fibrillation (AF) is less common among African Americans than European-descent populations. Genome-wide association studies (GWAS) for AF in European-descent populations have identified three predominant genomic regions associated with increased risk (1q21, 4q25, and 16q22). The contribution of these loci to AF risk in African American is unknown.

Methodology/Principal Findings

We studied 73 African Americans with AF from the Vanderbilt-Meharry AF registry and 71 African American controls, with no history of AF including after cardiac surgery. Tests of association were performed for 148 SNPs across the three regions associated with AF, and 22 SNPs were significantly associated with AF (P<0.05). The SNPs with the strongest associations in African Americans were both different from the index SNPs identified in European-descent populations and independent from the index European-descent population SNPs (r²<0.40 in HapMap CEU): 1q21 rs4845396 (odds ratio [OR] 0.30, 95% confidence interval [CI] 0.13–0.67, P = 0.003), 4q25 rs4631108 (OR 3.43, 95% CI 1.59–7.42, P = 0.002), and 16q22 rs16971547 (OR 8.1, 95% CI 1.46–45.4, P = 0.016). Estimates of European ancestry were similar among cases (23.6%) and controls (23.8%). Accordingly, the probability of having two copies of the European derived chromosomes at each region did not differ between cases and controls.

Conclusions/Significance

Variable European admixture at known AF loci does not explain decreased AF susceptibility in African Americans. These data support the role of 1q21, 4q25, and 16q22 variants in AF risk for African Americans, although the index SNPs differ from those identified in European-descent populations.     

Genome-wide association study in bipolar patients stratified by co-morbidity

Background

Bipolar disorder is a severe psychiatric disorder with high heritability. Co-morbid conditions are common and might define latent subgroups of patients that are more homogeneous with respect to genetic risk factors.

Methodology

In the Caucasian GAIN bipolar disorder sample of 1000 cases and 1034 controls, we tested the association of single nucleotide polymorphisms with patient subgroups defined by co-morbidity.

Results

Bipolar disorder with psychosis and/or substance abuse in the absence of alcohol dependence was associated with the rare variant rs1039002 in the vicinity of the gene phosphodiesterase 10A (PDE10A) on chromosome 6q27 (p = 1.7×10⁻⁸). PDE10A has been implicated in the pathophysiology of psychosis. Antagonists to the encoded protein are currently in clinical testing. Another rare variant, rs12563333 (p = 5.9×10⁻⁸) on chromosome 1q41 close to the MAP/microtubule affinity-regulating kinase 1 (MARK1) gene, approached the genome-wide level of significance in this subgroup. Homozygotes for the minor allele were present in cases and absent in controls. Bipolar disorder with alcohol dependence and other co-morbidities was associated with SNP rs2727943 (p = 3.3×10⁻⁸) on chromosome 3p26.3 located between the genes contactin-4 precursor (BIG-2) and contactin 6 (CNTN6). All three associations were found under the recessive genetic model. Bipolar disorder with low probability of co-morbid conditions did not show significant associations.

Conclusion

Conceptualizing bipolar disorder as a heterogeneous disorder with regard to co-morbid conditions might facilitate the identification of genetic risk alleles. Rare variants might contribute to the susceptibility to bipolar disorder.     

Allelic variants of melanocortin 3 receptor gene (MC3R) and weight loss in obesity: a randomised trial of hypo-energetic high- versus low-fat diets

Introduction

The melanocortin system plays an important role in energy homeostasis. Mice genetically deficient in the melanocortin-3 receptor gene have a normal body weight with increased body fat, mild hypophagia compared to wild-type mice. In humans, Thr6Lys and Val81Ile variants of the melanocortin-3 receptor gene (MC3R) have been associated with childhood obesity, higher BMI Z-score and elevated body fat percentage compared to non-carriers. The aim of this study is to assess the association in adults between allelic variants of MC3R with weight loss induced by energy-restricted diets.

Subjects and Methods

This research is based on the NUGENOB study, a trial conducted to assess weight loss during a 10-week dietary intervention involving two different hypo-energetic (high-fat and low-fat) diets. A total of 760 obese patients were genotyped for 10 single nucleotide polymorphisms covering the single exon of MC3R gene and its flanking regions, including the missense variants Thr6Lys and Val81Ile. Linear mixed models and haplotype-based analysis were carried out to assess the potential association between genetic polymorphisms and differential weight loss, fat mass loss, waist change and resting energy expenditure changes.

