A polymorphism of apolipoprotein E (APOE) gene is associated with age at natural menopause in Caucasian females

Objective

The present study aimed to investigate possible association of the apolipoprotein E (APOE) gene polymorphisms with age at natural menopause (ANM) in Caucasian females.

Design

Four SNPs (including two replacements, SNP3 Cys112Arg and SNP4 Arg158Cys) were genotyped in 253 randomly selected unrelated Caucasian women having experienced natural menopause. The comprehensive statistical analyses focusing on the association of the APOE gene and some environmental factors with ANM were conducted.

Results

Alcohol consumption was a significantly predictor of earlier natural menopause (P < 0.05). One SNP (rs769450) was significantly associated with ANM according to both population based and the transmission disequilibrium test (TDT) analyses (P = 0.007 and 0.046, respectively). However, no association was observed between APOE ?2, ?3, ?4 and ANM.

Conclusions

Genetic variation in the APOE gene may influence the variation in ANM in Caucasian women.     

Common variants at the PCOL2 and Sp1 binding sites of the COL1A1 gene and their interactive effect influence bone mineral density in Caucasians

Background: Osteoporosis, mainly characterised by low bone mineral density (BMD), is a serious public health problem. The collagen type I alpha 1 (COL1A1) gene is a prominent candidate gene for osteoporosis. Here, we examined whether genetic variants at the COL1A1 gene can influence BMD variation.

Methods: BMD was measured at nine skeletal sites in 313 Caucasian males and 308 Caucasian females. We screened four single nucleotide polymorphisms (SNPs) at the COL1A1 gene: PCOL2 (-1997 G/T) in the promoter, Sp1 (1546 G/T) in the intron 1, Gly19Cys (3911 G/A) in exon 8, and Ala897Thr (13 773 G/A) in exon 45. Univariate and multivariate association approaches were used in the analyses.

Results: In multivariate analyses, we found a strong association between the PCOL2 SNP and BMD (p = 0.007 to 0.024) and a suggestive association between the Sp1 SNP and BMD (p = 0.023 to 0.048) in elderly Caucasian females. Interestingly, the interaction of these two SNPs was highly significantly associated with BMD variation (p = 0.001 to 0.003). The haplotype GG at the two SNPs had, on average, 2.7% higher BMD than non-carriers (p = 0.006 to 0.026).

Conclusions: Our data suggested that the common genetic variants at the PCOL2 and Sp1 sites, and importantly, their interactive effects, may contribute to BMD variation in elderly Caucasian females. Further studies are necessary to delineate the mechanisms underlying the effects of these common variants on BMD variation and to test their clinical relevance for general populations. In addition, our study highlighted the importance of multivariate analyses when multiple correlated phenotypes are under study.

     

LMX1A基因多态性与中国汉族人群先天性脊柱侧凸遗传易感性的关联

背景：先天性脊柱侧凸是由于胚胎期脊柱椎体发育异常引起的脊柱侧凸,其遗传病因学假说开始引起许多学者的重视。 目的：通过候选基因LMX1A上关键单核苷酸多态性位点的筛查,探索LMX1A与中国汉族人群先天性脊柱侧凸及其不同临床表型之间的关联。 方法：入选127例中国汉族先天性脊柱侧凸患者,另选取外伤、感染、炎症性疾病等患者127例为对照组。根据国际人类基因组单体型图计划提供的基因型数据,应用Haploview 4.1软件选取LMX1A的标签和功能单核苷酸多态性位点。根据椎体畸形特点、畸形部位、畸形受累程度、有无合并肋骨畸形和椎管内畸形将病例组进一步分为不同临床表型。所有样本应用SNPstream UHT Genotyping系统对所选单核苷酸多态性位点进行基因型鉴定;进一步进行基于基因型/等位基因频率的关联分析,并用Haploview 4.1软件分析对照组单核苷酸多态性位点间是否存在连锁不平衡。 结果与结论：共筛选6个位点：SNP1(rs1819768)、SNP2(rs12023709)、SNP3(rs16841013)、SNP4(rs4656435)和SNP5(rs4657412)和SNP6(rs4657411),其基因型分布在病例组和对照组中均符合Hardy-Weinberg平衡;在基于基因型的关联分析中发现阳性位点SNP1和SNP2,单位点分析显示两位点基因型在病例组和对照组中的分布频率差异有显著性意义(P=0.026和P=0.026),在进一步非条件Logistic回归分析中发现这两个位点的基因型分布最符合Ressessive(OR=0.38;95%CI=0.15~0.94,P=0.029,AIC=354.9)遗传模型;SNP1、SNP2、SNP3和SNP6处于连锁不平衡状态,SNP4和SNP5也处于完全连锁不平衡状态,但单倍体型与先天性脊柱侧凸的发生风险之间不存在相关性;在进一步与先天性脊柱侧凸临床表型的关联分析中发现SNP1基因型AC型、SNP2基因型AG型、SNP3基因型CT型与有椎体形成障碍先天性脊柱侧凸的易感性升高有关。结果提示在中国汉族人群中LMX1A基因可能和先天性脊柱侧凸的发生、发展相关,是一个重要的易感基因。     

