SNPs In Candidate Genes Research Articles

Associations of variants of CNR1 with obesity and obesity-related traits in Chinese women

The aim of this study was to investigate associations of two candidate gene SNPs of the endocannabinoid receptor type 1 gene (CNR1) with overweight, obesity and obesity-related traits in Chinese retired women. The study subjects were a subsample of the Taizhou Retiree Women Cohort, consisting of 2812 retired women aged 50–64years recruited from Taizhou, Jiangsu, China. Neither rs2023239 nor rs806381 polymorphism was significantly associated with body mass index-defined overweight and obesity or waist-to-hip-ratio-defined obesity. For obesity-related traits, rs2023239 was significantly associated with glutamate pyruvate transaminase (GPT) (median, 18.00 vs 17.00 for TT and TC genotypes, respectively, P=0.043). The rs806381 also showed significant association with triglyceride (TG) (mean±SD, 1.46±0.20 vs 1.53±0.20 for GA and GG+AA genotypes, respectively, P=0.013) under the dominant genetic model. In conclusion, the rs2023239 and rs806381 polymorphisms of CNR1 were not associated with increased overweight and obesity risk. But the rs2023239 polymorphism was significantly associated with GPT, and the rs806381 polymorphism was significantly associated with TG.

Identification of SNPs in candidate genes related to water stress in Eucalyptus

Background Forestry companies have occupied Northern and Northeastern of Brazil with plantations of Eucalyptus species; however, limitations on water supply are affecting the biomass production and reducing the yield significantly [1].Tolerant plants develop defense mechanisms like hormone production of abscisic acid (ABA) and osmoprotector glycine betain (GB) when submitted to drought conditions [2]. Identifying and studying genomic regions related to water stress tolerance are important for tree improvement programs. In this work, SNPs in candidate genes, 9-cis-epoxy-carotenoid dioxygenase (NCED) and choline monooxygenase (CMO), of ABA and GB biosynthetic pathways related to drought tolerance in a population of Eucalyptus were identified, as well as, a possible molecular marker associated to genomic regions related to plant response to water stress through AFLP technique [3] combined with bulk segregant analysis method [4].

Polymorphisms in genes of the somatotrophic axis are independently associated with milk production, udder health, survival and animal size in Holstein‐Friesian dairy cattle

The somatotrophic axis consisting of pituitary-derived growth hormone and circulating insulin-like growth factor 1 has been well established as key regulators of animal health, metabolism, lactation, fertility, body composition and growth rate. The aim of this study was to simultaneously quantify the associations between SNPs in candidate genes of the somatotrophic axis (i.e., IGF-1, GH1 and GHR) with performance traits in Holstein-Friesian (HF) dairy cattle. Both novel SNPs identified previously by this group alongside other published SNPs within these genes were analysed for associations with performance in dairy cattle. Multiple regression analyses regressing genetic merit of up to 848 HF sires on novel SNPs (n = 76) and published SNPs (n = 33) were undertaken using weighted animal mixed linear models. Twenty-three SNPs were significantly associated with at least one of 18 traits analysed and involved in milk production, udder health, fertility and growth. Eight traits including milk fat composition, carcass conformation, stature, chest width, body depth, rump width, carcass and cull cow weight were independently associated with SNPs in two genes. Furthermore, for several traits including milk fat yield, somatic cell count, survival and carcass fat, SNPs in all three genes were independently associated with performance. Milk fat yield and carcass fat showed the highest number of independent associations across all three genes with five SNPs associated with both traits. The cumulative effects of the favourable alleles of all five SNPs across GH1, GHR and IGF-1 result in an increase of 5.9 kg and 28.6 units of milk fat and carcass fat, respectively. Cow survival was associated with a single SNP in each of the three genes with a cumulative allele effect of 1.5%. Independent effects of polymorphisms in GH1, GHR and IGF-1 reinforce the central role of the somatotrophic axis on animal development and performance.

