Prostate Cancer Susceptibility Loci Research Articles

Association between sequence variants at 17q12 and 17q24.3 and prostate cancer risk in European and African Americans

Three SNPs at 17q12 and four SNPs at 17q24.3 were recently identified to be associated with prostate cancer risk using a genome-wide association study. We evaluated these 7 SNPs in two hospital-based case-control study populations, including European Americans (EA; 1,563 cases and 576 controls) and African Americans (AA; 364 cases and 353 controls). Each of the reported risk alleles of these seven SNPs were more common in cases than in controls among EA and AA. The differences were highly significant in EA (P = 10(-4)) and marginally significant in AA (P = 0.04) for SNPs at 17q12. In contrast, the differences were not statistically significant in EA or AA for SNPs at 17q24.3, but were marginally significant for two SNPs (P = 0.04-0.06) when EA and AA subjects were combined. Similar results were obtained when genotype and haplotype frequencies between cases and controls were analyzed. These risk variants were not associated with more aggressive prostate cancer or other clinical variables such as TNM stage, pre-operative PSA, or age at diagnosis. Results from our study provide the first confirmation of these 17q SNPs as novel prostate cancer susceptibility loci in EA and the first indication that these two loci may also play roles in prostate cancer risk among AA.

Chromosome 8q24 risk variants in hereditary and non‐hereditary prostate cancer patients

Multiple variants in three regions at 8q24 are consistently found to be associated with prostate cancer (PCa) risk in population-based association studies. The role that these variants may play in familial prostate cancer risk has not been extensively investigated. We evaluated 12 SNPs at three 8q24 regions using population-based association and family-based linkage and association methods in hereditary PCa (HPC) probands and their families, non-HPC patients, and unaffected screened controls, all recruited at Johns Hopkins Hospital. For multiple variants in Region 1 (e.g., rs1447295) and Region 2 (e.g., rs16901979), we found statistically significantly higher frequencies of previously identified risk alleles and genotypes in HPC probands than in unaffected controls. Furthermore, in Region 2 the risk alleles were statistically significantly more frequent in HPC probands than in non-HPC patients. Family-based transmission tests found risk alleles of SNPs in Region 2, but not in Regions 1 and 3, were significantly over-transmitted to affected men in these families. We found little evidence supporting PCa linkage at 8q24 in 168 HPC families, in part explained by the observation of multiple, different risk allele-containing haplotypes segregating in the vast majority of these families. Our study further supports the presence of PCa susceptibility loci at 8q24, particular at Region 2, and also provides evidence that these SNPs play an important role in familial prostate cancer. Large family-based studies are needed to confirm our novel findings.

The role of genetic variation in Toll-like receptor 4 in prostate cancer susceptibility: a review

Toll-like receptor 4 (TLR4) is a key innate immunity receptor that initiates an inflammatory response against invading pathogens. Recent association studies have identified genetic variants in TLR4 that appear to influence the risk of prostate cancer. To evaluate critically whether genetic variation in TLR4 influences prostate cancer susceptibility, a systematic review of the literature on TLR4 and prostate cancer is done. All genetic association studies of TLR4 and prostate cancer are evaluated. In particular, issues related to genetic coverage, study heterogeneity and multiple hypothesis testing are examined. Although all three of the published studies suggest that the TLR4 locus itself is associated with prostate cancer, there is no corroboratory evidence for which specific variants influence the risk of disease. Clearly, these studies alone cannot establish TLR4 as a prostate cancer susceptibility locus. By evaluating candidate genes such as TLR4 further in conjunction with other variants identified by genome-wide association studies of prostate cancer, we shall be better poised to develop the appropriate panel of markers to improve prevention and diagnosis.

8q24 and prostate cancer: association with advanced disease and meta-analysis

Compelling evidence demonstrates chromosome 8q24 as a prostate cancer susceptibility locus. Multiple variants within three adjacent regions at 8q24 have recently been identified to impact the risk of prostate cancer. Yet, the role of these variants in more advanced disease has not been rigorously assessed. To examine the relationship between 8q24 variants and advanced disease, we tested 10 previously associated 8q24 variants in a case-control study of advanced prostate cancer (N=1012). Of these ten 8q24 variants, six were associated with the risk of advanced prostate cancer (P=0.001-0.038). Three of these variants (rs10090154-region 1, rs16901979-region 2, and rs6983267-region 3), each variant residing in one of the three previously reported 8q24 regions, could account for our 8q24 effects on advanced disease. A meta-analysis across 10 studies including our results of four 8q24 variants (rs1442295 and DG8S737-region 1, rs16901979-region 2, and rs6983267-region 3) and prostate cancer risk demonstrated strong associations across a wide array of study designs and populations. Our findings provide the first confirmation that the three 8q24 regions independently influence the risk of prostate cancer and, in particular, advanced disease.

