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Fulltext Genetic researches among malaysian familial hypercholesterolaemic population

Al-Khateeb, A, Al-Talib, H

JUMMEC, 2016;19(2):1-11.
MyJurnal

Background:
Familial hypercholesterolaemia (FH) is one of the most frequent inherited metabolic disorders that can lead
to a risk of premature cardiovascular disease. Publications on FH are mainly from western patients as there is
little research on Asians, including Malaysians. The aim of this review is to provide an up-to- date information
on Malaysian studies on FH genotyping and its relation to the phenotype of the affected patients.
Method:
A search was conducted for data from online databases on FH in Malaysia.
Results:
The mutation spectrum for FH among Malaysian patients was extremely broad. The gene variants were located
mainly in the low-density lipoprotein receptor (LDLR) and apolipoprotein B-100 (APOB-100) genes rather than
in the proprotein convertase subtilisin kexin type 9 (PCSK9) gene. The exon 9 and 14 were the hotspots in the
LDLR gene. The most frequent mutation was p.Cys255Ser, at 12.5%, followed by p.Arg471Gly, at 11%, and the
most common single nucleotide polymorphism (SNP) was c.1060+7 T>C at 11.7%. The LDLR gene variants were
more common compared to the APOB-100 gene variants, while variants in the PCSK9 gene were very few.
Phenotype-genotype associations were identified. Subjects with LDLR and APOB-100 genes mutations had a
higher frequency of cardiovascular disease, a family history of hyperlipidaemia and tendon xanthoma and a
higher low-density lipoprotein cholesterol (LDL-C) level than non-carriers.
Conclusion:
Research on Malaysian familial hypercholesterolaemic patients by individual groups is encouraging. However,
more extensive molecular studies on FH on a national scale, with a screening of the disease-causing mutations
together with a comprehensive genotype-phenotype association study, can lead to a better outcome for
patients with the disease.

Matched MeSH terms: Genetic Association Studies
Genetic polymorphisms of EGF 5'-UTR and NAT2 857G/A associated with glioma in a case control study of Malaysian patients

Muthusamy KA, Lian LH, Vairavan N, Chua KH, Waran V

Genet. Mol. Res., 2012;11(3):2939-45.
PMID: 22782629

Studies of genetic mutations that have been used in predicting glioma prognosis have revealed a complex relationship between clinical and genetic factors. Epidermal growth factor (EGF) and the NAT2 gene play a central role in carcinogenesis. An adenine (A) to guanine (G) single nucleotide polymorphism at position 61 in the 5'-untranslated region (5'-UTR) of the EGF gene has been found to be associated with levels of EGF production, and the mutations in the NAT2 gene have been postulated as a risk factor for cancer. We investigated EGF and the NAT2 gene in 13 glioma tissue samples and 12 normal controls. In the EGF 5'-UTR 61G polymorphism, the heterozygote GA was the most common genotype in the glioma patients. In the NAT2 polymorphism at nucleotide position 857G/A, the G allele and the GG genotype were the most prevalent forms in both the glioma and normal samples. We did not find any homozygous AA genotypes in the glioma patients. Based on this preliminary evidence, the EGF 5'-UTR at position 61 and the NAT2 SNP at position 857 polymorphisms are associated with increased risk for glioma.

Matched MeSH terms: Genetic Association Studies
Genetic association of LMAN2L gene in schizophrenia and bipolar disorder and its interaction with ANK3 gene polymorphism

Lim CH, Zain SM, Reynolds GP, Zain MA, Roffeei SN, Zainal NZ, et al.