Matching on Race and Ethnicity in Case-Control Studies as a Means of Control for Population Stratification

Some investigators argue that controlling for self-reported race or ethnicity, either in statistical analysis or in study design, is sufficient to mitigate unwanted influence from population stratification. In this report, we evaluated the effectiveness of a study design involving matching on self-reported ethnicity and race in minimizing bias due to population stratification within an ethnically admixed population in California. We estimated individual genetic ancestry using structured association methods and a panel of ancestry informative markers, and observed no statistically significant difference in distribution of genetic ancestry between cases and controls (P=0.46). Stratification by Hispanic ethnicity showed similar results. We evaluated potential confounding by genetic ancestry after adjustment for race and ethnicity for 1260 candidate gene SNPs, and found no major impact (>10%) on risk estimates. In conclusion, we found no evidence of confounding of genetic risk estimates by population substructure using this matched design. Our study provides strong evidence supporting the race- and ethnicity-matched case-control study design as an effective approach to minimizing systematic bias due to differences in genetic ancestry between cases and controls.

Homozygous deletion of the UGT2B17 gene is not associated with osteoporosis risk in elderly Caucasian women

Previously, homozygous deletion of the UGT2B17 gene has shown association with hip fracture. Using a high-throughput qRT-PCR assay, we genotyped UGT2B17 copy number variation (CNV) in 1,347 elderly Caucasian women and examined for effects on bone phenotypes. We found no evidence of association between UGT2B17 CNV and osteoporosis risk in this population. Genetic studies of osteoporosis commonly examine SNPs in candidate genes or whole genome analyses, but insertions and deletions of DNA, collectively called CNV, also comprise a large amount of the genetic variability between individuals. Previously, homozygous deletion of the UGT2B17 gene in CNV 4q13.2, which encodes an enzyme that mediates the glucuronidation of steroid hormones, has shown association with the risk of hip fracture. We used a quantitative real-time PCR assay for genotyping the UGT2B17 CNV in a well-characterized population study of 1,347 Caucasian women aged 75.2 ± 2.7 years (mean ± SD), to assess the effect of the CNV on bone mass density (BMD) at the total hip site and osteoporosis risk. The UGT2B17 CNV distribution was consistent with the expected Hardy-Weinberg distribution and not different from frequencies previously reported in a Caucasian population. Data from ANCOVA of age- and weight-adjusted BMD for UGT2B17 CNV genotype showed no significant difference between genotype groups. Individuals with homozygous or heterozygous deletion of the UGT2B17 gene showed no increased risk of incident fragility fracture. These data suggest that quantitative real-time PCR is a rapid and efficient technique for determination of candidate CNVs, including the UGT2B17 CNV; however, we found no evidence of an effect of UGT2B17 CNV on osteoporosis risk in elderly Caucasian women.

FOUR HUMAN GENE VARIANTS PREDICT THE ANTIHYPERTENSIVE ACTIVITY OF ROSTAFUROXIN, A SELECTIVE INHIBITOR OF THEIR EFFECTS ON THE NA, K PUMP: PP.21.316

Background: The genetic complexity of arterial hypertension hampers the approaches aimed at establishing the clinical impact of SNPs either in candidate genes or loci detected with GWAS. The combination of genotyping of these genes with the inhibition of their function with a selective drug may overcome their complexity and help in defining the right drug for the right patient. Cellular effects of human mutated adducin and endogenous ouabain (EO) on the Na-K pump are selectively inhibited by rostafuroxin at sub nanomolar concentrations. Objective: Here we evaluated whether the alleles of genes (ADD1/3, LSS, HSD3B1/2 and MDR1) involved in EO metabolism and adducin-rostafuroxin effects influence the blood pressure response of these drugs in new discovered and never treated patients. Design and Methods: Patients are classified as responder (R) or non responder (NR) according to the first tertile of SBP variation (primary end-point) after 1 month therapy. Results: The antihypertensive activity of nanomoles oral doses of rostafuroxin, but not the other commonly used antihypertensives losartan or hydrochlorothiazide, was predicted by combinations of the above gene variants; BP fell -16.2 ± 1.2 mmHg in patients with and -2.5 ± 1.2 mmHg without this gene profile (p = 9*10–8). Furthermore, this genetic profile discriminates R patients with a sensitivity of 52%, a specificity of 89% and an Odd Ratio to be responder of 8.9 in rostafuroxin patients only. Conclusions: The combination of genetics with selective targeting of specific mechanism(s) can overcome contemporary limitations of the genetic complexity of human hypertension and provide a specific therapy for 23% of patients.