Results

No differences in drop-out rate were found by MC3R genotypes. The rs6014646 polymorphism was significantly associated with weight loss using co-dominant (p = 0.04) and dominant models (p = 0.03). These p-values were not statistically significant after strict control for multiple testing. Haplotype-based multivariate analysis using permutations showed that rs3827103–rs1543873 (p = 0.06), rs6014646–rs6024730 (p = 0.05) and rs3746619–rs3827103 (p = 0.10) displayed near-statistical significant results in relation to weight loss. No other significant associations or gene*diet interactions were detected for weight loss, fat mass loss, waist change and resting energy expenditure changes.

Conclusion

The study provided overall sufficient evidence to support that there is no major effect of genetic variants of MC3R and differential weight loss after a 10-week dietary intervention with hypo-energetic diets in obese Europeans.     

Genetic Variants at 12p11 and 12q24 Are Associated with Breast Cancer Risk in a Chinese Population

Background

A recent genome-wide association study (GWAS) has identified three new breast cancer susceptibility loci at 12p11, 12q24 and 21q21 in populations of European descent. However, because of the genetic heterogeneity, it is largely unknown for the role of these loci in the breast cancer susceptibility in the populations of non-European descent.

Methodology/Principal Findings

Here, we genotyped three variants (rs10771399 at 12p11, rs1292011 at 12q24 and rs2823093 at 21q21) in an independent case–control study with a total of 1792 breast cancer cases and 1867 cancer-free controls in a Chinese population. We found that rs10771399 and rs1292011 were significantly associated with risk of breast cancer with per-allele odds ratios (ORs) of 0.85 (95% confidence interval (CI): 0.76–0.96; P = 0.010) and 0.84 (95% CI: 0.76–0.95; P = 4.50×10⁻³), respectively, which was consistent with those reported in populations of European descent. Similar effects were observed between ER/PR positive and negative breast cancer for both loci. However, we did not found significant association between rs2823093 and breast cancer risk (OR = 0.97, 95%CI = 0.76–1.24; P  = 0.795).

Conclusions/Significance

Our results indicate that genetic variants at 12p11 and 12q24 may also play an important role in breast cancer development in Chinese women.     

Common Genetic Variants Associated with Sudden Cardiac Death: The FinSCDgen Study

Background

Sudden cardiac death (SCD) accounts for up to half of cardiac mortality. The risk of SCD is heritable but the underlying genetic variants are largely unknown. We investigated whether common genetic variants predisposing to arrhythmia or related electrocardiographic phenotypes, including QT-interval prolongation, are associated with increased risk of SCD.

Methodology/Principal Findings

We studied the association between 28 candidate SNPs and SCD in a meta-analysis of four population cohorts (FINRISK 1992, 1997, 2002 and Health 2000, n = 27,629) and two forensic autopsy series (The Helsinki Sudden Death Study and The Tampere Autopsy Study, n = 694). We also studied the association between established cardiovascular risk factors and SCD. Causes of death were reviewed using registry-based health and autopsy data. Cox regression and logistic regression models were adjusted for age, sex, and geographic region. The total number of SCDs was 716. Two novel SNPs were associated with SCD: SCN5A rs41312391 (relative risk [RR] 1.27 per minor T allele, 95% CI 1.11–1.45, P = 3.4×10⁻⁴) and rs2200733 in 4q25 (RR 1.28 per minor T allele, 95% CI 1.11–1.48, P = 7.9×10⁻⁴). We also replicated the associations for 9p21 (rs2383207, RR 1.13 per G allele, 95% CI 1.01–1.26, P = 0.036), as well as for male sex, systolic blood pressure, diabetes, cigarette smoking, low physical activity, coronary heart disease, and digoxin use (P<0.05).

Conclusions/Significance

Two novel genetic variants, one in the cardiac sodium channel gene SCN5A and another at 4q25 previously associated with atrial fibrillation, are associated with SCD.     

Germline Variation in Colorectal Risk Loci Does Not Influence Treatment Effect or Survival in Metastatic Colorectal Cancer

Background

Colorectal cancer (CRC) risk is partly conferred by common, low-penetrance single nucleotide polymorphisms (SNPs). We hypothesized that these SNPs are associated with outcomes in metastatic CRC.