Genetic Variation at the Chromosome 16 Chemokine Gene Cluster: Development of a Strategy for Association Studies in Complex Disease

The chemokine gene cluster [CCL22, CX3CL1, CCL17] (previously known as [SCYA22, SCYD1, SCYA17]) is a candidate locus for one of the susceptibility genes for inflammatory bowel disease that are located in the peri‐centromeric region of chromosome 16. Screening for sequence variation at this locus led to the detection of 14 single nucleotide polymorphisms (SNPs). An efficient experimental and computational approach was developed to estimate allele frequencies and pairwise linkage disequilibrium relationships between SNPs at this locus, and to test them for association with inflammatory bowel disease. The 12 common SNPs were assigned to 5 distinct linkage disequilibrium groups. Genotyping of one SNP from each linkage disequilibrium group in a large cohort of families with inflammatory bowel disease did not provide convincing evidence of association with either Crohn's disease or ulcerative colitis. We describe an efficient experimental design from SNP screening to association testing. This strategy can be used to test candidate genes for involvement in susceptibility to complex disease.     

Lack of association between a polymorphism in the interleukin-13 gene and total serum immunoglobulin E level among nuclear families in Costa Rica

BACKGROUND: IL-13 has been implicated in the pathogenesis of asthma and in the regulation of IgE synthesis in humans. Single nucleotide polymorphisms (SNPs) in the IL-13 gene have been associated with asthma and total serum IgE level in Caucasian populations. OBJECTIVE: To test for genetic association between an SNP in exon 4 of the IL-13 gene (IL-13 + 2044 or Arg130Gln) and total serum IgE level and asthma-related phenotypes in a population with high prevalence of asthma living in Costa Rica. METHODS: Family-based association study. RESULTS: Among 83 Costa Rican school children with asthma and their parents (249 individuals), there was no evidence of linkage disequilibrium between the IL-13 + 2044 SNP and any of the outcomes of interest (total serum IgE level on a logarithmic scale, number of positive skin tests to aeroallergens, and asthma). These results were not significantly changed after adjustment for age and gender. CONCLUSIONS: No significant evidence of linkage disequilibrium between an SNP in exon 4 of the IL-13 gene and total serum IgE level, sensitization to allergens or asthma was found in a family-based association study in Costa Rica.     

A systematic approach to the assessment of known TNF-alpha polymorphisms in Graves' disease

Single-nucleotide polymorphisms (SNPs) within the tumour necrosis factor alpha (TNF-alpha) gene on chromosome 6p21.3 have been associated with many autoimmune diseases; however, results have been conflicting and accurate allele frequencies have never been established in a UK Caucasian population. The aim of this study was to assess the frequency of 22 known TNF-alpha SNPs in a UK Caucasian control population and investigate association of all polymorphisms with >5% minor allele frequency in a large case-control data set of patients with Graves' disease (GD). Eight of the 22 SNPs had minor allele frequencies >5% and were investigated further. The other 14 SNPs were present in the UK population at frequencies ranging from 0 to 4.7%. A significant increase of the A allele of the -238 SNP was seen in GD patients when compared with control subjects (9.6 vs 6.8%, respectively; P=0.003) and mirrored in the genotype distribution (P=0.009). Furthermore, association of the -238 SNP appears not to be due to linkage disequilibrium of the known HLA-DRB1(*)03 associations with GD. This study has established accurate allele frequencies of TNF-alpha SNPs in a UK population and provides preliminary evidence for association of the TNF-alpha gene with GD.     