Prog Neuropsychopharmacol Biol Psychiatry, 2014 Oct 3;54:157-62.
PMID: 24914473 DOI: 10.1016/j.pnpbp.2014.05.017

Recent studies have shown that bipolar disorder (BPD) and schizophrenia (SZ) share some common genetic risk factors. This study aimed to examine the association between candidate single nucleotide polymorphisms (SNPs) identified from genome-wide association studies (GWAS) and risk of BPD and SZ. A total of 715 patients (244 BPD and 471 SZ) and 593 controls were genotyped using the Sequenom MassARRAY platform. We showed a positive association between LMAN2L (rs6746896) and risk of both BPD and SZ in a pooled population (P-value=0.001 and 0.009, respectively). Following stratification by ethnicity, variants of the ANK3 gene (rs1938516 and rs10994336) were found to be associated with BPD in Malays (P-value=0.001 and 0.006, respectively). Furthermore, an association exists between another variant of LMAN2L (rs2271893) and SZ in the Malay and Indian ethnic groups (P-value=0.003 and 0.002, respectively). Gene-gene interaction analysis revealed a significant interaction between the ANK3 and LMAN2L genes (empirical P=0.0107). Significant differences were shown between patients and controls for two haplotype frequencies of LMAN2L: GA (P=0.015 and P=0.010, for BPD and SZ, respectively) and GG (P=0.013 for BPD). Our study showed a significant association between LMAN2L and risk of both BPD and SZ.

Matched MeSH terms: Genetic Association Studies
Genetic abnormalities in a large cohort of Coffin-Siris syndrome patients

Sekiguchi F, Tsurusaki Y, Okamoto N, Teik KW, Mizuno S, Suzumura H, et al.

J Hum Genet, 2019 Dec;64(12):1173-1186.
PMID: 31530938 DOI: 10.1038/s10038-019-0667-4

Coffin-Siris syndrome (CSS, MIM#135900) is a congenital disorder characterized by coarse facial features, intellectual disability, and hypoplasia of the fifth digit and nails. Pathogenic variants for CSS have been found in genes encoding proteins in the BAF (BRG1-associated factor) chromatin-remodeling complex. To date, more than 150 CSS patients with pathogenic variants in nine BAF-related genes have been reported. We previously reported 71 patients of whom 39 had pathogenic variants. Since then, we have recruited an additional 182 CSS-suspected patients. We performed comprehensive genetic analysis on these 182 patients and on the previously unresolved 32 patients, targeting pathogenic single nucleotide variants, short insertions/deletions and copy number variations (CNVs). We confirmed 78 pathogenic variations in 78 patients. Pathogenic variations in ARID1B, SMARCB1, SMARCA4, ARID1A, SOX11, SMARCE1, and PHF6 were identified in 48, 8, 7, 6, 4, 1, and 1 patients, respectively. In addition, we found three CNVs including SMARCA2. Of particular note, we found a partial deletion of SMARCB1 in one CSS patient and we thoroughly investigated the resulting abnormal transcripts.

Matched MeSH terms: Genetic Association Studies/methods
Fulltext Genetic Analysis of the Atrial Natriuretic Peptide Gene Polymorphisms among Essential Hypertensive Patients in Malaysia

Ghodsian N, Ismail P, Ahmadloo S, Eskandarian N, Etemad A

Biomed Res Int, 2016;2016:6712529.
PMID: 27413750 DOI: 10.1155/2016/6712529

Background. Atrial natriuretic peptide (ANP) considerably influences blood pressure regulation through water and sodium homoeostasis. Several of the studies have utilized anonymous genetic polymorphic markers and made inconsequent claims about the ANP relevant disorders. Thus, we screened Insertion/Deletion (ID) and G191A polymorphisms of ANP to discover sequence variations with potential functional significance and to specify the linkage disequilibrium pattern between polymorphisms. The relationships of detected polymorphisms with EH with or without Type 2 Diabetes Mellitus (T2DM) status were tested subsequently. Method. ANP gene polymorphisms (I/D and A191G) were specified utilizing mutagenically separated Polymerase Chain Reaction (PCR) in 320 subjects including 163 EH case subjects and 157 controls. Result. This case-control study discovered a significant association between I/D polymorphisms of ANP gene in EH patient without T2DM. However, the study determined no association between G191A polymorphisms of ANP in EH with or without T2DM. In addition, sociodemographic factors in the case and healthy subjects exhibited strong differences (P < 0.05). Conclusion. As a risk factor, ANP gene polymorphisms may affect hypertension. Despite the small sample size in this study, it is the first research assessing the ANP gene polymorphisms in both EH and T2DM patients among Malaysian population.