Molecular evolution of the prostate cancer susceptibility locus RNASEL: Evidence for positive selection

Recent research implicates viral infection as a factor that may contribute to the risk of prostate cancer. Allelic variation at the RNASEL locus is associated with the risk of infection by a newly discovered retrovirus called XMRV, and with hereditary risk of prostate cancer. This evidence suggests that the RNASEL locus has undergone antagonistic coevolution with the retrovirus over evolutionary time. If this is the case, then both the RNASEL locus and the retrovirus should show evidence of positive selection. Here we use molecular-evolutionary methods to investigate the prediction that the RNASEL locus will exhibit evidence of positive selection. We find evidence that positive selection has acted on this locus over evolutionary time. We further find, using a Bayesian estimation procedure, that Asp541Glu, which was found to be associated with prostate cancer risk in Caucasians in a recent meta-analysis, shows an elevated probability of positive selection. Previous studies provide evidence for rapid evolution of the infection-mediating gag gene in the XMRV retrovirus. Taken together, these results suggest that antagonistic coevolution may have occurred between a specific host locus involved in immune defense ( RNASEL) and a viral pathogen. In turn, genetic variation associated with this apparent coevolution may influence susceptibility to prostate cancer.

Higher Frequency of Familial Clustering of Prostate Cancer in French-Canadian Men

Prostate cancer is the second cause of cancer related death in North American men. We investigated the frequency of familial clustering in a French-Canadian population of prostate cancer cases. Between October 2004 and September 2005, 179 consecutively seen patients with localized prostate cancer identified each of their parents as being of French-Canadian descent. They were asked for their family history of cancer in first-degree relatives, age at diagnosis, whether affected relatives were alive, age and markers of tumor aggressiveness, including prostate specific antigen, Gleason and disease stage. ANOVA was used to compare the distribution of quantitative factors according to qualitative factors identified in our population. Differences between qualitative factors were assessed by the Fisher exact test. All p values were 2-sided. Mean age at diagnosis was 67 years. A total of 45 French-Canadian patients (25.1%) had at least 1 first-degree relative with prostate cancer, including 34 (19%) with 1 first-degree relative, 9 with a father-son pair, 25 with a brother-brother pair and 11 (6.1%) with at least 2 first-degree relatives. In our series the frequency of familial clustering defined by at least 1 relative with prostate cancer was high. We found a higher percent of French-Canadian men with at least 1 first-degree relative with prostate cancer than what was previously reported for an unselected population in Canada (25.1% vs 14.7%, p <0.0001). Those preliminary results open a new perspective to a better understanding of familial prostate cancer in the Province of Quebec.

Confirmation of a Positive Association between Prostate Cancer Risk and a Locus at Chromosome 8q24

Family-based linkage studies, association studies, and studies of tumors have highlighted human chromosome 8q as a genomic region of interest for prostate cancer susceptibility loci. Recently, a locus at 8q24, characterized by both a single nucleotide polymorphism (SNP) and a microsatellite marker, was shown to be associated with prostate cancer risk in Icelandic, Swedish, and U.S. samples. Although the data were provocative, the U.S. samples were not population based, which precludes assessment of the potential contribution of this locus to prostate cancer incidence in the United States. We analyzed both markers in a population-based, case-control study of middle-aged men from King County, Washington. Overall, there was a significant positive association between the A allele of the SNP rs1447295 and prostate cancer risk [odds ratio, 1.4; 95% confidence interval (95% CI), 1.1-2.0] but no significant association with the microsatellite DG8S737. However, significant associations were observed for both markers in men with high Gleason scores. Adjusting for age, first-degree family history of prostate cancer, and prostate cancer screening history, the adjusted odds ratios were 1.4 (95% CI, 1.1-1.8) for the A allele of the SNP and 1.9 (95% CI, 1.2-2.8) for the -10 allele of the microsatellite. These data suggest that the locus on chromosome 8q24 harbors a genetic variant associated with prostate cancer and that the microsatellite marker is a stronger risk factor for aggressive prostate cancers defined by poorly differentiated tumor morphology.

