Rates of adenocarcinoma of the esophagus (EAC) and esophagogastric junction (EGJAC) have been rising rapidly in recent decades, in contrast to the declining rates of esophageal squamous cell carcinomas (ESCC). Obesity is a major risk factor for both EAC and EGJAC, but not ESCC, and there is speculation that obesity promotes adenocarcinoma development through endocrine and related pathways. We therefore compared the prevalence of 12 single nucleotide polymorphisms (SNPs) in nine candidate genes previously implicated in obesity pathways (LEP, LEPR, ADIPOQ, POMC, PPARα, PPARγ, RXRγ, GHRL, and INSIG2) in a large Australian case-control study comprising DNA samples from 260 EAC cases, 301 EGJAC cases, 213 ESCC cases, and 1,352 population controls. No SNPs were associated with EGJAC or ESCC. Although several SNPs seemed to be associated with EAC on crude analysis [ADIPOQ (rs1501299), LEP (5′-untranslated region), PPARγ (H447H), and GHRL (M72L)], effect sizes were modest and none of the associations was significant after correcting for multiple comparisons. Further, we found no consistent evidence that any of the genotypes were associated with risk of EAC or EGJAC within strata of body mass index (<25.0 kg/m2, 25.0-29.9 kg/m2, >30 kg/m2). In conclusion, our data suggest that these SNPs do not play a major role in esophageal carcinogenesis. (Cancer Epidemiol Biomarkers Prev 2008;17(4):1007–12)

The incidence of adenocarcinomas of the esophagus (EAC) and esophagogastric junction (EGJAC) has been rising in many Western populations, whereas the incidence of esophageal squamous cell carcinomas (ESCC) has been declining (1-3). Obesity has been identified as a major risk factor for EAC and EGJAC (4-8), and it is likely that the increasing prevalence of obesity (9) underlies the rising incidence of these cancers. Because obesity has been associated with increased risks of several cancers (10), there is speculation that obesity may promote tumor development through endocrine and related pathways. Leading candidate genes include leptin (LEP; ref. 11), leptin receptor (LEPR; ref. 12), adiponectin (ADIPOQ; ref. 13), proopiomelanocortin (POMC; ref. 14), peroxisome proliferative-activated receptor α (PPARα; ref. 15), peroxisome proliferative-activated receptor γ (PPARγ; ref. 16), retinoid X receptor γ (RXRγ; ref. 17), ghrelin (GHRL; ref. 18), and insulin-induced gene 2 (INSIG2; ref. 19). To address the hypothesis that single nucleotide polymorphisms (SNPs) in these genes are specifically associated with EAC, we investigated possible associations between SNPs in these genes and risk of developing EAC, EGJAC, and ESCC in a population-based case-control study conducted in Australia.

Study Population

Full details of the study have been published previously (8). Briefly, we recruited patients diagnosed between July 1, 2002 (July 1, 2001 in the state of Queensland) and June 30, 2005 with histologically confirmed EAC, EGJAC, or ESCC. Simultaneously, we recruited 1,580 matched controls selected at random from a population register. Detailed information was collected about height, weight 1 y before diagnosis (before recruitment for controls), cigarette smoking, alcohol consumption, and frequency of symptoms of gastroesophageal acid reflux, as reported previously (8, 20). Complete epidemiologic data and DNA were available for 260 EAC cases, 301 EGJAC cases, 213 SCC cases, and 1,352 controls. Approval was obtained from the human research ethics committees of the Queensland Institute of Medical Research and participating hospitals throughout mainland Australia and written informed consent was obtained from all participants.

SNP Selection and Genotyping

Twelve SNPs were selected from nine obesity-related genes: LEP, LEPR, ADIPOQ, POMC, PPARα, PPARγ, RXRγ, GHRL, and INSIG2. SNP selection was based on previously published results showing allelic associations between these polymorphisms and obesity (11-22). Polymorphisms included six coding region nonsynonymous mutations, two synonymous mutations, three 5′ and 3′ SNPs, and one intronic SNP (Table 1). Genotyping was conducted using the Sequenom iPLEX protocol (Sequenom) as previously published (20).

Table 1.

