Family-based Association Test Analysis Research Articles

Chromosomal regions strongly associated with waist circumference and body mass index in metabolic syndrome in a family-based study

Obesity is the most crucial phenotype in metabolic syndrome (MetS), and waist circumference (WC) and body mass index (BMI) are two common indexes to define obesity. It is an accepted fact that genetic and environmental interaction influence obesity and MetS. Microsatellites are a subcategory of tandem repeats with a length of 1 to 10 nucleotides. Tandem repeats make up repetitive genomic regions. Differences in the number of tandem repeats or their variation (alleles) result in microsatellite polymorphisms. Thus, we attempted to find microsatellite variation associated with WC and BMI in a family-based study. Twelve microsatellite markers were selected to investigate possible genes or chromosomal regions in 91 families with at least one affected MetS. The cut-off values for BMI and WC were considered 25 kg/m2 and 90 cm, respectively. In all members of the families, the strongest association was observed between the marker D11S1304 (allele 1) with both WC and BMI, independently, by the biallelic model in the family-based association test analysis (P < 0.05). Besides, when we compared high- and low-level groups in members with MetS, the markers D8S1743 and D11S1304 (allele 1) showed a strong association with WC (P = 0.0080) and BMI (P = 0.0074), respectively. When the simultaneous detection of the high WC and MetS status was used as a trait, the strongest association was observed with the marker D8S1743 (P = 0.0034). Moreover, when BMI with the high MetS status was used as a trait, the strongest association was observed with the marker D8S1743 (allele 4) (P = 0.0034). The obtained results showed a relationship between obesity and MetS with markers on the selected regions on chromosomes 8 and 11, and to a lesser degree, on chromosome 12.

Associations between homocysteine metabolism related SNPs and carotid intima-media thickness: a Chinese sib pair study

Carotid intima-media thickness (CIMT) is a good surrogate for atherosclerosis. Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases. We aim to investigate the relationships between homocysteine (Hcy) related biochemical indexes and CIMT, the associations between Hcy related SNPs and CIMT, as well as the potential gene–gene interactions. The present study recruited full siblings (186 eligible families with 424 individuals) with no history of cardiovascular events from a rural area of Beijing. We examined CIMT, intima-media thickness for common carotid artery (CCA-IMT) and carotid bifurcation, tested plasma levels for Hcy, vitamin B6 (VB6), vitamin B12 (VB12) and folic acid (FA), and genotyped 9 SNPs on MTHFR, MTR, MTRR, BHMT, SHMT1, CBS genes. Associations between SNPs and biochemical indexes and CIMT indexes were analyzed using family-based association test analysis. We used multi-level mixed-effects regression model to verify SNP-CIMT associations and to explore the potential gene–gene interactions. VB6, VB12 and FA were negatively correlated with CIMT indexes (p < 0.05). rs2851391 T allele was associated with decreased plasma VB12 levels (p = 0.036). In FABT, CBS rs2851391 was significantly associated with CCA-IMT (p = 0.021) and CIMT (p = 0.019). In multi-level mixed-effects regression model, CBS rs2851391 was positively significantly associated with CCA-IMT (Coef = 0.032, se = 0.009, raw p < 0.001) after Bonferoni correction (corrected α = 0.0056). Gene–gene interactions were found between CBS rs2851391 and BHMT rs10037045 for CCA-IMT (p = 0.011), as well as between CBS rs2851391 and MTR rs1805087 for CCA-IMT (p = 0.007) and CIMT (p = 0.022). Significant associations are found between Hcy metabolism related genetic polymorphisms, biochemical indexes and CIMT indexes. There are complex interactions between genetic polymorphisms for CCA-IMT and CIMT.

A family-based association study of the HTR1B gene in eating disorders.