IGF1 and IGFBP3 tagging polymorphisms are associated with circulating levels of IGF1, IGFBP3 and risk of breast cancer

Experimental and observational studies in humans and animals suggest that insulin-like growth factor 1 (IGF1) and its principal binding protein, IGFBP3, may influence breast cancer susceptibility. We have examined the association of nine and four single nucleotide polymorphisms (SNPs) in the IGF1 gene and in the IGFBP3 genes, respectively, with circulating levels of their gene products in a population-based study of 600 middle-aged men and women, and in a breast cancer case-control study, comprised 4647 cases and 4564 controls. All study participants are from the East Anglian region of UK. SNPs were specifically chosen to tag all other known SNPs in each gene. Several SNPs in each gene are associated both with circulating levels of their respective proteins and with risk of breast cancer. In particular, the c allele of IGF1 SNPrs1520220 is associated with increased circulating IGF1 (r2=2.1%, P-trend=0.003) in females and an increased risk of breast cancer: odds ratio (OR) (cc/gg)=1.41; 95% confidence intervals (95% CI) 1.11-1.79, P-trend=0.03. The a allele of IGFBP3 SNP rs2854744 is associated with increased circulating IGFBP3 (r2=9.7%, P<10(-9)) and a decreased risk of breast cancer: OR (aa/cc)=0.87; 95% CI 0.77-0.99, P=0.03. Our data indicate that common variants in the IGF1 and IGFBP3 genes are associated with differences in circulating levels of IGF1 and IGFBP3 and with breast cancer risk. More specifically and consistent with experimental models, our data suggest that higher IGF1 levels may increase the risk of breast cancer but higher IGFBP3 levels may be protective.     

Comprehensive association analyses of IGF1, ESR2, and CYP17 genes with adult height in Caucasians

Human adult height is closely related to body growth that is regulated by multiple cytokines or hormones like growth hormone (GH) and estrogen. Our study focused on three potential candidate genes to human height, namely IGF1 (insulin-like growth factor 1), ESR2, and CYP17. We genotyped 43 single nucleotide polymorphisms (SNPs) and tested their associations in 1873 subjects from 405 nuclear families, using both the family-based quantitative transmission disequilibrium test (QTDT) and population-based ANOVA methods. Both analyses consistently detected that two novel SNPs of IGF1, rs5742694 and rs2033178, were significantly associated with human height, with the P-values of 0.0097 and 0.0057 in QTDT analyses, 0.0002/0.004 (sample 1/sample 2) and 8.46 x 10(-5)/1.92 x 10(-5) in ANOVA analyses. For ESR2, significant associations were only detected in women (rs1256061: QTDT P=0.002, ANOVA P=0.002/0.012; rs17766755: QTDT P=0.019, ANOVA P=0.023/0.006; rs1256044: QTDT P=0.022, ANOVA P=0.002/0.034). Haplotype analyses corroborated our single-SNP results. However, no association was detected between CYP17 and human height. In conclusion, we identified the important effects of IGF1 and ESR2 on adult height variation in Caucasians, and first suggested the potential sex-specific effect of ESR2 on height variation in Caucasian women. It will be valuable for other independent studies to replicate and confirm these findings.     

DVL2基因多态性与中国汉族人群先天性脊柱侧凸遗传易感性的关联研究

背景：近20年来小鼠的分子胚胎学研究进展获得了大量关于脊椎发育的分子信息,用同线性分析法确立先天性脊柱侧凸的候选基因已成为可能。 目的：通过候选基因DVL2上关键单核苷酸多态性位点的筛查,探索DVL2与中国汉族人群先天性脊柱侧凸及其不同临床表型之间的关联。 方法：采用病例-对照研究,入选127例中国汉族先天性脊柱侧凸患者和127例对照组。根据国际人类基因组单体型图计划提供的基因型数据,应用Haploview 4.1软件选取DVL2的标签和功能单核苷酸多态性。根据椎体畸形特点、畸形部位、畸形受累程度、有无合并肋骨畸形和椎管内畸形将病例组进一步分为不同临床表型。对所有样本应用SNPstream UHT Genotyping系统对所选单核苷酸多态性位点进行基因型鉴定;进一步进行基于基因型/等位基因频率的关联分析,并用Haploview 4.1软件分析对照组单核苷酸多态性位点间是否存在连锁不平衡。 结果与结论：共筛选5个位点：单核苷酸多态性1(rs2074222)、单核苷酸多态性2(rs222837)、单核苷酸多态性3(rs222835)、单核苷酸多态性4(rs10671352)和单核苷酸多态性5(rs222836),其基因型分布在病例和对照组中均符合Hardy-Weinberg平衡;5个位点处于完全连锁不平衡状态;5个位点的基因型/等位基因/单倍体型与先天性脊柱侧凸的发生风险之间不存在相关性。在进一步与先天性脊柱侧凸临床表型的关联分析中没有发现阳性位点。提示在中国汉族人群中DVL2基因可能不是引起先天性脊柱侧凸及其不同临床表型的主要因素,有待于进一步深入研究。     