ICAM gene cluster SNPs and prostate cancer risk in African Americans

Intercellular adhesion molecules (ICAMs) are known to be involved in various human cancers. An ICAM gene cluster lying within a 26 kb region on chromosome 19p13.2, and containing ICAM1, ICAM4, and ICAM5 has recently been identified as harboring a breast and prostate cancer susceptibility locus in two populations of European ancestry from Germany and Australia. The objective of this study was to confirm the ICAM association with prostate cancer in a sample of African American prostate cancer cases (N = 286) and controls (N = 391). Six single nucleotide polymorphisms (SNPs) within the three ICAM genes were genotyped. To control for potential population stratification an ancestry-adjusted association analysis was performed. We found that ICAM1 SNPs, -9A/C (rs5490) and K469E (rs5498) were associated with prostate cancer risk in men with a family history of prostate cancer (P = 0.008). Specifically, increased risk was observed for individuals who possessed the CC genotype of the -9 A/C variant (odds ratio = 2.5; 95% CI = 1.0-6.3) and at least one G allele of non-synonymous K469E variant (odds ratio = 1.8; 95% CI = 1.2-3.1). Strong linkage disequilibrium was observed across the ICAM region (P < 0.001). A common haplotype within the ICAM gene cluster, harboring the -9A/C variant was significantly associated with prostate cancer (P = 0.03), mainly due to men with family history (P = 0.01). Our results replicate previous findings of association of the ICAM gene cluster with prostate cancer and suggest that common genetic variation within ICAM1 and not ICAM5 may be an important risk factor for prostate cancer.

Prohibitin mutations are uncommon in prostate cancer families linked to chromosome 17q

Linkage studies have provided evidence for a prostate cancer susceptibility locus on chromosome 17q. The mitochondrial protein prohibitin (PHB) is a plausible candidate gene based on its chromosomal location (17q21) and known function. All coding regions and intron/exon junctions of the PHB gene were sequenced in 32 men from families participating in the University of Michigan Prostate Cancer Genetics Project that demonstrated evidence of linkage to 17q markers. Although a number of nucleotide variants were identified, no coding region substitutions were identified in any of the 32 men with prostate cancer from 32 unrelated multiplex prostate cancer families. PHB mutations do not appear to account for the linkage signal on 17q21-22 detected in PCGP families. Fine mapping of this region is in progress to refine the candidate region and highlight additional candidate prostate cancer susceptibility genes for sequence analysis.

Polymorphisms in the ICAM Gene Locus are not Associated with Breast Cancer Risk

In a recent case-control study which examined >25,000 single nucleotide polymorphisms (SNP), the intercellular adhesion molecule (ICAM) locus was proposed as a susceptibility locus for breast and prostate cancer ([1][1]). The genes ICAM1, ICAM4 , and ICAM5 are all located within a 20 kb region of

HIGHLIGHTS FROM THE SOCIETY OF UROLOGIC ONCOLOGY, 5TH ANNUAL MEETING, DECEMBER 3–4, 2004, BETHESDA, MARYLAND, UNITED STATES OF AMERICA

The fifth annual meeting of the Society of Urologic Oncology was held December 3 and 4, 2004 in Bethesda, Maryland. The program provides a forum for the discussion of important issues in genitourinary malignancies among urologists, radiation oncologists and medical oncologists. Agenda topics included kidney cancer, bladder cancer and prostate cancer. Several sessions featured new developments in basic, translational and clinical research. Each session was reviewed for content following the meeting and the highlights were summarized. The Young Urologic Oncologists' Forum was again a successful component of the meeting but it is beyond the scope of this summary. Sessions on kidney cancer focused on molecular genetics and advances in molecular therapeutics. Radio frequency ablation of renal masses was also addressed. Topics discussed in bladder cancer included screening and surgical management. Dr. Donald Skinner received the Huggins Medal and he addressed the society on the management of invasive bladder cancer. Reviewed session topics in prostate cancer included neoadjuvant treatment paradigms, radiation treatment and adjuvant therapy in patients in whom primary treatment has failed. A state-of-the-art lecture addressed hereditary prostate cancer. The Society of Urologic Oncology meeting is unique in its multidisciplinary forum and focus on urological oncology. The meeting this year highlighted emerging trends, and the current state-of-the-art in kidney, bladder and prostate cancer. Additional focus was given to new molecular based diagnostic and therapeutic strategies for genitourinary malignancies.