Methods

Six candidate SNPs from 8q24, 10p14, 15q13, 18q21 were investigated for their association with response rate (RR), time to progression (TTP) and overall survival (OS) among 524 patients treated on a phase III clinical trial of first-line chemotherapy for metastatic CRC.

Results

rs10795668 was weakly associated with TTP (p = 0.02), but not RR or OS. No other SNPs carried statistically significant HRs for any of the primary outcomes (RR, TTP or OS).

Conclusion

Common low-penetrance CRC risk SNPs were not associated with outcomes among patients with metastatic CRC.     

Genome-wide linkage scan of a pedigree with familial hypercholesterolemia suggests susceptibility loci on chromosomes 3q25-26 and 21q22

Background

Familial hypercholesterolemia (FH) is a heritable disorder that can increase the risk of premature coronary heart disease. Studies suggest there are substantial genetic heterogeneities for different populations. Here we tried to identify novel susceptibility loci for FH in a Chinese pedigree.

Methodology/Principal Findings

We performed a SNP-based genome-wide linkage scan with the Chinese FH pedigree. Two suggestive linkage loci not previously reported were identified on chromosomes 3q25.1-26.1 (NPL = 9.01, nominal P<0.00001, and simulated occurrence per genome scan = 1.08) and 21q22.3 (NPL = 8.95, nominal P<0.00001, and simulated occurrence per genome scan = 1.26). In the interaction analysis with a trimmed version of the pedigree, we obtained a significantly increased joint LOD score (2.70) compared with that obtained when assuming the two loci uncorrelated, suggesting that more than one locus was involved in this pedigree. Exon screening of two candidate genes ABCG1 and LSS from one of the suggestive region 21q22 didn''t report any causative mutations.

Conclusions/Significances

These results confirm complex etiologies and suggest new genetic casual factors for the FH disorder. Further study of the two candidate regions is advocated.     

Incidence and severity of coronary artery disease in patients with atrial fibrillation undergoing first-time coronary angiography

Background

In standard reference sources, the incidence of coronary artery disease (CAD) in patients with atrial fibrillation (AF) ranged between 24 and 46.5%. Since then, the incidence of cardiovascular risk factors (CRF) has increased and modern treatment strategies (“pill in the pocket”) are only applicable to patients without structural heart disease. The aim of this study was to investigate the incidence and severity of CAD in patients with AF.

Methods

From January 2005 until December 2009, we included 261 consecutive patients admitted to hospital with paroxysmal, persistent or permanent AF in this prospective study. All patients underwent coronary angiography and the Framingham risk score (FRS) was calculated. Patients with previously diagnosed or previously excluded CAD were excluded.

Results

The overall incidence of CAD in patients presenting with AF was 34%; in patients >70 years, the incidence of CAD was 41%. The incidence of patients undergoing a percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) was 21%. Patients with CAD were older (73±8 years vs 68±10 years, p = 0.001), had significantly more frequent hypercholesterolemia (60% vs 30%, p<0.001), were more frequent smokers (26% vs 13%, p = 0.017) and suffered from angina more often (37% vs 2%, p<0.001). There was a significant linear trend among the FRS categories in percentage and the prevalence of CAD and PCI/CABG (p<0.0001).

Conclusions

The overall incidence of CAD in patients presenting with AF was relatively high at 34%; the incidence of PCI/CABG was 21%. Based upon increasing CRF in the western world, we recommend a careful investigation respecting the FRS to either definitely exclude or establish an early diagnosis of CAD – which could contribute to an early and safe therapeutic strategy considering type Ic antiarrhythmics and oral anticoagulation.     

Common genetic variation in the SERPINF1 locus determines overall adiposity, obesity-related insulin resistance, and circulating leptin levels

Objective

Pigment epithelium-derived factor (PEDF) belongs to the serpin family of peptidase inhibitors (serpin F1) and is among the most abundant glycoproteins secreted by adipocytes. In vitro and mouse in vivo data revealed PEDF as a candidate mediator of obesity-induced insulin resistance. Therefore, we assessed whether common genetic variation within the SERPINF1 locus contributes to adipose tissue-related prediabetic phenotypes in humans.