Objective:To explore the association of three polymorphisms of the serotonin receptor 1Dβ gene (HTR1B) in the etiology of eating disorders and their relationship with clinical characteristics.Methods:We analyzed the G861C, A-161T, and A1180G polymorphisms of the HTR1B gene through a family-based association test (FBAT) in 245 nuclear families. The sample was stratified into anorexia nervosa (AN) spectrum and bulimia nervosa (BN) spectrum. In addition, we performed a quantitative FBAT analysis of anxiety severity, depression severity, and Yale-Brown-Cornell Eating Disorders Scale (YBC-EDS) in the AN and BN-spectrum groups.Results:FBAT analysis of the A-161T polymorphism found preferential transmission of allele A-161 in the overall sample. This association was stronger when the sample was stratified by spectrums, showing transmission disequilibrium between the A-161 allele and BN spectrum (z = 2.871, p = 0.004). Quantitative trait analysis showed an association between severity of anxiety symptoms and the C861 allele in AN-spectrum participants (z = 2.871, p = 0.004). We found no associations on analysis of depression severity or preoccupation and ritual scores in AN or BN-spectrum participants.Conclusions:Our preliminary findings suggest a role of the HTR1B gene in susceptibility to development of BN subtypes. Furthermore, this gene might have an impact on the severity of anxiety in AN-spectrum patients.

Microarray Analysis of Two Single-Nucleotide Polymorphisms of Transforming Growth Factor Alpha in Patients with Nonsyndromic Cleft of North China

To investigate the association between the TGFA:c.3851T > C (rs11466285) and TGFA:c.3822G > A (rs3771523) single-nucleotide polymorphisms (SNPs) and nonsyndromic cleft lip and/or cleft palate (CL/P) with microarray in north China. Test association by both case-control and case-parent analysis. Two SNPs of 150 controls, 166 cases, and 271 of their parents were genotyped using microarray based on the allele-specific primer extension, and chi-square statistics and family-based association test analyses were performed. Both sequencing and microarray analysis produced identical results. We found significant evidence of overtransmission of the C allele of c.3851T > C and the A allele of c.3822G > A in case-parent trios for CL/P but not for cleft palate only (CP). Significant differences for both genotypic and allelic distributions between cases and controls were found at c.3822G > A and c.3851T > C for CL/P but not for CP. The TGFA [C; G] and [T; A] haplotypes showed significant overtransmission. These results support that two SNPs are associated with nonsyndromic CL/P but not for CP in northern Chinese populations. It was demonstrated that this microarray is suitable to test SNPs associated with nonsyndromic CL/P.

MSX1 gene and nonsyndromic oral clefts in a Southern Brazilian population

Nonsyndromic oral clefts (NSOC) are the most common craniofacial birth defects in humans. The etiology of NSOC is complex, involving both genetic and environmental factors. Several genes that play a role in cellular proliferation, differentiation, and apoptosis have been associated with clefting. For example, variations in the homeobox gene family member MSX1, including a CA repeat located within its single intron, may play a role in clefting. The aim of this study was to investigate the association between MSX1 CA repeat polymorphism and NSOC in a Southern Brazilian population using a case-parent triad design. We studied 182 nuclear families with NSOC recruited from the Hospital de Clínicas de Porto Alegre in Southern Brazil. The polymorphic region was amplified by the polymerase chain reaction and analyzed by using an automated sequencer. Among the 182 families studied, four different alleles were observed, at frequencies of 0.057 (175 bp), 0.169 (173 bp), 0.096 (171 bp) and 0.67 (169 bp). A transmission disequilibrium test with a family-based association test (FBAT) software program was used for analysis. FBAT analysis showed overtransmission of the 169 bp allele in NSOC (P=0.0005). These results suggest that the CA repeat polymorphism of the MSX1 gene may play a role in risk of NSOC in populations from Southern Brazil.