Chromosomal Instability in Peripheral Blood Lymphocytes and Risk of Prostate Cancer

Prostate cancer is an extremely complex disease, and it is likely that chromosomal instability is involved in the genetic mechanism of tumorigenesis. Several chromosomes have been labeled as "players" in the development of prostate cancer, among them chromosome 1 and X chromosome have been reported to harbor prostate cancer susceptibility loci. However, there is little information regarding the background levels of chromosome instability in these patients. In this pilot study, we examined spontaneous chromosome instability in short-term lymphocyte cultures from 126 study subjects, 61 prostate cancer patients, and 65 healthy controls. We evaluated chromosomal instability using a fluorescence in situ hybridization assay using two probes targeting specific regions on X chromosome and chromosome 1. Our results showed a significantly higher mean level of spontaneous breaks involving the X chromosome in patients compared with controls (mean +/- SE, 2.41 +/- 0.26 and 0.62 +/- 0.08, respectively; P < 0.001). Similarly, chromosome 1 spontaneous breaks were significantly higher among cases compared with controls (mean +/- SE, 1.95 +/- 0.24 and 1.09 +/- 0.16, respectively; P < 0.001). Using the median number of breaks in the controls as the cutoff value, we observed an odds ratio (95% confidence interval) of 15.53 (5.74 - 42.03; P < 0.001) for spontaneous X chromosome breaks and 3.71 (1.60 - 8.63; P < 0.001) for chromosome 1 breaks and risk of development of prostate cancer. In conclusion, our preliminary results show that spontaneous chromosome instability could be a risk factor for prostate cancer.

Confirmation of the HPCX prostate cancer predisposition locus in large Utah prostate cancer pedigrees

Several genetic predisposition loci for prostate cancer have been identified through linkage analysis, and it is now generally recognized that no single gene is responsible for more than a small proportion of prostate cancers. However, published confirmations of these loci have been few, and failures to confirm have been frequent. The genetic etiology of prostate cancer is clearly complex and includes significant genetic heterogeneity, phenocopies, and reduced penetrance. Powerful analyses that involve robust statistics and methods to reduce genetic heterogeneity are therefore necessary. We have performed linkage analysis on 143 Utah pedigrees for the previously published Xq27-28 (HPCX) prostate cancer susceptibility locus. We employed a robust multipoint statistic (TLOD) and a novel splitting algorithm to reduce intra-familial heterogeneity by iteratively removing the top generation from the large Utah pedigrees. In a dataset containing pedigrees having no more than five generations, we observed a multipoint TLOD of 2.74 (P=0.0002), which is statistically significant after correction for multiple testing. For both the full-structure pedigrees (up to seven generations) and the smaller sub-pedigrees, the linkage evidence was much reduced. This study thus represents the first significant confirmation of HPCX (Xq27-28) and argues for the continued utility of large pedigrees in linkage analyses for complex diseases.

Comparison of Microsatellites Versus Single-Nucleotide Polymorphisms in a Genome Linkage Screen for Prostate Cancer–Susceptibility Loci

Prostate cancer is one of the most common cancers among men and has long been recognized to occur in familial clusters. Brothers and sons of affected men have a 2-3-fold increased risk of developing prostate cancer. However, identification of genetic susceptibility loci for prostate cancer has been extremely difficult. Although the suggestion of linkage has been reported for many chromosomes, the most promising regions have been difficult to replicate. In this study, we compare genome linkage scans using microsatellites with those using single-nucleotide polymorphisms (SNPs), performed in 467 men with prostate cancer from 167 families. For the microsatellites, the ABI Prism Linkage Mapping Set version 2, with 402 microsatellite markers, was used, and, for the SNPs, the Early Access Affymetrix Mapping 10K array was used. Our results show that the presence of linkage disequilibrium (LD) among SNPs can lead to inflated LOD scores, and this seems to be an artifact due to the assumption of linkage equilibrium that is required by the current genetic-linkage software. After excluding SNPs with high LD, we found a number of new LOD-score peaks with values of at least 2.0 that were not found by the microsatellite markers: chromosome 8, with a maximum model-free LOD score of 2.2; chromosome 2, with a LOD score of 2.1; chromosome 6, with a LOD score of 4.2; and chromosome 12, with a LOD score of 3.9. The LOD scores for chromosomes 6 and 12 are difficult to interpret, because they occurred only at the extreme ends of the chromosomes. The greatest gain provided by the SNP markers was a large increase in the linkage information content, with an average information content of 61% for the SNPs, versus an average of 41% for the microsatellite markers. The strengths and weaknesses of microsatellite versus SNP markers are illustrated by the results of our genome linkage scans.