Abstract SSY01-02: Notch and radiation resistance in glioma stem cells

Abstract SSY01-02: Notch and radiation resistance in glioma stem cells

Abstract SSY01-04: Discovery and validation of genome-wide genetic signatures of chemotherapy susceptibility: A translational model

Abstract SSY01-04: Discovery and validation of genome-wide genetic signatures of chemotherapy susceptibility: A translational model

Analysis of Three Functional Polymorphisms in Relation to Osteoporosis Phenotypes: Replication in a Spanish Cohort

Osteoporosis is a complex disease involving many putative genetic factors. Association analysis of functional SNPs in candidate genes is an important tool for their identification. However, this approach is affected by limited power, population stratification, and other drawbacks that lead to discordant results. Replication in independent cohorts is essential. We performed association analyses of three functional polymorphisms previously associated with bone phenotypes--namely, Ala222Val in MTHFR, Ile1062Val in LRP6, and -13910C>T in LCT--in a cohort of 944 postmenopausal Spanish women, all of them with lumbar spine (LS) bone mineral density (BMD) data and most with femoral neck (FN) BMD and fracture data. We found significant differences between genotypes only for the MTHFR polymorphism and vertebral factures, with an OR of 2.27 (95% CI 1.17-4.38) for the TT vs. CC/CT genotypes, P = 0.018. We present genotype and allele frequency data for LCT -13910C>T for a Spanish population, where the T allele (conferring lactase persistence) has a frequency of 38.6%. Genotype frequencies were consistent with observed clines in Europe and with the prevalence of lactase nonpersistence. The LCT -13910C>T polymorphism was significantly associated with height and weight, such that T allele carriers were 0.88 cm taller (95% CI 0.08-1.59 cm, P = 0.032, adjusted by age) than CC individuals and TT homozygotes were 1.91 kg heavier than CC/CT individuals (95% CI 0.11-3.71 kg, P = 0.038, adjusted by age). In conclusion, no significant association was observed between the studied polymorphisms and LS BMD or FN BMD in postmenopausal Spanish women, and only MTHFR Ala222Val was associated with vertebral fractures.

Genetic analysis of epistatic effects between <I>ApoB</I> and <I>UCP</I> on abdominal fat trait in chicken

It has been found that epistasis for selective response plays an indispensible role in animal genetics and breeding. In this study, the polymorphisms of T123G in apoliprotein B (ApoB) and C1197A in uncoupling protein (UCP) among individuals from the 8th to the 10th generation populations of the Northeast Agricultural University broiler lines divergently selected for abdominal fat content (NEAUHFL) were detected, and genetic analysis of the epistatic effects between the two SNPs on abdominal fat percentage (AFP) was performed using Natural and Orthogonal InterActions (NOIA) model. According to these assays, we concluded that at least one out of four epistatic components between these two SNPs was significantly associated with AFP (Plt;0.05) in fat lines from the 8th to the 10th generations of NEAUHFL; on the contrary, none was significantly associated with AFP (P>0.05) in lean lines. Our results suggested that epistatic interactions among QTLs and functional SNPs in candidate genes affecting fat traits might lead to differences in growth patterns of fat traits between lean and fat chicken lines.

Concurrent or Sequential Adjuvant Hormonoradiotherapy after Conservative Surgery for Early-Stage Breast Cancer: Clinical Results of the CO-HO-RT Phase II Randomized Trial.