Associations between polymorphisms in multiple obesity-related genes and risk of EAC, EGJAC, and ESCC

Locus descriptionGenotypeControl proportion (n = 1,352)EAC
EGJAC
ESCC
Proportion (n = 260)P*OR† (95% CI)Proportion (n = 301)P*OR† (95% CI)Proportion (n = 213)P*OR† (95% CI)
rs1501299 GG 0.56 0.63  1.0 (reference) 0.53  1.0 (reference) 0.60  1.0 (reference) 
ADIPOQ GT 0.37 0.34  0.75 (0.54-1.03) 0.36  0.96 (0.72-1.29) 0.34  0.89 (0.64-1.25) 
Intron TT 0.07 0.03  0.38 (0.17-0.83) 0.10  1.50 (0.94-2.39) 0.05  0.72 (0.36-1.43) 
 Minor allele 0.26 0.20 0.008  0.29 0.2  0.22 0.2  
rs2167270 GG 0.40 0.36  1.0 (reference) 0.38  1.0 (reference) 0.40  1.0 (reference) 
LEP GA 0.46 0.50  1.41 (1.02-1.95) 0.44  1.04 (0.77-1.39) 0.49  1.09 (0.77-1.53) 
5′-UTR AA 0.13 0.13  1.21 (0.75-1.95) 0.18  1.40 (0.94-2.08) 0.12  0.87 (0.52-1.45) 
 Minor allele 0.36 0.39 0.4  0.40 0.2  0.36 0.9  
rs1137100 (K109R) AA 0.53 0.52  1.0 (reference) 0.53  1.0 (reference) 0.54  1.0 (reference) 
LEPR AG 0.39 0.38  0.93 (0.67-1.27) 0.42  1.0 (0.76-1.33) 0.38  0.89 (0.64-1.25) 
Nonsynonymous coding GG 0.09 0.09  1.20 (0.70-2.05) 0.05  0.72 (0.40-1.31) 0.08  1.0 (0.55-1.80) 
 Minor allele 0.28 0.29 0.8  0.26 0.3  0.27 0.5  
rs1137101 (Q223R) AA 0.31 0.28  1.0 (reference) 0.27  1.0 (reference) 0.30  1.0 (reference) 
LEPR AG 0.49 0.54  1.25 (0.88-1.76) 0.53  1.28 (0.93-1.75) 0.50  1.01 (0.70-1.45) 
Nonsynonymous coding GG 0.20 0.18  1.08 (0.69-1.68) 0.20  1.30 (0.87-1.93) 0.20  1.08 (0.68-1.70) 
 Minor allele 0.44 0.45 0.9  0.46 0.3  0.45 1.0  
rs8179183 (K656N) GG 0.69 0.69  1.0 (reference) 0.68  1.0 (reference) 0.66  1.0 (reference) 
LEPR GC 0.28 0.28  1.12 (0.80-1.57) 0.27  0.98 (0.72-1.33) 0.32  1.16 (0.82-1.64) 
Nonsynonymous coding CC 0.03 0.03  1.09 (0.48-2.52) 0.04  1.51 (0.77-2.96) 0.02  0.91 (0.34-2.44) 
 Minor allele 0.17 0.17 1.0  0.18 0.6  0.18 0.5  
rs1042571 GG 0.66 0.65  1.0 (reference) 0.67  1.0 (reference) 0.64  1.0 (reference) 
POMC GA 0.31 0.31  1.05 (0.76-1.44) 0.28  0.93 (0.69-1.25) 0.31  1.09 (0.77-1.54) 
3′-UTR AA 0.03 0.04  2.08 (0.95-4.58) 0.04  1.56 (0.76-3.22) 0.04  1.85 (0.84-4.10) 
 Minor allele 0.18 0.20 0.5  0.19 0.9  0.20 0.4  
rs1800206 (L162V) CC 0.88 0.87  1.0 (reference) 0.88  1.0 (reference) 0.85  1.0 (reference) 
PPARα CG 0.12 0.13  1.26 (0.81-1.98) 0.11  0.96 (0.63-1.48) 0.15  1.21 (0.77-1.92) 
Nonsynonymous coding GG 0.00 0.01  2.59 (0.34-19.7) 0.01  3.42 (0.65-18.0) 0.00  1.23 (0.12-12.8) 
 Minor allele 0.06 0.07 0.6  0.06 1.0  0.08 0.4  
rs3856806 (H447H) CC 0.79 0.73  1.0 (reference) 0.74  1.0 (reference) 0.80  1.0 (reference) 
PPARγ CT 0.20 0.25  1.36 (0.95-1.93) 0.24  1.24 (0.90-1.71) 0.19  1.03 (0.69-1.53) 