Effect of angiotensin II type I receptor A1166C polymorphism on benazepril action in hypertensive patients: A family-based association test study

Few studies have examined the effect of the angiotensin II type I receptor (AT1R) A1166C polymorphism on the antihypertensive effect of the angiotensin-converting-enzyme inhibitor benazepril in patients with hypertension, and no such studies have performed analysis using the Family-Based Association Test (FBAT), The aim of our study was to examine the association between AT1R A1166C gene polymorphism and the antihypertensive effect of benazepril using the FBAT. A total of 864 patients (aged, 26-62 years) with essential hypertension were identified in an epidemiological survey and enrolled in this study. Blood pressure (BP) was measured before and after 16 days of treatment with benazepril (10 mg/day). The association between the A1166C gene polymorphism and the antihypertensive effect of benazepril was assessed by FBAT. The frequencies of alleles A and C were 95.1% and 4.9%, respectively. FBAT analysis revealed that the C allele was significantly associated with high baseline diastolic BP (Z = 2.041, p = 0.041), decreased systolic BP after treatment (Z = 2.549, p = 0.011), and decreased diastolic BP after treatment (Z = 2.320, p = 0.020). Our results, determined using the FBAT, are the first evidence that the AT1R A1166C polymorphism may increase the antihypertensive effect of benazepril in patients with hypertension.

Association Among Polymorphisms atMYH9, Environmental Factors, and Nonsyndromic Orofacial Clefts in Western China

Myosin heavy chain 9, nonmuscle (MYH9) and environmental factors have been shown to be associated with nonsyndromic cleft lip with or without cleft palate in several populations. Our study aimed to confirm the contribution of MYH9 and environmental factors to nonsyndromic orofacial cleft risk in western Han Chinese. Four single-nucleotide polymorphisms were investigated in 180 case trios and 224 normal peers in western China using transmission disequilibrium test, family-based association test analysis, and logistic regression models. Strong evidence of linkage disequilibrium was found between these markers and the disease by both single-nucleotide polymorphism analysis (G allele at rs2269529 and T allele at rs16996652) and haplotype analysis (G-T [for rs2269529 and rs16996652] and G-A-T [for rs2269529, rs3752462, and rs16996652] among others). Mothers' illness, medication, and passive smoking during the first trimester may increase the risk of nonsyndromic orofacial clefts, but mothers' vitamin (including folic acid) supplementation during the first trimester is a protective factor. Interactions between mothers' passive smoking during the first trimester and T/T genotype of rs16996652 had statistical significance. Risk factors identified in our study may provide a better understanding of the etiological role of MYH9 and influence of environmental factors in nonsyndromic orofacial cleft incidence.

Genetic Evidence for the Aggravation ofPlasmodium falciparumMalaria by Interleukin 4

Severe malaria (SM) due to Plasmodium falciparum causes millions of child deaths in sub-Saharan Africa. It comprises a variety of clinical disorders, including cerebral malaria (CM) and severe anemia (SA). In previous work, we have shown that interferon gamma and interleukin 12 protect against CM. Here, we investigated whether interleukin 4 (IL-4) aggravates the risk of severe disease. We prospectively recruited children with CM (n = 240), SA (n = 101), and uncomplicated malaria (UM) (n = 42) in Bamako, Mali, and measured IL-4 production in plasma by enzyme-linked immunosorbent assay. We then assessed the influence of 11 polymorphisms on predisposition to SM by the family-based association test (FBAT). IL-4 concentrations were higher in children with CM than in children with UM during malaria (P = .003). FBAT analyses showed that the most significant association was between the IL4 variable-number tandem repeat (VNTR) 1/2 genotype and SM (P < .001); an association was also observed for IL4 -33 C/T, rs2243267 G/C, rs2243268 C/A, and rs2243282 C/A (P < .05). Interestingly, we found that the plasma concentration of IL-4 was higher in subjects with the IL4 VNTR 1/2 or 1/1 genotype than with the IL4 VNTR 2/2 genotype (P = .003). These results support the view that IL-4 may be a risk factor for SM. IL-4 may aggravate the disease by interfering with type 1 T helper cell differentiation or by promoting local inflammation at sites of parasite sequestration.