Abstract Purpose: Letrozole (LET) has recently been shown to be superior to tamoxifen for postmenopausal patients (pts). In addition, LET radiosensitizes breast cancer cells in vitro. We conducted a phase II randomized study to evaluate concurrent and sequential radiotherapy (RT)-LET in the adjuvant setting. We present here clinical results with a minimum follow-up of 24 months.Patients and Methods: Postmenopausal pts with early-stage breast cancer were randomized after conservative surgery to either: A) concurrent RT-LET (LET started 3 weeks before the first day of RT) or B) sequential RT-LET (LET started 3 weeks after the end of RT). Whole breast RT was delivered to a total dose of 50 Gy. A 10-16 Gy boost was allowed according to age and pathological prognostic factors. Pts were stratified by center, adjuvant chemotherapy, boost, and radiation-induced CD8 apoptosis (RILA). RILA was performed before RT as previously published (Ozsahin et al. Clin Cancer Res, 2005). An independent monitoring committee reviewed individual safety data. Skin toxicities were evaluated by two different clinicians at each medical visit (CTCAE v3.0). Lung CT-scan and functional pulmonary tests were performed regularly. DNA samples were screened for SNPs in candidate genes as recently published (Azria et al., Clin Cancer Res, 2008).Results: A total of 150 pts were randomized between 01/05 and 02/07. Median follow-up is 26 months (range, 3-40 months). No statistical differences were identified between the two arms in terms of mean age; initial TNM; median surgical bed volume; post surgical breast volume. Chemotherapy and RT boost were delivered in 19% and 38% of pts, respectively. Nodes received 50 Gy in 23% of patients without differences between both arms. During RT and within the first 6 weeks after RT, 10 patients (6.7%) presented grade 3 acute skin dermatitis during RT but no differences were observed between both arms (4 and 6 patients in arm A and B, respectively). At 26 month of follow-up, grade 2 and more radiation-induced subcutaneous fibrosis (RISCF) was present in 4 patients (3%) without any difference between arm A (n = 2) and B (n = 2), p=0.93. In both arms, all patients that presented a RICSF had a RILA lower than 16%. Sensitivity and specificity were 100% and 39%, respectively.No acute lung toxicities were observed and quality of life was good to excellent for all patients.SNPs analyses are still on-going (Pr Rosenstein, NY).Conclusion: Acute and early late grade ≥ 2 dermatitis were similar in both arms. The only factor that influenced RISCF was a low radiation-induced lymphocyte apoptosis yield. We confirmed prospectively the capacity of RILA for identifying hypersensitive patients to radiation. Indeed, patients with RILA superior to 16% did not present late effects to radiation and confirmed the first prospective trial we published in 2005 (Ozsahin et al., Clin Cancer Res). Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 956.

Parsing the Effects of Individual SNPs in Candidate Genes with Family Data

We introduce a stepwise approach for family-based designs for selecting a set of markers in a gene that are independently associated with the disease. The approach is based on testing the effect of a set of markers conditional on another set of markers. Several likelihood-based approaches have been proposed for special cases, but no model-free based tests have been proposed. We propose two types of tests in a family-based framework that are applicable to arbitrary family structures and completely robust to population stratification. We propose methods for ascertained dichotomous traits and unascertained quantitative traits. We first propose a completely model-free extension of the FBAT main genetic effect test. Then, for power issues, we introduce two model-based tests, one for dichotomous traits and one for continuous traits. Lastly, we utilize these tests to analyze a continuous lung function phenotype as a proxy for asthma in the Childhood Asthma Management Program. The methods are implemented in the free R package fbati.

Genetic determinants of extracellular magnesium concentration: Analysis of multiple candidate genes, and evidence for association with the estrogen receptor α ( ESR1) locus