Polymorphisms in the PON gene cluster are associated with Alzheimer disease

Paraoxonase is an arylesterase enzyme that is expressed in the liver and found in the circulation in association with apoA1 and the high-density lipoprotein, and prevents the accumulation of oxidized lipids in low-density lipoproteins in vitro. Common polymorphisms in genes encoding paraoxonase are established risk factors in a variety of vascular disorders including coronary artery disease and carotid artery stenosis, but their association with Alzheimer disease (AD) is controversial. We tested the association of 29 SNPs in PON1, PON2 and PON3 with AD in 730 Caucasian and 467 African American participants of the MIRAGE Study, an ongoing multi-center family-based genetic epidemiology study of AD. Eight SNPs were associated with AD in the African American families (0.0001< or =P< or =0.04) and two SNPs were associated with AD in Caucasian families (0.01< or =P< or =0.04). Of note, the pattern of association for the PON1 promoter SNP -161[C/T] was the same in both ethnic groups (P=0.006). Haplotype analysis using sliding windows revealed 11 contiguous SNP combinations spanning the three PON genes with significant global test scores (0.006< or =P< or =0.04) in the two ethnic groups combined. The most significantly associated haplotype comprised SNPs in the region spanning the -161[C/T] SNP (P=0.00009). Our results demonstrate association between AD and variants in the PON gene cluster in Caucasians and African Americans.     

Positive associations between single nucleotide polymorphisms in the IGF2 gene region and body mass index in adult males.

We previously demonstrated an association between the insulin-like growth factor 2 (IGF2) gene 3'-untranslated region (3'-UTR) ApaI polymorphism and body mass index (BMI) in over 2500 middle-aged Caucasoid males. In the same cohort, we have now tested association with 11 more markers, including seven novel single nucleotide polymorphisms (SNPs), spanning >30 kb across the IGF2 gene. Three SNPs showed significant positive associations with BMI: 6815 A/T in the IGF2 P1 promoter (P = 0.00012, n = 2394) and the newly identified SNPs 1156 C/T in intron 2 (P = 0.017, n = 1567) and 1926 C/G in the 3'-UTR (P = 0.0062, n = 1872). There was strong pairwise linkage disequilibrium (LD) between the ApaI and 1926 C/G sites, whereas LD between ApaI and 6815 A/T, and between ApaI and 1156 T/C, was minimal. Univariately 6815 A/T, 1156 T/C and ApaI explained 1.03, 1.02 and 0.67% of the variation in BMI. Multi-way analysis of variance (ANOVA) models showed that 6815 A/T and 1156 T/C explained a further 0.4 and 0.8% of the variation beyond that accounted for by ApaI and the association of 1926 C/G with BMI disappeared after adjustment. The 6815 A/T, 1156 T/C and ApaI markers in effect constitute independent affirmations of our original hypothesized candidate gene region. In a stepwise multi-way ANOVA model, all three terms were significantly independently associated with BMI. The total proportion of BMI variance explained by this model was 2.25%, strongly suggesting that IGF2 genetic variation is a significant determinant of body weight in middle-aged males.     

Family-based association study between autism and glutamate receptor 6 gene in Chinese Han trios.

The glutamate pathways are involved in diverse processes such as learning and memory, epilepsy, and they play important roles in neural plasticity, neural development, and neurodegeneration. It has been proposed that autism could be a hypoglutamatergic disorder. Recently, Jamain et al. reported that the glutamate receptor 6 (GluR6 or GRIK2) is in linkage disequilibrium with autism. In the present study, the transmission disequilibrium test (TDT) and the haplotype transmission were performed to analyze the four SNPs (SNP1: rs995640; SNP2: rs2227281; SNP3: rs2227283; SNP4: rs2235076) of GluR6 in 174 Chinese Han parent-offspring trios. The TDT demonstrated that the two SNPs (SNP2 and SNP3) showed preferential transmission (TDT P = 0.032). The global chi(2) test for haplotype transmission also revealed an association between GluR6 and autism (chi(2) = 10.78, df = 3, P = 0.013). Our results suggested that GluR6 is in linkage disequilibrium with autism.     