Subjects/Methods

A population of 1,974 White European individuals at increased risk for type 2 diabetes was characterized by an oral glucose tolerance test with glucose and insulin measurements (1,409 leptin measurements) and genotyped for five tagging SNPs covering 100% of common genetic variation (minor allele frequency ≥0.05) in the SERPINF1 locus. In addition, a subgroup of 486 subjects underwent a hyperinsulinaemic-euglycaemic clamp and a subgroup of 340 magnetic resonance imaging (MRI) and spectroscopy (MRS).

Results

After adjustment for gender and age and Bonferroni correction for the number of SNPs tested, SNP rs12603825 revealed significant association with MRI-derived total adipose tissue mass (p = 0.0094) and fasting leptin concentrations (p = 0.0035) as well as nominal associations with bioelectrical impedance-derived percentage of body fat (p = 0.0182) and clamp-derived insulin sensitivity (p = 0.0251). The association with insulin sensitivity was completely abolished by additional adjustment for body fat (p = 0.8). Moreover, the fat mass-increasing allele of SNP rs12603825 was significantly associated with elevated fasting PEDF concentrations (p = 0.0436), and the PEDF levels were robustly and positively associated with all body fat parameters measured and with fasting leptin concentrations (p<0.0001, all).

Conclusion

In humans at increased risk for type 2 diabetes, a functional common genetic variant in the gene locus encoding PEDF contributes to overall body adiposity, obesity-related insulin resistance, and circulating leptin levels.     

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.     

Nasopharyngeal bacterial colonization and gene polymorphisms of mannose-binding lectin and toll-like receptors 2 and 4 in infants

Background

Human nasopharynx is often colonized by potentially pathogenic bacteria. Gene polymorphisms in mannose-binding lectin (MBL), toll-like receptor (TLR) 2 and TLR4 have been reported. The present study aimed to investigate possible association between nasopharyngeal bacterial colonization and gene polymorphisms of MBL, TLR2 and TLR4 in healthy infants.

Methodology/Principal Findings

From August 2008 to June 2010, 489 nasopharyngeal swabs and 412 blood samples were taken from 3-month-old healthy Finnish infants. Semi-quantitative culture was performed and pyrosequencing was used for detection of polymorphisms in MBL structural gene at codons 52, 54, and 57, TLR2 Arg753Gln and TLR4 Asp299Gly. Fifty-nine percent of subjects were culture positive for at least one of the four species: 11% for Streptococcus pneumoniae, 23% for Moraxella catarrhalis, 1% for Haemophilus influenzae and 25% for Staphylococcus aureus. Thirty-two percent of subjects had variant types in MBL, 5% had polymorphism of TLR2, and 18% had polymorphism of TLR4. Colonization rates of S. pneumoniae and S. aureus were significantly higher in infants with variant types of MBL than those with wild type (p = .011 and p = .024). Colonization rates of S. aureus and M. catarrhalis were significantly higher in infants with polymorphisms of TLR2 and of TLR4 than those without (p = .027 and p = .002).

Conclusions

Our study suggests that there is an association between nasopharyngeal bacterial colonization and genetic variation of MBL, TLR2 and TLR4 in young infants. This finding supports a role for these genetic variations in susceptibility of children to respiratory infections.     

Association of caucasian-identified variants with colorectal cancer risk in singapore chinese

Background

Genome-wide association studies (GWAS) in Caucasians have identified fourteen index single nucleotide polymorphisms (iSNPs) that influence colorectal cancer (CRC) risk.

Methods

We investigated the role of eleven iSNPs or surrogate SNPs (sSNPs), in high linkage disequilibrium (LD, r²≥0.8) and within 100 kb vicinity of iSNPs, in 2,000 age- and gender-matched Singapore Chinese (SCH) cases and controls.