Background Serum magnesium concentration is a quantitative trait with substantial heritability. Although the pool of candidate genes continues to grow, only the histocompatibility locus has been associated with magnesium levels. To explore other possibilities, we targeted 6 candidate genes physiologically relevant to magnesium metabolism. Methods We studied a large cohort ( n = 471) derived from a well-characterized population of healthy Caucasian women 18 to 35 years. Total serum magnesium and calcium were measured by atomic absorption spectrophotometry (aaMg & aaCa). Genomic DNA was amplified and SNPs in candidate genes ( CASR, VDR, ESR1, CLDN16, EGF1, TRPM6) genotyped by routine methods. Results We found a significant association between estrogen receptor α ( ESR1) polymorphisms, PvuII and XbaI, and magnesium ( r = − 0.116, p = 0.012 and r = − 0.126, p = 0.006, respectively). Stratifying by PvuII genotype (P/p alleles), the mean adjusted total magnesium (aaMg) concentration was significantly higher ( p = 0.01) in the pp group (0.823 ± 0.005 mmol/l, n = 130) than in PP homozygotes (0.805 ± 0.006 mmol/l, n = 70), and the mean in Pp heterozygotes was intermediate (0.810 ± 0.005 mmol/l, n = 180). No significant associations were observed with the other candidate genes tested. Conclusions The significant association between magnesium and ESR1 polymorphisms supports previous studies linking physiologic changes in serum magnesium to estrogen status.

ARVCF single marker and haplotypic association with schizophrenia

We present a schizophrenia association study using an extensive linkage disequilibrium (LD) mapping approach in seven candidate genes with a well established link to dopamine, including receptors ( DRD2, DRD3) and genes involved in its metabolism and transport ( ACE, COMT, DAT, MAO-A, MAO-B). The sample included 242 subjects diagnosed with schizophrenia and related disorders and 373 hospital-based controls. 84 tag SNPs in candidate genes were genotyped. After extensive data cleaning 70 SNPs were analyzed for association of single markers and haplotypes. One block of four SNPs (rs165849, rs2518823, rs887199 and rs2239395) in the 3′ downstream region of the COMT gene which included a non-dopaminergic candidate gene, the ARVCF (Armadillo like VeloCardio Facial) gene, was associated with the risk of schizophrenia. The genetic region including the ARVCF gene in the 22q11.21 chromosome is associated with schizophrenia in a Spanish series. Our results will assist in the interpretation of the controversy generated by genetic associations of COMT and schizophrenia, which could be the result of different LD patterns between COMT markers and the 3′ region of the ARVCF gene.

SNPs in bovine candidate genes for mediating resistance to infestations with the cattle tick

SNPs in bovine candidate genes for mediating resistance to infestations with the cattle tick

Genome Scan, Fine-Mapping, and Candidate Gene Analysis of Non-Syndromic Cleft Lip with or without Cleft Palate Reveals Phenotype-Specific Differences in Linkage and Association Results

Objectives: Non-syndromic orofacial clefts, i.e. cleft lip (CL) and cleft palate (CP), are among the most common birth defects. The goal of this study was to identify genomic regions and genes for CL with or without CP (CL/P). Methods: We performed linkage analyses of a 10 cM genome scan in 820 multiplex CL/P families (6,565 individuals). Significant linkage results were followed by association analyses of 1,476 SNPs in candidate genes and regions, utilizing a weighted false discovery rate (wFDR) approach to control for multiple testing and incorporate the genome scan results. Results: Significant (multipoint HLOD ≥3.2) or genome-wide-significant (HLOD ≥4.02) linkage results were found for regions 1q32, 2p13, 3q27-28, 9q21, 12p11, 14q21-24 and 16q24. SNPs in IRF6 (1q32) and in or near FOXE1 (9q21) reached formal genome-wide wFDR-adjusted significance. Further, results were phenotype dependent in that the IRF6 region results were most significant for families in which affected individuals have CL alone, and the FOXE1 region results were most significant in families in which some or all of the affected individuals have CL with CP. Conclusions: These results highlight the importance of careful phenotypic delineation in large samples of families for genetic analyses of complex, heterogeneous traits such as CL/P.