Synonymous coding TT 0.01 0.02  2.09 (0.74-5.94) 0.02  1.58 (0.54-4.61) 0.01  1.14 (0.24-5.28) 
 Minor allele 0.11 0.15 0.04  0.14 0.1  0.11 0.8  
rs1128977 (A140A) GG 0.38 0.41  1.0 (reference) 0.33  1.0 (reference) 0.39  1.0 (reference) 
RXRγ GA 0.46 0.42  0.81 (0.59-1.13) 0.52  1.28 (0.95-1.72) 0.46  0.98 (0.69-1.38) 
Synonymous coding AA 0.15 0.18  1.07 (0.70-1.64) 0.14  1.06 (0.70-1.61) 0.15  0.95 (0.59-1.53) 
 Minor allele 0.39 0.39 1.0  0.41 0.3  0.38 1.0  
rs4684677 (L90Q) AA 0.88 0.91  1.0 (reference) 0.90  1.0 (reference) 0.90  1.0 (reference) 
GHRL AT 0.11 0.09  0.77 (0.46-1.29) 0.09  0.70 (0.44-1.13) 0.10  0.81 (0.48-1.37) 
Nonsynonymous coding TT 0.00 0.00   0.01  1.28 (0.23-7.03) 0.00   
 Minor allele 0.06 0.05 0.2  0.05 0.4  0.05 0.4  
rs696217 (M72L) CC 0.85 0.79  1.0 (reference) 0.84  1.0 (reference) 0.88  1.0 (reference) 
GHRL CA 0.14 0.21  1.69 (1.14-2.50) 0.16  1.13 (0.77-1.66) 0.11  0.81 (0.49-1.33) 
Nonsynonymous coding AA 0.01 0.00   0.00  0.43 (0.05-3.39) 0.01  1.20 (0.26-5.62) 
 Minor allele 0.08 0.10 0.05  0.08 0.6  0.06 0.5  
rs7566605 GG 0.46 0.48  1.0 (reference) 0.46  1.0 (reference) 0.42  1.0 (reference) 
INSIG2 GC 0.44 0.40  0.82 (0.59-1.13) 0.45  0.98 (0.74-1.32) 0.48  1.13 (0.81-1.58) 
10 kb upstream CC 0.11 0.12  1.0 (0.61-1.65) 0.09  0.81 (0.49-1.32) 0.11  1.13 (0.66-1.94) 
 Minor allele 0.32 0.32 0.9  0.32 0.7  0.34 0.5  
Locus descriptionGenotypeControl proportion (n = 1,352)EAC
EGJAC
ESCC
Proportion (n = 260)P*OR† (95% CI)Proportion (n = 301)P*OR† (95% CI)Proportion (n = 213)P*OR† (95% CI)
rs1501299 GG 0.56 0.63  1.0 (reference) 0.53  1.0 (reference) 0.60  1.0 (reference) 
ADIPOQ GT 0.37 0.34  0.75 (0.54-1.03) 0.36  0.96 (0.72-1.29) 0.34  0.89 (0.64-1.25) 
Intron TT 0.07 0.03  0.38 (0.17-0.83) 0.10  1.50 (0.94-2.39) 0.05  0.72 (0.36-1.43) 
 Minor allele 0.26 0.20 0.008  0.29 0.2  0.22 0.2  
rs2167270 GG 0.40 0.36  1.0 (reference) 0.38  1.0 (reference) 0.40  1.0 (reference) 
LEP GA 0.46 0.50  1.41 (1.02-1.95) 0.44  1.04 (0.77-1.39) 0.49  1.09 (0.77-1.53) 
5′-UTR AA 0.13 0.13  1.21 (0.75-1.95) 0.18  1.40 (0.94-2.08) 0.12  0.87 (0.52-1.45) 
 Minor allele 0.36 0.39 0.4  0.40 0.2  0.36 0.9  
rs1137100 (K109R) AA 0.53 0.52  1.0 (reference) 0.53  1.0 (reference) 0.54  1.0 (reference) 
LEPR AG 0.39 0.38  0.93 (0.67-1.27) 0.42  1.0 (0.76-1.33) 0.38  0.89 (0.64-1.25) 
Nonsynonymous coding GG 0.09 0.09  1.20 (0.70-2.05) 0.05  0.72 (0.40-1.31) 0.08  1.0 (0.55-1.80) 
 Minor allele 0.28 0.29 0.8  0.26 0.3  0.27 0.5  
rs1137101 (Q223R) AA 0.31 0.28  1.0 (reference) 0.27  1.0 (reference) 0.30  1.0 (reference) 
LEPR AG 0.49 0.54  1.25 (0.88-1.76) 0.53  1.28 (0.93-1.75) 0.50  1.01 (0.70-1.45) 