Results

Only iSNP rs6983267 at 8q24.21 and sSNPs rs6695584, rs11986063, rs3087967, rs2059254, and rs7226855 at 1q41, 8q23.3, 11q23.1, 16q22.1 and 18q21.1 respectively showed evidence of association with CRC risk, with odds ratios (OR) ranging from 1.13 to 1.40. sSNP rs827401 at 10p14 was associated with rectal cancer risk (OR = 0.74, 95% CI 0.63–0.88) but not disease prognosis (OR = 0.91, 95% CI 0.69–1.20). Interestingly, sSNP rs3087967 at 11q23.1 was associated with CRC risk in men (OR = 1.34, 95% CI 1.14–1.58) but not women (OR = 1.07, 95% CI: 0.88–1.29), suggesting a gender-specific role. Half of the Caucasian-identified variants, including the recently fine-mapped BMP pathway loci, BMP4, GREM1, BMP2 and LAMA 5, did not show any evidence for association with CRC in SCH (OR ∼1; p-value >0.1). Comparing the results of this study with that of the Northern and Hong Kong Chinese, only variants at chromosomes 8q24.21, 10p14, 11q23.1 and 18q21.1 were replicated in at least two out of the three Chinese studies.

Conclusions

The contrasting results between Caucasians and Chinese could be due to different LD patterns and allelic frequencies or genetic heterogeneity. The results suggest that additional common variants contributing to CRC predisposition remained to be identified.     

A genetic association study of single nucleotide polymorphisms in FGFR1OP2/wit3.0 and long-term atrophy of edentulous mandible

Background

After dental extraction, the external surface of alveolar bone undergoes resorption at various rates, and a group of patients develop excessive jawbone atrophy. Oral mucosa overlying the atrophied jawbone is unusually thin; therefore, we have hypothesized that excessive jawbone atrophy may be associated with abnormal oral mucosa contraction. FGFR1OP2/wit3.0, a cytoskeleton molecule initially identified in oral wound fibroblasts, has been shown to induce oral mucosa contraction after dental extraction. This study examined the genetic association between single nucleotide polymorphisms (SNPs) of FGFR1OP2/wit3.0 and excessive atrophy of edentulous mandible.

Methods and Findings

First, the expression of FGFR1OP2/wit3.0 was determined in gingival tissues of 8 subjects before and after dental extraction. In situ hybridization revealed that all subject increased FGFR1OP2/wit3.0 expression in the post-operative oral mucosa tissues; however, significantly high levels of FGFR1OP2/wit3.0 were observed in 3 out of 8 subjects. In a separate study, 20 long-term edentulous subjects (66.4±9.4 years) were recruited. Tag-SNPs in the FGFR1OP2/wit3.0 allele were determined by Taqman-based polymerase chain reaction. The mandibular bone height was determined following the American College of Prosthodontists (ACP) protocol. Subjects with minor allele of rs840869 or rs859024 were found in the highly atrophied group by the ACP classification (Chi square test, p = 0.0384 and p = 0.0565, respectively; Fisher''s Exact, p = 0.0515 and p = 0.2604, respectively). The linear regression analysis indicated a suggestive association between rs859024 and the decreased bone heights (Mann-Whitney, p = 0.06). The average bone height of the subjects with rs840869 or rs859024 minor alleles (10.6±3.2 mm and 9.6±3.2 mm, respectively) was significantly smaller than that of those subjects with the major alleles (14.2±4.5 mm, p<0.05).

Conclusions

The patients with the minor allele of rs840869 or rs859024 were associated with excessive atrophy of edentulous mandible. This study may provide the basis for a genetic marker identifying susceptible individuals to develop jawbone atrophy after dental extraction.     

BMP4 was associated with NSCL/P in an Asian population

Background

The Bone Morphogenetic Protein 4 gene (BMP4) is located in chromosome 14q22-q23 which has shown evidence of linkage for isolated nonsyndromic cleft lip with or without cleft palate (NSCL/P) in a genome wide linkage analysis of human multiplex families. BMP4 has been shown to play crucial roles in lip and palatal development in animal models. Several candidate gene association analyses also supported its potential risk for NSCL/P, however, results across these association studies have been inconsistent. The aim of the current study was to test for possible association between markers in and around the BMP4 gene and NSCL/P in Asian and Maryland trios.

Methodology/Principal Findings

Family Based Association Test was used to test for deviation from Mendelian assortment for 12 SNPs in and around BMP4. Nominal significant evidence of linkage and association was seen for three SNPs (rs10130587, rs2738265 and rs2761887) in 221 Asian trios and for one SNP (rs762642) in 76 Maryland trios. Statistical significance still held for rs10130587 after Bonferroni correction (corrected p = 0.019) among the Asian group. Estimated odds ratio for carrying the apparent high risk allele at this SNP was 1.61 (95%CI = 1.20, 2.18).

