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1.  Identification of modifier genes for cutaneous malignant melanoma in melanoma-prone families with and without CDKN2A mutations 
CDKN2A is a major susceptibility gene for cutaneous malignant melanoma (CMM) but the variable penetrance and clinical manifestations among mutation carriers suggest the existence of modifier factors. The goal of this study was to identify modifier genes for CMM in CMM-prone families with or without CDKN2A mutations. We genotyped 537 individuals (107 CMM) from 28 families (19 CDKN2A+, 9 CDKN2A−) for 1536 SNPs in 152 genes involved in DNA repair, apoptosis, and immune response pathways. We used conditional logistic regression to account for family ascertainment and differences in disease prevalence among families. Pathway- and gene-based permutation analyses were used to assess the risk of CMM associated with genes in the five pathways (DNA repair, apoptosis, TNF/NFκB, TH1:TH2, and other immune regulation). Our analyses identified some candidate genes such as FAS, BCL7A, CASP14, TRAF6, WRN, IL9, IL10RB, TNFSF8, TNFRSF9, and JAK3 that were associated with CMM risk (P<0.01, gene-based test). After correction for multiple comparisons, IL9 remained significant (Bonferroni P<0.05). The effects of some genes were stronger in CDKN2A-positive families (BCL7A and IL9), while some were stronger in CDKN2A-negative families (BCL2L1). Our findings support the hypothesis that common genetic polymorphisms in DNA repair, apoptosis, and immune response pathways may modify the risk of CMM in CMM-prone families with or without CDKN2A mutations.
PMCID: PMC2767393  PMID: 19626699
modifier gene; cutaneous malignant melanoma; high-risk family; CDKN2A; pathway
Human immunology  2009;70(11):910-914.
Association between specific human leukocyte antigens (HLA) alleles and NPC have been reported for sporadic NPC but studies of familial NPC are lacking. We evaluated this association with familial NPC in a study of 301 NPC cases and 1010 family and community controls from Taiwan. Class I HLA alleles were characterized using a sequence-based typing protocol. Allele frequencies between case and control groups were compared by chi-square or exact tests. For alleles associated with NPC, odds ratios (OR) and 95% confidence intervals (CI) were calculated. Similar allelic frequency distribution and HLA associations were found as those previously reported for sporadic NPC: protective effect for HLA-A*1101 and increased risk for HLA-A*0207, HLA-A*3303, HLA-B*3802, and HLA-B*5801. Overall, the magnitude of observed associations was weakest when cases were compared to sibling controls and strongest when compared to unrelated community controls. Evaluating the joint effect of HLAA*0207 and HLA-B*4601, individuals who were carriers of HLA-A*0207 with or without the presence of HLA-B*4601 had a 1.9-fold (95% CI = 1.0-3.4) and 2.1-fold (95% CI = 0.83-5.3) risk of NPC, respectively. Conversely, carriers of HLA-B*4601 in the absence of HLA-A*0207 had a 50% reduction in NPC risk (95% CI = 0.27-0.93). Comparable findings from our family study and those from previous sporadic studies were found with the notable exception of a lack of positive association between HLA-B*4601 and familial NPC in the absence of HLA-A*0207. This finding requires replication in larger studies.
PMCID: PMC2764811  PMID: 19683024
Human leukocyte antigens; nasopharyngeal carcinoma; epidemiology; genetics
3.  Identification of susceptibility loci for complex diseases in a case-control association study using the Genetic Analysis Workshop 14 dataset 
BMC Genetics  2005;6(Suppl 1):S102.
Although current methods in genetic epidemiology have been extremely successful in identifying genetic loci responsible for Mendelian traits, most common diseases do not follow simple Mendelian modes of inheritance. It is important to consider how our current methodologies function in the realm of complex diseases. The aim of this study was to determine the ability of conventional association methods to fine map a locus of interest. Six study populations were selected from 10 replicates (New York) from the Genetic Analysis Workshop 14 simulated dataset and analyzed for association between the disease trait and locus D2. Genotypes from 45 single-nucleotide polymorphisms in the telomeric region of chromosome 3 were analyzed by Pearson's chi-square tests for independence to test for association with the disease trait of interest. A significant association was detected within the region; however, it was found 3 cM from the documented location of the D2 disease locus. This result was most likely due to the method used for data simulation. In general, this study showed that conventional case-control association methods could detect disease loci responsible for the development of complex traits.
PMCID: PMC1866837  PMID: 16451558
4.  Linkage analysis of the GAW14 simulated dataset with microsatellite and single-nucleotide polymorphism markers in large pedigrees 
BMC Genetics  2005;6(Suppl 1):S14.
Recent studies have suggested that a high-density single nucleotide polymorphism (SNP) marker set could provide equivalent or even superior information compared with currently used microsatellite (STR) marker sets for gene mapping by linkage. The focus of this study was to compare results obtained from linkage analyses involving extended pedigrees with STR and single-nucleotide polymorphism (SNP) marker sets. We also wanted to compare the performance of current linkage programs in the presence of high marker density and extended pedigree structures. One replicate of the Genetic Analysis Workshop 14 (GAW14) simulated extended pedigrees (n = 50) from New York City was analyzed to identify the major gene D2. Four marker sets with varying information content and density on chromosome 3 (STR [7.5 cM]; SNP [3 cM, 1 cM, 0.3 cM]) were analyzed to detect two traits, the original affection status, and a redefined trait more closely correlated with D2. Multipoint parametric and nonparametric linkage analyses (NPL) were performed using programs GENEHUNTER, MERLIN, SIMWALK2, and S.A.G.E. SIBPAL. Our results suggested that the densest SNP map (0.3 cM) had the greatest power to detect linkage for the original trait (genetic heterogeneity), with the highest LOD score/NPL score and mapping precision. However, no significant improvement in linkage signals was observed with the densest SNP map compared with STR or SNP-1 cM maps for the redefined affection status (genetic homogeneity), possibly due to the extremely high information contents for all maps. Finally, our results suggested that each linkage program had limitations in handling the large, complex pedigrees as well as a high-density SNP marker set.
PMCID: PMC1866796  PMID: 16451599
5.  Genomic regions linked to alcohol consumption in the Framingham Heart Study 
BMC Genetics  2003;4(Suppl 1):S101.
Pedigree, demographic, square-root transformed maximum alcohol (SRMAXAPD) and maximum cigarette (MAXCPD) consumption, and genome-wide scan data from the Framingham Heart Study (FHS) were used to investigate genetic factors that may affect alcohol and cigarette consumption in this population-based sample.
A significant sister:sister correlation greater than spouse correlation was observed for MAXCPD only. Single-point sib-pair regression analysis provided nominal evidence for linkage of loci to both SRMAXAPD and MAXCPD consumption traits, with more significant evidence of linkage to SRMAXAPD than to MAXCPD. One genomic region, chr9q21.11, exhibits significant multi-point sib-pair regression to SRMAXAPD.
SRMAXAPD exhibits greater evidence for genetic linkage than does MAXCPD in the FHS sample. Four regions of the genome exhibiting nominal evidence for linkage to SRMAXAPD in the FHS sample correspond to regions of the genome previously identified as linked to alcoholism or related traits in the family data set ascertained on individuals affected with alcohol dependence known as COGA.
PMCID: PMC1866439  PMID: 14975169

Results 1-5 (5)