HSPD1 is not a major susceptibility gene for rheumatoid arthritis in the French Caucasian population

The heat shock 60-kDa protein 1 (HSP60) is involved in immune and inflammatory reactions, which are hallmarks of rheumatoid arthritis (RA). HSP60 is encoded by the HSPD1 gene located on 2q33, one of the suggested RA susceptibility loci in the French Caucasian population. Our aim was to test whether HSPD1 is a major susceptibility gene by studing families from the French Caucasian population. Three single nucleotide polymorphisms (SNPs) were studied in 100 RA trio families, and 100 other families were used for replication. Genetic analyses were performed by comparing allelic frequencies, by applying the transmission disequilibrium test, and by assessing the genotype relative risk. We observed a significant RA association for the C/C genotype of rs2340690 in the first sample. However, this association was not confirmed when the second sample was added. The two other SNPs and the haplotype analysis did not give any significant results. We conclude that HSPD1 is not a major RA susceptibility gene in the French Caucasian population.     

Identification of genetic variants that influence circulating IGF1 levels: a targeted search strategy

An important class of genetic variants that affect disease susceptibility may lie within regulatory elements that influence gene expression. Regulatory sequences are difficult to identify and may be distant from the genes they regulate, but many lie within evolutionarily conserved regions (ECRs). We used comparative genomics to identify 12 ECRs up to 75 kb 5' to and within introns of IGF1. These were screened by high-resolution melting curve analysis, and 18 single-nucleotide polymorphisms (SNPs) were identified, including five novel variants. We analysed two large population-based series of healthy women to test the nine SNPs with minor allele frequency (MAF) >1% within ECRs. Three of the nine SNPs within ECRs (rs35455143, rs35765817 and rs3839984) were significantly associated with circulating IGF1 levels in a multivariate analysis (P 70 kb 5' of IGF1. Two (rs35455143 and rs35765817) are in strong LD with each other and appear to have opposite effects on circulating IGF1. Our results on a subset of other SNPs in or near IGF1 were consistent with previously reported associations with IGF1 levels, although only one (rs35767: P = 0.05) was statistically significant. We believe that this is the first systematic study of an association between a phenotype and SNPs within ECRs extending over a large region adjacent to a gene. Targeting ECRs appears to be a useful strategy for identifying a subset of potentially functional non-coding regulatory SNPs.     

Asthma is associated with single-nucleotide polymorphisms in ADAM33

BACKGROUND : The ADAM33 gene has recently been associated with asthma and bronchial hyper-reactivity. It codes for a disintegrin and metalloproteinase that triggers intra- and extracellular signalling by protein shedding. OBJECTIVE : We examined whether polymorphisms in ADAM33 are associated with asthma and related traits in two German populations. METHODS : We genotyped 15 intragenic single-nucleotide polymorphisms (SNPs) by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry of allele-specific primer extension products. The transmission disequilibrium test was used for association analysis in the German asthma family study. Additionally, we tested for association of these SNPs in a case-control sample from the European Community Respiratory Health Study using Armitage's trend test. RESULTS : In both studies, we found SNPs that were significantly associated with asthma and related traits. In the family study, significant associations were observed for the SNPs F+1, ST+4 and ST+5 (with the lowest P-value for F+1, P=0.005). Remarkably, this association is seen even in the absence of linkage with two microsatellite markers from a previous genome scan either 3.1 million bases (Mb) up- or 5.6 Mb downstream. In the case-control study, SNP ST+7 (P=0.008) was significantly associated with asthma. Some of these SNPs overlapped with those found to be associated with elevated total IgE levels and bronchial hyper-responsiveness. CONCLUSION : This study replicates the recently published association between asthma and ADAM33 gene variants. However, most of the associated SNPs were at non-identical positions in the German, UK and US samples. As linkage disequilibrium is high among the tested SNPs, and there is no known functional polymorphism, either not-tested variants in ADAM33, unknown regulatory elements or a gene in close proximity is responsible for this association.     

Bivariate genome-wide linkage analysis for traits BMD and AAM: Effect of menopause on linkage signals

Osteoporosis is an age-related systemic skeletal disease, characterized by low bone mineral density (BMD). Low BMD is closely associated with late age at menarche (AAM). Our previous bivariate genome-wide linkage analyses (GWLAs) between BMD and AAM identified two shared genomic regions in 2584 Caucasian females including both pre- and post-menopausal females. However, menopause often causes dramatic bone loss in post-menopausal females; this may introduce some confounding effects on the bivariate GWLA for BMD and AAM.     