Conclusions

Our results provided further evidence of association between BMP4 and NSCL/P.     

The ESR1 (6q25) locus is associated with calcaneal ultrasound parameters and radial volumetric bone mineral density in European men

Purpose

Genome-wide association studies (GWAS) have identified 6q25, which incorporates the oestrogen receptor α gene (ESR1), as a quantitative trait locus for areal bone mineral density (BMD_a) of the hip and lumbar spine. The aim of this study was to determine the influence of this locus on other bone health outcomes; calcaneal ultrasound (QUS) parameters, radial peripheral quantitative computed tomography (pQCT) parameters and markers of bone turnover in a population sample of European men.

Methods

Eight single nucleotide polymorphisms (SNP) in the 6q25 locus were genotyped in men aged 40–79 years from 7 European countries, participating in the European Male Ageing Study (EMAS). The associations between SNPs and measured bone parameters were tested under an additive genetic model adjusting for centre using linear regression.

Results

2468 men, mean (SD) aged 59.9 (11.1) years had QUS measurements performed and bone turnover marker levels measured. A subset of 628 men had DXA and pQCT measurements. Multiple independent SNPs showed significant associations with BMD using all three measurement techniques. Most notably, rs1999805 was associated with a 0.10 SD (95%CI 0.05, 0.16; p = 0.0001) lower estimated BMD at the calcaneus, a 0.14 SD (95%CI 0.05, 0.24; p = 0.004) lower total hip BMD_a, a 0.12 SD (95%CI 0.02, 0.23; p = 0.026) lower lumbar spine BMD_a and a 0.18 SD (95%CI 0.06, 0.29; p = 0.003) lower trabecular BMD at the distal radius for each copy of the minor allele. There was no association with serum levels of bone turnover markers and a single SNP which was associated with cortical density was also associated with cortical BMC and thickness.

Conclusions

Our data replicate previous associations found between SNPs in the 6q25 locus and BMD_a at the hip and extend these data to include associations with calcaneal ultrasound parameters and radial volumetric BMD.     

Polymorphisms in FTO and MAF Genes and Birth Weight,BMI, Ponderal Index,Weight Gain in a Large Cohort of Infants with a Birth Weight below 1500 Grams

Background

The FTO gene, located on chromosome 16q12.2, and the MAF gene, located on chromosome 16q22-23, were identified as genes harboring common variants with an impact on obesity predisposition. We studied the association of common variants with birth weight, gain of body weight, body mass index (BMI), Ponderal index and relevant neonatal outcomes in a large German cohort of infants with a birth weight below 1500 grams.

Methods

The single nucleotide polymorphisms rs9939609 (FTO gene) and rs1424233 (MAF gene) were genotyped using allelic discrimination assays in a prospective multicenter cohort study conducted in 15 neonatal intensive care units in Germany from September 2003 until January 2008. DNA samples were extracted from buccal swabs according to standard protocols.

Results

1946 infants were successfully genotyped at FTO and 2149 infants at MAF. Allele frequencies were not significantly different from other European cohorts. The polymorphisms were in Hardy-Weinberg equilibrium. The polymorphisms did not show associations with birth weight, BMI and Ponderal Index at discharge, and weight gain, neither testing for a dominant, additive nor for a recessive model.

Discussion

Since an association of the polymorphisms with weight gain has been demonstrated in multiple populations, the lack of association in a population of preterm infants with regular tube feeding after birth and highly controlled feeding volumes provides evidence for the hypothesis that these polymorphisms affect food intake behavior and hunger rather than metabolism and energy consumption.     

Role of a Genetic Variant on the 15q25.1 Lung Cancer Susceptibility Locus in Smoking-Associated Nasopharyngeal Carcinoma

Background

The 15q25.1 lung cancer susceptibility locus, containing CHRNA5, could modify lung cancer susceptibility and multiple smoking related phenotypes. However, no studies have investigated the association between CHRNA5 rs3841324, which has been proven to have the highest association with CHRNA5 mRNA expression, and the risk of other smoking-associated cancers, except lung cancer. In the current study we examined the association between rs3841324 and susceptibility to smoking-associated nasopharyngeal carcinoma (NPC).