Matched MeSH terms: Genetic Association Studies
Fulltext GWAS signals revisited using human knockouts

Maddirevula S, AlZahrani F, Anazi S, Almureikhi M, Ben-Omran T, Abdel-Salam GMH, et al.

Genet Med, 2018 01;20(1):64-68.
PMID: 28640246 DOI: 10.1038/gim.2017.78

PurposeGenome-wide association studies (GWAS) have been instrumental to our understanding of the genetic risk determinants of complex traits. A common challenge in GWAS is the interpretation of signals, which are usually attributed to the genes closest to the polymorphic markers that display the strongest statistical association. Naturally occurring complete loss of function (knockout) of these genes in humans can inform GWAS interpretation by unmasking their deficiency state in a clinical context.MethodsWe exploited the unique population structure of Saudi Arabia to identify novel knockout events in genes previously highlighted in GWAS using combined autozygome/exome analysis.ResultsWe report five families with homozygous truncating mutations in genes that had only been linked to human disease through GWAS. The phenotypes observed in the natural knockouts for these genes (TRAF3IP2, FRMD3, RSRC1, BTBD9, and PXDNL) range from consistent with, to unrelated to, the previously reported GWAS phenotype.ConclusionWe expand the role of human knockouts in the medical annotation of the human genome, and show their potential value in informing the interpretation of GWAS of complex traits.

Matched MeSH terms: Genetic Association Studies
Fulltext GABRG2 rs211037 polymorphism and epilepsy: a systematic review and meta-analysis

Haerian BS, Baum L

Seizure, 2013 Jan;22(1):53-8.
PMID: 23140995 DOI: 10.1016/j.seizure.2012.10.007

PURPOSE: The gamma-aminobutyric acid A receptor, gamma 2 (GABRG2) gene encodes the GABRγ2 protein, which has been implicated in susceptibility to epilepsy. Several studies have examined a possible link between the exonic GABRG2 rs211037 locus and susceptibility to febrile seizure (FS) and idiopathic generalized epilepsy (IGE), however results have been inconclusive. We therefore performed a systematic review and meta-analysis to examine whether this polymorphism is associated with FS or IGE.
METHODS: Eight studies comprising 1871 epilepsy patients and 1387 controls, which evaluated association of the GABRG2 rs211037 polymorphism with susceptibility to epilepsy, were included in this meta-analysis. Meta-analysis was carried out separately for FS and IGE.
RESULTS: Meta-analysis showed a significant association between this polymorphism and susceptibility to FS in a codominant (TT vs. CC, OR 0.47, 95% CI 0.30-0.73, p=0.0008 and TT vs. CT, OR 0.59, 95% CI 0.42-0.83, p=0.003) and dominant (OR 0.54, 95% CI 0.39-0.75, p=0.0002) genetic models, influenced by two studies with small sample size. Neither allele nor genotype association was observed with IGE.
CONCLUSION: This study showed significant association of GABRG2 rs211037 with susceptibility to FS, caused by two studies with small sample sizes, however the possibility of false positive results due to the effect of significant studies for FS cannot be excluded. Future studies with larger sample sizes of these patients are suggested to verify the results.

Matched MeSH terms: Genetic Association Studies/statistics & numerical data
Fulltext G2677T polymorphism can predict treatment outcome of Malaysians with complex partial seizures being treated with Carbamazepine

Subenthiran S, Abdullah NR, Muniandy PK, Joseph JP, Cheong KC, Ismail Z, et al.