ATOM: a powerful gene-based association test by combining optimally weighted markers

Large-scale candidate-gene and genome-wide association studies genotype multiple SNPs within or surrounding a gene, including both tag and functional SNPs. The immense amount of data generated in these studies poses new challenges to analysis. One particularly challenging yet important question is how to best use all genetic information to test whether a gene or a region is associated with the trait of interest. Here we propose a powerful gene-based Association Test by combining Optimally Weighted Markers (ATOM) within a genomic region. Due to variation in linkage disequilibrium, different markers often associate with the trait of interest at different levels. To appropriately apportion their contributions, we assign a weight to each marker that is proportional to the amount of information it captures about the trait locus. We analytically derive the optimal weights for both quantitative and binary traits, and describe a procedure for estimating the weights from a reference database such as the HapMap. Compared with existing approaches, our method has several distinct advantages, including (i) the ability to borrow information from an external database to increase power, (ii) the theoretical derivation of optimal marker weights and (iii) the scalability to simultaneous analysis of all SNPs in candidate genes and pathways. Through extensive simulations and analysis of the FTO gene in our ongoing genome-wide association study on childhood obesity, we demonstrate that ATOM increases the power to detect genetic association as compared with several commonly used multi-marker association tests.

Pharmacogenetics of Glucose-Lowering Drug Treatment

Intensive blood glucose lowering can significantly reduce the risk of micro- and macrovascular complications in patients with diabetes mellitus. However, 30% of all treated patients do not achieve optimal blood glucose levels. Genetic factors may influence the response to glucose-lowering medication. A search of MEDLINE-indexed literature published between January 1966 and July 2007 revealed 37 studies reporting data on genetic polymorphisms and response to glucose-lowering drugs. Most studies involving cytochrome P450 (CYP) genes had small sample sizes (21 studies <50 subjects) and were among healthy volunteers. Multiple studies indicated that the CYP2C9 *3 allele (Ile359Leu polymorphism) was associated with decreased clearance of sulfonylurea drugs. Supporting this, one study reported an increased insulin secretion in CYP2C9*3 allele carriers when using the sulfonylurea agent glyburide. The CYP2C9*3 allele was also associated with a decreased clearance of meglitinides, whereas the CYP2C8*3 (Arg139Lys; Lys399Arg) variant increased the clearance of meglitinides. Polymorphisms in genes encoding the inwardly rectifying potassium channel Kir6.2 (KCNJ11) and the insulin receptor substrate-1 (IRS1) were reported to be associated with an increased risk of (secondary) failure to respond to sulfonylurea therapy. A significant decrease in fasting plasma glucose and hemoglobin A(1c) (HbA(1c)) in response to rosiglitazone was seen in subjects carrying the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma (PPARG) gene. Conversely, carriers of this polymorphism also had a higher conversion to diabetes mellitus when treated with acarbose; this effect was also seen in adiponectin (ADIPOQ) gene polymorphism carriers. Future studies with adequate sample sizes in which several SNPs in multiple candidate genes are genotyped in patients with diabetes should provide reliable information on genetic variants and response to glucose-lowering drugs.

Genome-wide association with bone mass and geometry in the Framingham Heart Study.

BackgroundOsteoporosis is characterized by low bone mass and compromised bone structure, heritable traits that contribute to fracture risk. There have been no genome-wide association and linkage studies for these traits using high-density genotyping platforms.MethodsWe used the Affymetrix 100K SNP GeneChip marker set in the Framingham Heart Study (FHS) to examine genetic associations with ten primary quantitative traits: bone mineral density (BMD), calcaneal ultrasound, and geometric indices of the hip. To test associations with multivariable-adjusted residual trait values, we used additive generalized estimating equation (GEE) and family-based association tests (FBAT) models within each sex as well as sexes combined. We evaluated 70,987 autosomal SNPs with genotypic call rates ≥80%, HWE p ≥ 0.001, and MAF ≥10% in up to 1141 phenotyped individuals (495 men and 646 women, mean age 62.5 yrs). Variance component linkage analysis was performed using 11,200 markers.ResultsHeritability estimates for all bone phenotypes were 30–66%. LOD scores ≥3.0 were found on chromosomes 15 (1.5 LOD confidence interval: 51,336,679–58,934,236 bp) and 22 (35,890,398–48,603,847 bp) for femoral shaft section modulus. The ten primary phenotypes had 12 associations with 100K SNPs in GEE models at p < 0.000001 and 2 associations in FBAT models at p < 0.000001. The 25 most significant p-values for GEE and FBAT were all less than 3.5 × 10-6 and 2.5 × 10-5, respectively. Of the 40 top SNPs with the greatest numbers of significantly associated BMD traits (including femoral neck, trochanter, and lumbar spine), one half to two-thirds were in or near genes that have not previously been studied for osteoporosis. Notably, pleiotropic associations between BMD and bone geometric traits were uncommon. Evidence for association (FBAT or GEE p < 0.05) was observed for several SNPs in candidate genes for osteoporosis, such as rs1801133 in MTHFR; rs1884052 and rs3778099 in ESR1; rs4988300 in LRP5; rs2189480 in VDR; rs2075555 in COLIA1; rs10519297 and rs2008691 in CYP19, as well as SNPs in PPARG (rs10510418 and rs2938392) and ANKH (rs2454873 and rs379016). All GEE, FBAT and linkage results are provided as an open-access results resource at .ConclusionThe FHS 100K SNP project offers an unbiased genome-wide strategy to identify new candidate loci and to replicate previously suggested candidate genes for osteoporosis.