Methods

In this case-control study we genotyped the CHRNA5 rs3841324 polymorphism with 400 NPC cases and 491 healthy controls who were Han Chinese and frequency-matched by age (±5 years), gender, and alcohol consumption. Univariate and multivariate logistic regression analyses were used to calculate the odds ratio (OR) and 95% confidence intervals (95% CI).

Results

We found that individuals with CHRNA5 rs3841324 combined variant genotypes (ins/del+del/del) had a >1.5-fold elevated risk for NPC than those with the ins/ins genotype (adjusted OR = 1.52; 95% CI, 1.16–2.00), especially among ever smokers (adjusted OR = 2.07; 95% CI, 1.23–3.48). The combined variant genotypes acted jointly with cigarette smoking to contribute to a 4.35-fold increased NPC risk (adjusted OR = 4.35; 95% CI, 2.57–7.38). There was a dose-response relationship between deletion alleles and NPC susceptibility (trend test, P = 0.011).

Conclusions

Our results suggest that genetic variants on the 15q25.1 lung cancer susceptibility locus may influence susceptibility to NPC, particularly for smoking-associated NPC. Such work may be helpful to facilitate an understanding of the etiology of smoking-associated cancers and improve prevention efforts.     

Association between Polymorphisms of the IKZF3 Gene and Systemic Lupus Erythematosus in a Chinese Han Population

Objective

It has been reported that IKAROS family of zinc finger 3 (IKZF3)-deficient mice spontaneously develop human systemic lupus erythematosus (SLE)-like phenotypes and produce anti-dsDNA Ab leading to immune complex-mediated glomerulonephritis. Polymorphism of the IKZF3 gene corresponds with the susceptibility to several immune-related diseases. Our intention was to establish an association between polymorphisms in the IKZF3 gene and SLE in the Chinese Han population.

Methods

The study involved obtaining blood samples for DNA extraction and genotyping the 4 selected single-nucleotide polymorphisms (SNPs) in IKZF3, including rs12150079, rs9909593, rs907091, and rs2872507, by performing PCR restriction fragment length polymorphism analysis (PCR-RFLP). A group of 366 SLE patients were compared to 455 healthy controls.

Results

A significant decrease in frequencies of the rs907091 CC genotype and C allele appeared in the SLE patients unlike that observed in the controls (p = 0.001 and 0.015, respectively). The frequencies of the rs12150079 genotype and allele were different between the SLE patients and the control individuals, although the significance was only marginal (p = 0.046 and 0.049, respectively). In addition, a significantly low frequency of the GGCG haplotype was observed in the SLE patients, suggesting that it may provide protection against SLE (p = 0.011).

Conclusion

To the best of our knowledge, this is the first study to demonstrate an important association between polymorphisms in IKZF3 and SLE in the Chinese Han population. A strong association between rs907091 in the IKZF3 gene and SLE was identified.     

Single nucleotide polymorphisms of Toll-like receptor 4 decrease the risk of development of hepatocellular carcinoma

Background

Toll-like receptor 4 (TLR4) is a key innate immunity receptor that initiates an inflammatory response. Growing evidence suggests that mutation of TLR4 gene may play a role in the development of cancers. This study aimed to investigate the temporal relationship of single nucleotide polymorphisms of TLR4 and the risk of hepatocellular carcinoma, a single center-based case-control study was conducted.

Methods

A systematic genetic analysis of sequence variants of TLR4 by evaluating ten single-nucleotide polymorphisms was performed from 216 hepatocellular carcinoma cases and 228 controls.

Results

Six single nucleotide polymorphisms of the TLR4 in the 5′-untranslated region and intron were associated with risk of hepatocellular carcinoma. Individuals carrying the heterozygous genotypes for the rs10759930, rs2737190, rs10116253, rs1927914, rs12377632 and rs1927911 had significantly decreased risk of hepatocellular carcinoma (adjusted odds ratio [OR], from 0.527 to 0.578, P<0.01) comparing with those carrying wild-type homozygous genotypes. In haplotype analysis, one haplotype (GCCCTTAG) of TLR4 was associated significantly with decrease of the occurrence of hepatocellular carcinoma (OR, 0.556, 95% confidence interval [CI], 0.407–0.758, P = 0.000).

Conclusions

Collectively, these results suggested that the risk of hepatocellular carcinoma was associated with TLR4 sequence variation. TLR4 single nucleotide polymorphisms may play an important protective role in the development of hepatocellular carcinoma.