Nonsynonymous coding GG 0.20 0.18  1.08 (0.69-1.68) 0.20  1.30 (0.87-1.93) 0.20  1.08 (0.68-1.70) 
 Minor allele 0.44 0.45 0.9  0.46 0.3  0.45 1.0  
rs8179183 (K656N) GG 0.69 0.69  1.0 (reference) 0.68  1.0 (reference) 0.66  1.0 (reference) 
LEPR GC 0.28 0.28  1.12 (0.80-1.57) 0.27  0.98 (0.72-1.33) 0.32  1.16 (0.82-1.64) 
Nonsynonymous coding CC 0.03 0.03  1.09 (0.48-2.52) 0.04  1.51 (0.77-2.96) 0.02  0.91 (0.34-2.44) 
 Minor allele 0.17 0.17 1.0  0.18 0.6  0.18 0.5  
rs1042571 GG 0.66 0.65  1.0 (reference) 0.67  1.0 (reference) 0.64  1.0 (reference) 
POMC GA 0.31 0.31  1.05 (0.76-1.44) 0.28  0.93 (0.69-1.25) 0.31  1.09 (0.77-1.54) 
3′-UTR AA 0.03 0.04  2.08 (0.95-4.58) 0.04  1.56 (0.76-3.22) 0.04  1.85 (0.84-4.10) 
 Minor allele 0.18 0.20 0.5  0.19 0.9  0.20 0.4  
rs1800206 (L162V) CC 0.88 0.87  1.0 (reference) 0.88  1.0 (reference) 0.85  1.0 (reference) 
PPARα CG 0.12 0.13  1.26 (0.81-1.98) 0.11  0.96 (0.63-1.48) 0.15  1.21 (0.77-1.92) 
Nonsynonymous coding GG 0.00 0.01  2.59 (0.34-19.7) 0.01  3.42 (0.65-18.0) 0.00  1.23 (0.12-12.8) 
 Minor allele 0.06 0.07 0.6  0.06 1.0  0.08 0.4  
rs3856806 (H447H) CC 0.79 0.73  1.0 (reference) 0.74  1.0 (reference) 0.80  1.0 (reference) 
PPARγ CT 0.20 0.25  1.36 (0.95-1.93) 0.24  1.24 (0.90-1.71) 0.19  1.03 (0.69-1.53) 
Synonymous coding TT 0.01 0.02  2.09 (0.74-5.94) 0.02  1.58 (0.54-4.61) 0.01  1.14 (0.24-5.28) 
 Minor allele 0.11 0.15 0.04  0.14 0.1  0.11 0.8  
rs1128977 (A140A) GG 0.38 0.41  1.0 (reference) 0.33  1.0 (reference) 0.39  1.0 (reference) 
RXRγ GA 0.46 0.42  0.81 (0.59-1.13) 0.52  1.28 (0.95-1.72) 0.46  0.98 (0.69-1.38) 
Synonymous coding AA 0.15 0.18  1.07 (0.70-1.64) 0.14  1.06 (0.70-1.61) 0.15  0.95 (0.59-1.53) 
 Minor allele 0.39 0.39 1.0  0.41 0.3  0.38 1.0  
rs4684677 (L90Q) AA 0.88 0.91  1.0 (reference) 0.90  1.0 (reference) 0.90  1.0 (reference) 
GHRL AT 0.11 0.09  0.77 (0.46-1.29) 0.09  0.70 (0.44-1.13) 0.10  0.81 (0.48-1.37) 
Nonsynonymous coding TT 0.00 0.00   0.01  1.28 (0.23-7.03) 0.00   
 Minor allele 0.06 0.05 0.2  0.05 0.4  0.05 0.4  
rs696217 (M72L) CC 0.85 0.79  1.0 (reference) 0.84  1.0 (reference) 0.88  1.0 (reference) 
GHRL CA 0.14 0.21  1.69 (1.14-2.50) 0.16  1.13 (0.77-1.66) 0.11  0.81 (0.49-1.33) 
Nonsynonymous coding AA 0.01 0.00   0.00  0.43 (0.05-3.39) 0.01  1.20 (0.26-5.62) 
 Minor allele 0.08 0.10 0.05  0.08 0.6  0.06 0.5  
rs7566605 GG 0.46 0.48  1.0 (reference) 0.46  1.0 (reference) 0.42  1.0 (reference) 
INSIG2 GC 0.44 0.40  0.82 (0.59-1.13) 0.45  0.98 (0.74-1.32) 0.48  1.13 (0.81-1.58) 
10 kb upstream CC 0.11 0.12  1.0 (0.61-1.65) 0.09  0.81 (0.49-1.32) 0.11  1.13 (0.66-1.94) 
 Minor allele 0.32 0.32 0.9  0.32 0.7  0.34 0.5  
*