Association of SLC6A4 variants with obsessive-compulsive disorder in a large multicenter US family study

Genetic association studies of SLC6A4 (SERT) and OCD have been equivocal. We genotyped 1 241 persons in 278 pedigrees from the OCD Collaborative Genetics Study for 13 SNPs, the LPR indel with molecular haplotypes at rs25531, VNTR polymorphisms in introns 2 and 7, and a 381-bp deletion 3’ to the LPR. We analyzed using the Family Based Association Test (FBAT) under additive, dominant, recessive, and genotypic models, using both OCD and sex-stratified OCD as phenotype.Two-point FBAT analysis detected association with Int2 (p= 0.0089) and Int7 (p= 0.0187) (genotypic model). Sex-stratified 2-point analysis showed strong association in females with Int2 (p< 0.0002), significant after correction for LD, multiple marker- and model testing (pAdj= 0.0069). The SLC6A4 gene is composed of two haplotype blocks (our data and the HapMap); FBAT whole-marker analysis using this structure was not significant.Several noteworthy non-significant results emerged. We found no evidence for over-transmission of the LPR LA allele (GRR= 1.11, 95% CI: 0.77–1.60) (see Hu et al.1), however rare individual haplotypes containing LA with p<0.05 were observed. Similarly, 3 individuals (2 with OCD/OCPD) carried the rare I425V SLC6A4 variant- but none passed it on to their 6 OCD-affected offspring, suggesting it is unlikely solely responsible for the “OCD plus syndrome” (see Ozaki et al.2).In conclusion, we found evidence of genetic association at the SLC6A4 locus with OCD. Noteworthy lack of association at the LPR, LPR-rs25531, and rare 425V variants suggests hypotheses about OCD risk need revision to accommodate these new findings, including a possible gender effect.

Family-based analysis of apelin and AGTRL1 gene polymorphisms with hypertension in Han Chinese

Apelin and AGTRL1 (angiotensin receptor-like 1), elements of a newly identified pathway with a role in counter regulating the renin-angiotensin system, have been implicated in blood pressure regulation. This study aims to assess whether the apelin and AGTRL1 genetic polymorphisms might contribute to essential hypertension or its related phenotypes. We recruited 1015 Han Chinese from 248 families with essential hypertension. Each individual was genotyped for 6 single nucleotide polymorphisms (SNPs) in apelin and 6 SNPs in AGTRL1. Data were analyzed using the family-based association test (FBAT) and the haplotype-based association test (HBAT). FBAT analysis showed that two SNPs rs3761581 and T-1860C within apelin conferred significant association with hypertension and its related phenotypes even after correcting for age and gender. Three SNPs (rs7119375, rs10501367 and rs9943582) within AGTRL1 were found to be associated with hypertension, BMI and the onset age of hypertension, whereas after correction, only marginal associations were noted. Of the common haplotypes (with frequencies over 3%), haplotypes (A-T) and (C-C) comprising rs3761581 and T-1860C in apelin and haplotype (G-G) comprising rs10501367 and rs7119375 in AGTRL1 were shown to be significantly associated with hypertension, BMI and the onset age of hypertension, even after a permutation correction. Our study suggests that genetic variation within apelin and AGTRL1 likely contributes to essential hypertension, BMI and the onset age of hypertension. Future well designed epidemiological or functional studies would be warranted to validate this hypothesis.

Association of nasopharyngeal carcinoma risk with cytochrome P450 CYP1A1 gene polymorphisms

To investigate the association between CYP1A1 gene polymorphisms and susceptibility of nasopharyngeal carcinoma in Cantonese nuclear families through family-based association study. A total of 457 Cantonese nuclear families,consisting of 2134 members, were recruited as subjects. Each family included two parents and at least one offspring with nasopharyngeal carcinoma. Two single nucleotide polymorphisms (SNP) in CYP1A1 named m1 (rs4646903) and m2 (rs1048943), were genotyped by PCR-RFLP assay and verified by directly sequencing. The genotype data were analyzed with family-based association test (FBAT) software to check the linkage and association between the two genetic markers and susceptibility of nasopharyngeal carcinoma. FBAT analysis showed that the minor allele frequencies (MAF) of the two SNP were 0.442 (C) and 0.339 (G) respectively. For m1 polymorphism in CYP1A1 gene was not significantly associated with nasopharyngeal carcinoma in our study population whether stratified with VCA-IgA or not (without stratification: chi2 = 2.399, P = 0.301; with stratification: low-titer group (VCA-IgA <1:80), MAF = 0.457 (C), chi2 = 1.221, P = 0.543; high-titer group (VCA-IgA > or = 1:80), MAF = 0.427 (C), chi2 =2.832, P = 0.243) . For m2 polymorphism, when VCA-IgA <1:80, the G allele showed decreased transmission under additive and dominant model (MAF = 0.347 (G); Zadditive = -2.120, Padditive = 0.034; Zdominant = - 2.303, Pdominant = 0.021) and a boundary P value was got with global statistic (chi2 = 5.394, P = 0.067) . Haplotype TG (0.057), constructed by m1 and m2, might decrease nasopharyngeal carcinoma risk (Z= -2.002, P=0.045). A boundary P value was also got with global statistic (chi2 =7.067, P=0.070). There was no statistical significance between m1 polymorphism and susceptibility of nasopharyngeal carcinoma in Cantonese nuclear families. And this study showed that m2 polymorphism might associated with the decrease of nasopharyngeal carcinoma in Cantonese nuclear families.