Identification of a prostate cancer susceptibility locus on chromosome 7q11-21 in Jewish families.

Results from over a dozen prostate cancer susceptibility genome-wide scans, encompassing some 1,500 hereditary prostate cancer families, indicate that prostate cancer is an extremely heterogeneous disease with multiple loci contributing to overall susceptibility. In an attempt to reduce locus heterogeneity, we performed a genomewide linkage scan for prostate cancer susceptibility genes with 36 Jewish families, which represent a stratification of hereditary prostate cancer families with potentially increased locus homogeneity. The 36 Jewish families represent a combined dataset of 17 Jewish families from the Fred Hutchinson Cancer Research Center-based Prostate Cancer Genetic Research Study dataset and 19 Ashkenazi Jewish families collected at Johns Hopkins University. All available family members, including 94 affected men, were genotyped at markers distributed across the genome with an average interval of <10 centimorgans. Nonparametric multipoint linkage analyses were the primary approach, although parametric analyses were performed as well. Our strongest signal was a significant linkage peak at 7q11-21, with a nonparametric linkage (NPL) score of 3.01 (P = 0.0013). Simulations indicated that this corresponds to a genomewide empirical P = 0.006. All other regions had NPL P values >/=0.02. After genotyping additional markers within the 7q11-21 peak, the NPL score increased to 3.35 (P = 0.0004) at D7S634 with an allele-sharing logarithm of odds of 3.12 (P = 0.00007). These studies highlight the utility of analyzing defined sets of families with a common origin for reducing locus heterogeneity problems associated with studying complex traits.

The complex genetic epidemiology of prostate cancer.

Prostate cancer is the most frequent cancer among men in most developed countries, yet little is known about its causes. Older age, African ancestry and a positive family history of prostate cancer have long been recognized as important risk factors. The evidence that genetics probably plays a critical role is based on a variety of study designs, including case-control, cohort, twin and family-based, all of which are reviewed in detail. The search for prostate cancer susceptibility genes by linkage studies offered early hope that finding genes would be as 'easy' as finding genes for breast cancer and colon cancer susceptibilities. However, this hope has been dampened by the difficulty of replicating promising regions of linkage. This review provides updates on recent developments, and a broad view of the disparate findings from different linkage studies. Early linkage results have provided targeted candidate regions for prostate cancer susceptibility loci, including HPC1 on chromosome 1q23-25, PCAP on chromosome 1q42-43, CAPB on chromosome 1p36, linkage to chromosome 8p22-23, HPC2 on chromosome 17p, HPC20 on chromosome 20q13, and HPCX on chromosome Xq27-28. These linkage findings lead to refined mapping and mutation screening of several strong candidate genes, including ELAC2, RNASEL and MSR1. Up to now, a total of 10 genome-wide linkage scans for prostate cancer susceptibility have been completed, and are reviewed. Furthermore, recent findings that Gleason's grade, a measure of aggressiveness of prostate cancer, is linked to several genomic regions are reviewed. Finally, the roles of environmental and dietary risk factors, and common genetic polymorphisms of genes likely to play a role in common forms of prostate cancer, are briefly discussed within in the context of searching for genes that influence prostate cancer risk.

Hereditary prostate cancer in African American families: linkage analysis using markers that map to five candidate susceptibility loci.