Genet. Mol. Res., 2013;12(4):5937-44.
PMID: 24338387 DOI: 10.4238/2013.November.26.3

Carbamazepine (CBZ) is used as the first line of treatment of complex partial seizures (CPS) in Malaysia. While this drug is known to be effective for the treatment of CPS, more than 30% of patients remain drug resistant to CBZ mono-therapy. We examined a possible relationship between patients' response to CBZ mono-therapy and the G2677T SNP of the ABCB1 gene. Three hundred and fourteen patients with CPS were recruited from the Neurology Department of the Kuala Lumpur Hospital, of whom 152 were responders and the other 162 were non-responders to CBZ mono-therapy. DNA was extracted from blood samples and real-time PCR was performed to detect the G2677T SNP of the ABCB1 gene. Results were described as genotype frequencies and compared by logistic regression analysis. Among the 152 responders, 74% had the GG genotype. However, among the 162 non-responders, 26.5% had the GT genotype and 39% had the TT genotype. There was a significant difference in genotype frequency (TT vs GG; odds ratio 4.70; 95% confidence interval, 2.70-8.20) between responders and non-responders. The presence of the T allele of the G2677T SNP appears to be a useful screening marker to determine if a patient is going to be resistant to CBZ as a single drug therapy in the treatment of CPS.

Matched MeSH terms: Genetic Association Studies
Fulltext Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element

Baxter JS, Johnson N, Tomczyk K, Gillespie A, Maguire S, Brough R, et al.

Am J Hum Genet, 2021 Jul 01;108(7):1190-1203.
PMID: 34146516 DOI: 10.1016/j.ajhg.2021.05.013

A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10-31).

Matched MeSH terms: Genetic Association Studies
Fulltext Four novel p.N385K, p.V36A, c.1033-1034insT and c.1417-1418delCT mutations in the sphingomyelin Phosphodiesterase 1 (SMPD1) gene in patients with types A and B Niemann-Pick disease (NPD)

Manshadi MD, Kamalidehghan B, Keshavarzi F, Aryani O, Dadgar S, Arastehkani A, et al.

Int J Mol Sci, 2015 Mar 24;16(4):6668-76.
PMID: 25811928 DOI: 10.3390/ijms16046668

BACKGROUND: Types A and B Niemann-Pick disease (NPD) are autosomal-recessive lysosomal storage disorders caused by the deficient activity of acid sphingomyelinase due to mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene.
METHODS: In order to determine the prevalence and distribution of SMPD1 gene mutations, the genomic DNA of 15 unrelated Iranian patients with types A and B NPD was examined using PCR, DNA sequencing and bioinformatics analysis.
RESULTS: Of 8 patients with the p.G508R mutation, 5 patients were homozygous, while the other 3 were heterozygous. One patient was heterozygous for both the p.N385K and p.G508R mutations. Another patient was heterozygous for both the p.A487V and p.G508R mutations. Two patients (one homozygous and one heterozygous) showed the p.V36A mutation. One patient was homozygous for the c.1033-1034insT mutation. One patient was homozygous for the c.573delT mutation, and 1 patient was homozygous for the c.1417-1418delCT mutation. Additionally, bioinformatics analysis indicated that two new p.V36A and p.N385K mutations decreased the acid sphingomyelinase (ASM) protein stability, which might be evidence to suggest the pathogenicity of these mutations.
CONCLUSION: with detection of these new mutations, the genotypic spectrum of types A and B NPD is extended, facilitating the definition of disease-related mutations. However, more research is essential to confirm the pathogenic effect of these mutations.

Matched MeSH terms: Genetic Association Studies/methods
Fulltext Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

Orr N, Dudbridge F, Dryden N, Maguire S, Novo D, Perrakis E, et al.

Hum Mol Genet, 2015 May 15;24(10):2966-84.
PMID: 25652398 DOI: 10.1093/hmg/ddv035

We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 × 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 × 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 × 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 × 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.

Matched MeSH terms: Genetic Association Studies
Fulltext Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus

Horne HN, Chung CC, Zhang H, Yu K, Prokunina-Olsson L, Michailidou K, et al.