Creatinine Clearance in Sickle Cell Anemia Is Modulated by Genes in the TGF-β/BMP Pathway.

Renal failure is common in sickle cell anemia. The CSSCD, a longitudinal study of the natural history of sickle cell disease, enrolled 4,082 patients observing them for about 5 years, while obtaining laboratory data that included renal function estimated by serum creatinine. Blood samples were obtained for globin gene analysis and were used for SNP genotyping. We studied only patients with sickle cell anemia, with or without coincident α thalassemia. DNA samples and sufficient clinical and laboratory data were available for 779 patients. An adjusted creatinine clearance, using the Cockcroft-Gault and Schwartz formulas was computed for adults and children, respectively. These formulas were used since glomerular hyperfiltration and increased secretion of creatinine reduces the utility of serum creatinine as a measure of renal function in sickle cell anemia. DNA samples were screened for SNPs in candidate genes that included inflammatory mediators, modulators of oxidant injury and NO biology, vasoregulatory molecules and cell adhesion factors and that might be associated with the renal failure phenotype. Genotyping was first done using the Sequenom mass spectrometry SNP genotyping system. For quality control purposes about 3% of the DNA samples were regenotyped and Hardy-Weinberg equilibrium was assessed for each SNP among controls. In this initial screen, we considered a SNP to be associated with renal function when the p-value was less than or equal to 0.01, or more than one SNPs in the same gene was significant at the 0.05 level. If a SNP met these criteria, a second phase of genotyping was done to study additional haplotype tagging (ht) SNPs. We have previously reported the association of genes in the TGF-β/BMP pathway with sickle cell subphenotypes (Sebastiani et al, Nature Genet 37: 435, 2005; Baldwin et al, Blood 106: 372, 2005). Additional genes in this pathway were genotyped using the ABI SNPlex system. These genes included BMP6, bone morphogenetic protein (BMP) receptors, TGF-β receptors, SMADs, MAP kinases and their associated co-factors such as SARA, CDH1 and SMURF1. We analyzed the adjusted creatinine clearance as a continuous variable using multivariate linear regression and as a categorical variable by comparing the lower quartile (25th percentile) to the upper (75th percentile) using logistic regression. All analyses were adjusted for the presence of coincident α thalassemia. BMPR1B, a BMP receptor gene, was associated with creatinine clearance in both analyses. When analyzed as a continuous trait, 5 ht SNPs were associated with creatinine clearance (p values ranging from 0.0008 and 0.0378) and when treated as a qualitative trait, there were 4 significant associations (p values ranging from 0.0148 to 0.0461) Less striking associations of creatinine clearance with other genes in the TGF-β/BMP pathway were found. In previous studies of differential gene expression in the kidney of oxygenated and hypoxic HbS-S Antilles mice (Rybicki et al, BCMD, 2003), the ARG2 gene was found to be upregulated. We found an association of a single ht SNP (rs2295644) marking the ARG2 gene. ARG2, expressed in the kidney, is believed to play a role in NO metabolism. As with other subphenotypes of sickle cell disease, renal function may be genetically modulated.