Genetic variation in tumour necrosis factor and lymphotoxin is not associated with endometriosis in an Australian sample

BACKGROUND: Tumour necrosis factor (TNF) is a pleiotropic cytokine with a wide range of immunoregulatory effects. Variation in the promoter region of TNF and the neighbouring lymphotoxin alpha (LTA) gene might be associated with endometriosis. METHODS: We examined the association between endometriosis and common single-nucleotide polymorphisms (SNPs) or haplotypes in the TNF/LTA region in an Australian sample by analysing 26 SNPs in 958 endometriosis cases and 959 unrelated controls. We selected functional SNPs in the coding and the promoter region of the TNF gene and HapMap tagging SNPs and typed them on a Sequenom MassARRAY platform. A key SNP (rs1800630) in the promoter region typed in previous studies did not give reliable results. Therefore, we also examined a statistically identical (r(2) = 1) SNP (siSNP) (rs2844482), identified using the web based program ssSNPer. RESULTS: Genotype completion rate was 99.5% for SNPs spanning a region of 15.5 kb across the TNF/LTA locus. There was no evidence for association between endometriosis and TNF/LTA SNPs or SNP haplotypes in our case-control study. CONCLUSIONS: Our data suggest both TNF and LTA genes are not major susceptibility genes for endometriosis.     

Association analysis of delta-opioid receptor gene polymorphisms in methamphetamine dependence/psychosis.

The role of the delta-opioid receptor (OPRD1) in methamphetamine (MAP) addiction was investigated using association analysis between OPRD1 gene polymorphisms and MAP dependence/psychosis. DNA samples from Japanese patients with MAP dependence/psychosis were analyzed to find polymorphisms in OPRD1 gene exons and exon-intron boundaries. One novel single nucleotide polymorphism (SNP) in intron 1 and two SNPs in exon 3 were identified. The two SNPs in exon 3 were in linkage disequilibrium. No significant difference was observed in either genotypic or allelic frequencies of these SNPs between controls (n = 260) and MAP dependent/psychotic patients (n = 170). Global analyses using the three SNPs and subcategory analyses on clinical parameters also showed no significant differences. These results suggest that the OPRD1 gene variants may not be a factor in vulnerability to MAP dependence/psychosis.     

Polymorphisms in FADS1 and FADS2 alter desaturase activity in young Caucasian and Asian adults

Recent evidence indicates that genetic variation in fatty acid desaturases 1 and 2 (FADS1 and FADS2) is associated with changes in plasma fatty acid profiles; however, the association with altered desaturase activity has not been examined in different ethnic populations. The present study examined whether genetic variation in the FADS gene cluster regulates desaturase activity in two populations of young Canadian adults (Caucasian and Asian) and whether altered desaturase activity was reflected in both n-3 and n-6 fatty acid profiles. FADS1 and FADS2 were genotyped in a random subset of participants (Caucasian, n=78; Asian, n=69) from the Toronto Nutrigenomics and Health study using MALDI-TOF mass spectrometry, and plasma fatty acids were measured by gas chromatography. Desaturase activities were estimated using the following fatty acid ratios: γ-linoleic acid to linoleic acid (GLA:LA), arachidonic acid to linoleic acid (AA:LA), arachidonic acid to dihomo-γ-linoleic acid (AA:DGLA), and eicosapentaneoic acid to α-linolenic acid (EPA:ALA). Nineteen single nucleotide polymorphisms (SNPs) were examined, and several SNPs (9 in Caucasians and 8 in Asians) were associated with various desaturase activities. The most significant association detected was between the FADS1 rs174547 SNP and AA:LA in both Caucasians (p=4.0 × 10(-8)) and Asians (p=5.0 × 10(-5)). Although the minor allele for this SNP differed between Caucasians (T) and Asians (C), carriers of the C allele had a lower desaturase activity than carriers of the T allele in both groups. To determine whether rs174547 was a dominant SNP in the FADS gene cluster, we constructed an additional model which included this SNP as a covariate. Only one SNP (rs498793 in FADS2) remained associated with the EPA:ALA ratio (p=1.1 × 10(-5)) in Asians. This study shows that genetic variation in the FADS gene cluster (in particular rs174547) can alter desaturase activity in subjects of Caucasians and Asian descent.