PLoS One, 2016;11(8):e0160316.
PMID: 27556229 DOI: 10.1371/journal.pone.0160316

The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.

Matched MeSH terms: Genetic Association Studies
Fulltext Fine mapping of a grain weight quantitative trait locus, qGW6, using near isogenic lines derived from Oryza rufipogon IRGC105491 and Oryza sativa cultivar MR219

Ngu MS, Thomson MJ, Bhuiyan MA, Ho C, Wickneswari R

Genet. Mol. Res., 2014;13(4):9477-88.
PMID: 25501158 DOI: 10.4238/2014.November.11.13

Grain weight is a major component of rice grain yield and is controlled by quantitative trait loci. Previously, a rice grain weight quantitative trait locus (qGW6) was detected near marker RM587 on chromosome 6 in a backcross population (BC2F2) derived from a cross between Oryza rufipogon IRGC105491 and O. sativa cv. MR219. Using a BC2F5 population, qGW6 was validated and mapped to a region of 4.8 cM (1.2 Mb) in the interval between RM508 and RM588. Fine mapping using a series of BC4F3 near isogenic lines further narrowed the interval containing qGW6 to 88 kb between markers RM19268 and RM19271.1. According to the Duncan multiple range test, 8 BC4F4 near isogenic lines had significantly higher 100-grain weight (4.8 to 7.5% over MR219) than their recurrent parent, MR219 (P < 0.05). According to the rice genome automated annotation database, there are 20 predicted genes in the 88-kb target region, and 9 of them have known functions. Among the genes with known functions in the target region, in silico gene expression analysis showed that 9 were differentially expressed during the seed development stage(s) from gene expression series GSE6893; however, only 3 of them have known functions. These candidates provide targets for further characterization of qGW6, which will assist in understanding the genetic control of grain weight in rice.

Matched MeSH terms: Genetic Association Studies
Evaluation of novel Parkinson's disease candidate genes in the Chinese population

Chew EGY, Liany H, Tan LCS, Au WL, Prakash KM, Annuar AA, et al.

Neurobiol Aging, 2019 02;74:235.e1-235.e4.
PMID: 30337193 DOI: 10.1016/j.neurobiolaging.2018.09.013

Recent whole-exome sequencing studies in European patients with Parkinson's disease (PD) have identified potential risk variants across 33 novel PD candidate genes. We aim to determine if these reported candidate genes are similarly implicated in Asians by assessing common, rare, and novel nonsynonymous coding variants by sequencing all 33 genes in 198 Chinese samples and genotyping coding variants in an independent set of 9756 Chinese samples. We carried out further targeted sequencing of CD36 in an additional 576 Chinese and Korean samples. We found that only 8 of 43 reported risk variants were polymorphic in our Chinese samples. We identified several heterozygotes for rare loss-of-function mutations, including the reported CD36 p.Gln74Ter variant, in both cases and controls. We also observed 2 potential compound heterozygotes among PD cases for rare loss-of-function mutations in CD36 and SSPO. The other reported variants were common in East Asians and not associated with PD, completely absent, or only found in controls. Therefore, the 33 reported candidate genes and associated variants are unlikely to confer significant PD risk in the East Asian population.

Matched MeSH terms: Genetic Association Studies*
Evaluation of association studies and meta-analyses of MTHFR gene polymorphisms in colorectal cancer

Haerian BS, Haerian MS

Pharmacogenomics, 2015;16(4):413-25.
PMID: 25823789 DOI: 10.2217/pgs.14.177

There is a discrepancy between the results of 89 original studies and 15 meta-analyses investigating the association of MTHFR rs1801133 and rs1801131 polymorphisms with colorectal cancer (CRC) risk. We examined this hypothesis through meta-analyses of both loci and their diplotypes as well as evaluation of previous meta-analyses. The present meta-analysis showed that rs1801133 and rs1801131 might be CRC susceptibility variants in Americans and Australians and rs1801133 in Brazilians and Japanese. A strong linkage disequilibrium was observed between both loci and their diplotypes were associated with CRC risk. Evaluation of 15 meta-analyses showed a high discrepancy among their findings, mainly caused by population stratification of original studies and data analysis strategies in meta-analysis. Population stratification was more dominant in the studies from Australia, America and Brazil leading to false positive or negative results. In conclusion, these loci alone might modify the development of CRC in some ethnicities.