African American men have the highest incidence of prostate cancer in the world. Despite this statistic, linkage studies designed to localise prostate cancer susceptibility alleles have included primarily men of Caucasian descent. In this report, we performed a linkage analysis using 33 African American prostate cancer families from two independent research groups. In total, 126 individuals (including 89 men with prostate cancer) were genotyped using markers that map to five prostate cancer susceptibility loci, namely HPC1 at 1q24–25, PCAP at 1q42.2–43, CAPB at 1p36, HPC20 on chromosome 20, and HPCX at Xq27–28. Multipoint mode-of-inheritance-free linkage analyses were performed using the GENEHUNTER software. Some evidence of prostate cancer was detected to HPC1 using all families with a maximum NPL Z score of 1.12 near marker D1S413 (P=0.13). Increased evidence of linkage was observed in the 24 families with prostate cancer diagnosis prior to age 65 years and in the 20 families with male-to-male transmission. Some evidence of prostate cancer linkage was also detected at markers mapping to PCAP, HPC20, and HPCX. Continued collection and analysis of African American prostate cancer families will lead to an improved understanding of inherited susceptibility in this high-risk group.

Germline Mutation Analysis of the Androgen Receptor Gene in Finnish Patients With Prostate Cancer

Steroid hormones, particularly androgens, are suspected to have a major role in prostate carcinogenesis. Since androgen receptor mediates androgenic effects on cells and recent studies suggest that the androgen receptor gene is a putative prostate cancer susceptibility locus, we screened the coding region of the androgen receptor gene for germline mutations using the genomic DNA of patients with prostate cancer. DNA samples from 38 patients with early onset prostate cancer and 36 from Finnish prostate cancer families showing no male-to-male transmission of prostate cancer were analyzed for mutations in the androgen receptor gene using single strand conformation polymorphism analysis and subsequent sequencing. R726L substitution in the hormone binding region of androgen receptor was found in 1 prostate cancer family but no previously uncharacterized germline mutations were detected. Our results indicate that constitutional androgen receptor mutations explain only a small fraction of familial and early onset prostate cancer cases in Finland.

Genomewide linkage analysis of familial prostate cancer in the Japanese population.

Prostate cancer (PC) is one of the most common causes of cancer mortality in Western countries, and familial aggregation of PC is well known. Multiple PC susceptibility loci have been reported in Western countries, but attempts to confirm the loci in independent data sets have proven to be inconsistent. We performed a genomewide linkage analysis with 53 affected sib pairs to identify genetic loci related to PC in a Japanese population. Two linkage analyses, GENEHUNTER-PLUS and SIBPAL, were applied and detected nominal statistical significance of linkage to PC at chromosome 1p and 8p, which were reported as being loci for PC in Caucasians. The best evidence of linkage was detected near D8S550 on 8p23 (maximum Zlr=2.25, P=0.037), and the second-best evidence of linkage was observed near D1S2667 on 1p36 (maximum Zlr=2.24, P=0.034). This is the first genetic mapping of PC in Japanese, and the results suggest that susceptibilities to PC lie close to D8S550 on 8p23 and D1S2667 on 1p36.

Genome linkage screen for prostate cancer susceptibility loci: results from the Mayo Clinic Familial Prostate Cancer Study.

Prostate cancer is one of the most common cancers among men and has long been recognized to occur in familial clusters. Brothers and sons of affected men have a twofold to threefold increased risk of developing prostate cancer. However, identification of genetic susceptibility loci for prostate cancer has been extremely difficult. Several putative loci identified by genetic linkage have been reported to exist on chromosomes 1 (HPC1, PCAP, and CAPB), X (HPCX), 17 (HPC2), and 20 (HPC20), with genes RNASEL (HPC1) and ELAC2 (HPC2) tentatively defined. In this study, we report our genome linkage scan in 160 prostate cancer families, using the ABI Prism Linkage Mapping Set Version 2 with 402 microsatellite markers. The most significant linkage was found for chromosome 20, with a recessive model heterogeneity LOD score (HLOD) of 4.77, and a model-free LOD score (LOD - ZLR) of 3.46 for the entire group of pedigrees. Linkage for chromosome 20 was most prominent among families with a late age of diagnosis (average age at diagnosis >/= 66 years; maximum LOD - ZLR = 2.82), with <5 affected family members (LOD - ZLR = 3.02), with presence of hereditary prostate cancer (LOD - ZLR = 2.81), or with no male-to-male transmission of disease (LOD - ZLR = 3.84). No other chromosome showed significant evidence for linkage. However, chromosomes 6 and X showed suggestive results, with maximum LOD - ZLR values of 1.38 and 1.36, respectively. Subset analyses suggest additional chromosomal regions worth further follow-up.