Genetic evidence implicating multiple genes in the MET receptor tyrosine kinase pathway in autism spectrum disorder

A functional promoter variant of the gene encoding the MET receptor tyrosine kinase alters SP1 and SUB1 transcription factor binding, and is associated with autism spectrum disorder (ASD). Recent analyses of postmortem cerebral cortex from ASD patients revealed altered expression of MET protein and three transcripts encoding proteins that regulate MET signaling, hepatocyte growth factor (HGF), urokinase plasminogen activator receptor (PLAUR) and plasminogen activator inhibitor-1 (SERPINE1). To address potential risk conferred by multiple genes in the MET signaling pathway, we screened all exons and 5' promoter regions for variants in the five genes encoding proteins that regulate MET expression and activity. Identified variants were genotyped in 664 families (2,712 individuals including 1,228 with ASD) and 312 unrelated controls. Replicating our initial findings, family-based association test (FBAT) analyses demonstrated that the MET promoter variant rs1858830 C allele was associated with ASD in 101 new families (P=0.033). Two other genes in the MET signaling pathway also may confer risk. A haplotype of the SERPINE1 gene exhibited significant association. In addition, the PLAUR promoter variant rs344781 T allele was associated with ASD by both FBAT (P=0.006) and case-control analyses (P=0.007). The PLAUR promoter rs344781 relative risk was 1.93 (95% confidence interval [CI]: 1.12-3.31) for genotype TT and 2.42 (95% CI: 1.38-4.25) for genotype CT compared to genotype CC. Gene-gene interaction analyses suggested a significant interaction between MET and PLAUR. These data further support our hypothesis that genetic susceptibility impacting multiple components of the MET signaling pathway contributes to ASD risk.

Evidence for linkage of a new region (11p14) to eczema and allergic diseases.

Asthma, allergic rhinitis (AR) and atopic dermatitis also called eczema are allergic co-morbidites, which are likely to depend on pleiotropic genetic effects as well as on specific genetic factors. After a previous genome-wide linkage screen conducted for asthma and AR in a sample of 295 French EGEA families ascertained through asthmatic subjects, the aim here was to search for genetic factors involved in eczema and more particularly the ones shared by the three allergic diseases using the same EGEA data. In this sake, eczema and phenotypes of "allergic disease" accounting for the joint information on the presence/absence of the three diseases were examined by linkage analyses using the maximum likelihood binomial method. A fine mapping was carried out in regions detected for potential linkage, followed by association studies using the family-based association test (FBAT). Evidence for linkage to 11p14 region was shown for "allergic disease" and eczema. Linkage was also indicated between eczema and 5q13 and between "allergic disease" and both 5p15 and 17q21 regions. Fine mapping supported the evidence of linkage to 11p14 and FBAT analyses showed the association between "allergic disease" and a marker located at the linkage peak on 11p14. Further investigations in this region will allow identifying genetic factor(s) which could have pleiotropic effect in the three allergic diseases.