Matched MeSH terms: Genetic Association Studies*
Fulltext Evaluating genetic variants associated with breast cancer risk in high and moderate-penetrance genes in Asians

Han MR, Zheng W, Cai Q, Gao YT, Zheng Y, Bolla MK, et al.

Carcinogenesis, 2017 May 01;38(5):511-518.
PMID: 28419251 DOI: 10.1093/carcin/bgx010

Over the past 20 years, high-penetrance pathogenic mutations in genes BRCA1, BRCA2, TP53, PTEN, STK11 and CDH1 and moderate-penetrance mutations in genes CHEK2, ATM, BRIP1, PALB2, RAD51C, RAD50 and NBN have been identified for breast cancer. In this study, we investigated whether there are additional variants in these 13 genes associated with breast cancer among women of Asian ancestry. We analyzed up to 654 single nucleotide polymorphisms (SNPs) from 6269 cases and 6624 controls of Asian descent included in the Breast Cancer Association Consortium (BCAC), and up to 236 SNPs from 5794 cases and 5529 controls included in the Shanghai Breast Cancer Genetics Study (SBCGS). We found three missense variants with minor allele frequency (MAF) <0.05: rs80358978 (Gly2508Ser), rs80359065 (Lys2729Asn) and rs11571653 (Met784Val) in the BRCA2 gene, showing statistically significant associations with breast cancer risk, with P-values of 1.2 × 10-4, 1.0 × 10-3 and 5.0 × 10-3, respectively. In addition, we found four low-frequency variants (rs8176085, rs799923, rs8176173 and rs8176258) in the BRCA1 gene, one common variant in the CHEK2 gene (rs9620817), and one common variant in the PALB2 gene (rs13330119) associated with breast cancer risk at P < 0.01. Our study identified several new risk variants in BRCA1, BRCA2, CHEK2, and PALB2 genes in relation to breast cancer risk in Asian women. These results provide further insights that, in addition to the high/moderate penetrance mutations, other low-penetrance variants in these genes may also contribute to breast cancer risk.

Matched MeSH terms: Genetic Association Studies
Down syndrome in diverse populations

Kruszka P, Porras AR, Sobering AK, Ikolo FA, La Qua S, Shotelersuk V, et al.

Am J Med Genet A, 2017 Jan;173(1):42-53.
PMID: 27991738 DOI: 10.1002/ajmg.a.38043

Down syndrome is the most common cause of cognitive impairment and presents clinically with universally recognizable signs and symptoms. In this study, we focus on exam findings and digital facial analysis technology in individuals with Down syndrome in diverse populations. Photos and clinical information were collected on 65 individuals from 13 countries, 56.9% were male and the average age was 6.6 years (range 1 month to 26 years; SD = 6.6 years). Subjective findings showed that clinical features were different across ethnicities (Africans, Asians, and Latin Americans), including brachycephaly, ear anomalies, clinodactyly, sandal gap, and abundant neck skin, which were all significantly less frequent in Africans (P

Matched MeSH terms: Genetic Association Studies*
Fulltext Dietary Acid Load, IGF-1 Single Nucleotide Polymorphism and Bone Resorption among Postmenopausal Chinese Women

Lim SY, Zalilah MS, Chin YS, Ramachandran V, Chan YM

Nutrients, 2018 Jul 17;10(7).
PMID: 30018240 DOI: 10.3390/nu10070915

The interaction of dietary and genetic factors may affect the development of bone deterioration. This study investigated whether the effects of dietary acid load (DAL) on bone loss in postmenopausal Chinese women were moderated by the insulin-like growth factor-1 (IGF-1) single nucleotide polymorphism, a known gene that plays a role in the regulation of bone formation and bone remodeling. A total of 217 healthy participants were recruited from the National Council of Senior Citizens Organizations Malaysia. Serum collagen type 1 cross-linked C-telopeptide was used as a surrogate bone marker to assess bone resorption and Agena® MassARRAY genotyping analysis was used to identify the signaling of IGF-1 rs35767. The dietary acid load was measured by potential renal acid load score while physical activity was ascertained using the Global Physical Activity Questionnaire. Hierarchical regression was applied to test the main and interaction effects of DAL and IGF-1 genotypes in bone resorption. The result supported the diet-dependent acid-base balance theory that higher DAL was positively associated with bone resorption (β = 0.152, p = 0.031, F(6,207) = 2.11, sig-F = 0.036, R² = 0.079). However, the results indicated that there was no significant correlation between IGF-1 and bone resorption, or any significant interaction between DAL and IGF-1. In conclusion, there was no moderating effect of IGF-1 on the relationship between DAL and bone resorption.

Matched MeSH terms: Genetic Association Studies
Fulltext Copy number variation in exportin-4 (XPO4) gene and its association with histological severity of non-alcoholic fatty liver disease

Zain SM, Mohamed Z, Pirmohamed M, Tan HL, Alshawsh MA, Mahadeva S, et al.

Sci Rep, 2015 Aug 21;5:13306.
PMID: 26293807 DOI: 10.1038/srep13306

A recent genome-wide copy number (CNV) scan identified a 13q12.11 duplication in the exportin-4 (XPO4) gene to be associated with non-alcoholic steatohepatitis (NASH). We sought to confirm the finding in a larger cohort and to assess the serum XPO4 pattern in a broad spectrum of non-alcoholic fatty liver disease (NAFLD) cases. We analysed 249 NAFLD patients and 232 matched controls using TaqMan assay and serum XPO4 was measured. Copy number distribution was as follows: copy number neutral (NAFLD: 53.8%, controls: 68.6%), copy number losses (NAFLD: 13.3%, controls: 12.9%), copy number gains (NAFLD: 32.9%, controls: 18.5%). CNV gain was significantly associated with a greater risk of NAFLD (adjusted OR 2.22, 95% CI 1.42-3.46, P = 0.0004) and NASH (adjusted OR 2.33, 95% CI 1.47-3.68, P = 0.0003). Interestingly, subjects carrying extra copy number showed significantly higher serum ALT and triglyceride (P

Matched MeSH terms: Genetic Association Studies*
Contribution of MSX1 variants to the risk of non-syndromic cleft lip and palate in a Malay population

Salahshourifar I, Halim AS, Wan Sulaiman WA, Zilfalil BA

J Hum Genet, 2011 Nov;56(11):755-8.
PMID: 21866112 DOI: 10.1038/jhg.2011.95

Oral clefts are clinically and genetically heterogeneous disorders that are influenced by both genetic and environmental factors. The present family-based association study investigated the role of the MSX1 and TGFB3 genes in the etiology of non-syndromic oral cleft in a Malay population. No transmission distortion was found in the transmission disequilibrium analysis for either MSX1-CA or TGFB3-CA intragenic markers, whereas TGFB3-CA exhibited a trend to excess maternal transmission. In sequencing the MSX1 coding regions in 124 patients with oral cleft, five variants were found, including three known variants (A34G, G110G and P147Q) and two novel variants (M37L and G267A). The P147Q and M37L variants were not observed in 200 control chromosomes, whereas G267A was found in one control sample, indicating a very rare polymorphic variant. Furthermore, the G110G variant displayed a significant association between patients with non-syndromic cleft lip, with or without cleft palate, and normal controls (P=0.001, odds ratio=2.241, 95% confidence interval, 1.357-3.700). Therefore, these genetic variants may contribute, along with other genetic and environmental factors, to this condition.

Matched MeSH terms: Genetic Association Studies

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