Weighted variance FBAT: a powerful method for including covariates in FBAT analyses

The family-based association test (FBAT), an extension of transmission/disequilibrium test, capitalizes on linkage disequilibrium to assess the association of genetic markers and traits in nuclear families. It does not permit a formal inclusion of covariates, although an offset under the FBAT -o option allows for an overall trait-intercept adjustment. The PBAT software provides additional features and permits the inclusion of covariates in the FBAT test statistic, but does not account for the parental genotype information when the traits are adjusted for the covariates. We propose the weighted variance FBAT (WVF) method to generate trait values adjusted for both parental genotypes and covariate values. WVF is expected to be more powerful, because the variance is minimized considering both of these factors simultaneously using a weighted Gauss-Newton algorithm. Two simulated parent/child trio data sets, both with a covariate and the second with a gene by covariate interaction, were simulated to compare WVF power with FBAT and PBAT for a quantitative trait. WVF is most powerful when levels of significance are greater and covariates have a larger influence, indicating WVF may be especially effective when multiple comparisons are an important consideration, such as with whole genome association studies. WVF will also improve the cost of an association study when environmental covariates are considered. A SAS program (www.SAS.com) for generating WVF residuals that can be input to the current versions of the FBAT (www.biostat.harvard.edu/fbat/fbat.html) and PBAT (www.biostat.harvard.edu/clange/default.htm) software is provided.

Influence of polymorphisms at loci encoding DNA repair proteins on cancer susceptibility and G2chromosomal radiosensitivity

Sixteen candidate polymorphisms (13 SNPs and 3 microsatellites) in nine genes from four DNA repair pathways were examined in 83 subjects, comprising 23 survivors of childhood cancer, their 23 partners, and 37 offspring, all of whom had previously been studied for G(2) chromosomal radiosensitivity. Genotype at the Asp148Glu SNP site in the APEX gene of the base excision repair (BER) pathway was associated with childhood cancer in survivors (P = 0.001, significant even after multiple test adjustment), due to the enhanced frequency of the APEX Asp148 allele among survivors in comparison to that of their partners. Analysis of variance (ANOVA) of G(2) radiosensitivity in the pooled sample, as well as family-based association test (FBAT) of the family-wise data, showed sporadic suggestions of associations between G(2) radiosensitivity and polymorphisms at two sites (the Thr241Met SNP site in the XRCC3 gene of the homologous recombinational pathway by ANOVA, and the Ser326Cys site in the hOGG1 gene of the BER pathway by FBAT analysis), but neither of these remained significant after multiple-test adjustment. This pilot study provides an intriguing indication that DNA repair gene polymorphisms may underlie cancer susceptibility and variation in radiosensitivity.

Genome-wide scan for visceral leishmaniasis susceptibility genes in Brazil

A genome-wide scan was conducted for visceral leishmaniasis (VL) in Brazil. Initially, 405 markers were typed in 22 multicase pedigrees (28 nuclear families; 174 individuals; 66 affected). Non-parametric multipoint analysis detected nine chromosomal regions with provisional evidence (logarithm of the odds (LOD) scores 0.95-1.66; 0.003<P<0.018) for linkage. To confirm linkage, 132 individuals (43 affected) from 19 independently ascertained families were genotyped across these regions. Three regions (6q27, 7q11.22 and 17q11.2-q21.3) retained evidence (LOD scores 1.08, 1.34, 1.14; P=0.013, 0.007, 0.011) for linkage. To determine which genes contribute to linkage at 17q11.2-q21.3, 80 single nucleotide polymorphisms were genotyped in 98 nuclear families with 183 affected individuals. Family-based association test analysis indicated associations at two chemokine genes, CCL1 and CCL16, that lie 1.6 Mb apart, show some extended linkage disequilibrium with each other, but each lie within different clusters of candidate CCL genes. Multiple genes may therefore contribute to the linkage peak for VL at 17q12.

IL6−174 G/C Promoter Polymorphism Influences Susceptibility to Mucosal but Not Localized Cutaneous Leishmaniasis in Brazil

Mucosal leishmaniasis (ML) is associated with exaggerated tumor necrosis factor- alpha and interferon- gamma responses and tissue destruction. ML follows localized cutaneous leishmaniasis (CL) caused by Leishmania braziliensis infection. Interleukin (IL)-6 down-regulates T helper (Th) cell type 1 differentiation and drives Th2 cell differentiation. The IL6 -174 G/C polymorphism is associated with proinflammatory diseases and IL-6 regulation. The -174 G/C polymorphism was genotyped in population samples and families with CL and ML from Brazil. Genotype frequencies were compared among patients with ML, patients with CL, and 2 control groups by logistic regression and family-based association test (FBAT) analysis. IL-6 levels were measured in macrophages. The C allele was more common in patients with ML than in patients with CL (odds ratio [OR], 2.55 [95% confidence interval {CI}, 1.32-4.91]; P=.005), than in patients who were leishmanin skin-test positive (OR, 2.23 [95% CI, 1.23-4.05]; P=.009), and than in neighborhood control subjects (OR, 2.47 [95% CI, 1.24-4.90]; P=.01). FBAT analysis confirmed an association between allele C and ML under both additive (z=4.295; P=.000017) and dominant (z=4.325; P=.000015) models. Significantly lower levels of IL-6 were measured in unstimulated macrophages from CC individuals than from GG individuals (P=.003) as well as after stimulation with soluble leishmania antigen (P=.009). IL-6 may regulate type 1 proinflammatory responses, putting individuals with low macrophage IL-6 levels at increased risk for ML.

Association analyses of CYP19 gene polymorphisms with height variation in a large sample of Caucasian nuclear families

Human height is a complex trait regulated by multiple genetic and environmental factors. CYP19 (cytochrome P450 19) encodes aromatase, which catalyses the rate-limiting step in the conversion of androgens to estrogens. Deleterious mutations in CYP19 can result in estrogen deficiency that will influence adult height to certain extent. In the present study, we aimed to test the associations between the CYP19 gene polymorphisms with adult height variation, using family-based association methods, such as QTDT (quantitative transmission disequilibrium test) and FBAT (family-based association test) in 1,873 subjects from 405 Caucasian nuclear families. We found one SNP (rs730154) significantly associated with height by both QTDT (P=0.0030) and FBAT (P=0.0016) analyses. Haplotype analyses corroborated our single-marker results by showing that the haplotypes in block 4 containing rs730154 were significantly associated with height variation. We thus concluded that CYP19 could be one of the genetic factors influencing adult height in Caucasians. Further studies are required to identify the causal functional variants responsible for Caucasian height within the CYP19 gene.

Family-Based Association Tests Suggest Linkage Between Surfactant Protein B (SP-B) (and Flanking Region) and Respiratory Distress Syndrome (RDS): SP-B Haplotypes and Alleles From SP-B–Linked Loci Are Risk Factors for RDS

Genetic variants of surfactant protein B (SP-B) have been associated with respiratory distress syndrome (RDS) in the prematurely born infant. We wished to determine linkage between RDS and SP-B single nucleotide polymorphisms (SNPs) [-18 (A/C), 1013 (A/C), 1580 (C/T), and 9306 (A/G)] or SP-B-linked microsatellite [(D2S388, D2S2232, (AAGG)n, and GATA41E01 (or D2S1331)] loci and identify susceptibility or protective alleles and haplotypes. We genotyped 132 families consisting of one or two parents and at least one child affected with RDS and performed biallelic and multiallelic family-based association test (FBAT) analysis, and extended transmission disequilibrium test (ETDT). ETDT analysis identified the microsatellite SP-B-linked loci (except D2S2232) to be linked to RDS. One allele from each of these three marker loci contributes to the risk of RDS. Multiallelic FBAT analysis detected a signal of linkage for the region of the four SNP loci. Three haplotypes within this region contribute to RDS risk. Although no other region showed significant linkage as judged by multiallelic FBAT, biallelic FBAT analysis revealed three potential susceptibility haplotypes formed by two to four loci within the SP-B and SP-B-linked microsatellite region. Each haplotype included GATA41E01, which was identified by ETDT analysis to be linked to RDS. We conclude that SP-B or SP-B-linked loci are linked to RDS and certain alleles or haplotypes are susceptibility or protective factors for the development of RDS in infants born prematurely.