P control versus case comparison.

†

ORs and 95% CIs adjusted for age (in years), sex, smoking, BMI, and frequency of gastroesophageal reflux symptoms.

View Large

Statistical Analyses

We calculated Hardy-Weinberg equilibrium and allele frequencies and assessed linkage disequilibrium using Haploview (21). Minor allele frequencies between case and control groups were tested using χ2 analyses, with P values presented in Table 1. To estimate the relative risk of cancer associated with each SNP, we calculated the odds ratio (OR) and 95% confidence interval (95% CI) using multivariable logistic regression in Statistical Analysis System version 9.1 (SAS Institute, Inc.). Initial models were adjusted only for age and sex; final models included terms for age, sex, body mass index (BMI), smoking history, and frequency of gastroesophageal reflux symptoms 10 y before diagnosis. Additional adjustment for alcohol consumption, frequency of nonsteroidal anti-inflammatory drug use, and education made essentially no difference to the risk estimates. In further analyses, we assessed genotypic associations within strata of BMI using standard WHO cut points (22). We assessed statistical significance at α = 0.05, which became 0.004 after Bonferroni correction (0.05/12).

All SNPs were in Hardy-Weinberg equilibrium. Table 1 shows genotype and allele frequencies for each SNP in controls compared with the three case groups. P values are presented for the minor allele comparisons. Although several SNPs seemed to be associated with EAC {ADIPOQ (rs1501299), LEP [5′-untranslated region (UTR)], PPARγ (H447H), and GHRL (M72L)}, these were not statistically significant following Bonferroni correction.

After stratification for BMI, the effect sizes for PPARα, PPARγ, and GHRL markedly increased for persons with BMI <25 kg/m2 (Table 2, EAC only), whereas the OR for POMC was significantly increased in the BMI ≥30 kg/m2 group. There were no other consistent patterns across BMI strata for EAC, and none for EGJAC or ESCC.

Table 2.

Associations between polymorphisms in multiple obesity-related genes and the risk of EAC, EGJAC, and ESCC and BMI

Locus descriptionGenotypeEAC
EGJAC
ESCC
BMI ≤25 kg/m2
BMI 25-29.9 kg/m2
BMI ≥30 kg/m2
BMI ≤25
BMI 25-29.9
BMI ≥30
BMI ≤25
BMI 25-29.9
BMI ≥30
OR* (95% CI)OR* (95% CI)OR* (95% CI)OR* (95% CI)OR* (95% CI)OR* (95% CI)OR* (95% CI)OR* (95% CI)OR* (95% CI)
rs1501299 GG 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 
ADIPOQ GT 0.52 (0.25-1.11) 0.89 (0.56-1.43) 0.69 (0.40-1.20) 0.74 (0.42-1.30) 1.25 (0.8-1.96) 0.82 (0.48-1.41) 0.92 (0.57-1.50) 0.98 (0.55-1.74) 1.05 (0.48-2.30) 
Intron TT  0.80 (0.31-2.03) 0.22 (0.05-1.05) 1.29 (0.54-3.12) 1.46 (0.7-3.05) 1.63 (0.67-3.98) 0.52 (0.19-1.49) 0.93 (0.30-2.85) 1.01 (0.20-4.95) 
rs2167270 GG 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 
LEP GA 2.13 (0.98-4.63) 1.92 (1.15-3.20) 0.84 (0.49-1.45) 1.39 (0.79-2.47) 0.97 (0.60-1.54) 0.92 (0.54-1.57) 1.24 (0.76-2.03) 0.85 (0.47-1.54) 1.05 (0.48-2.30) 
5′-UTR AA 1.76 (0.59-5.25) 1.87 (0.94-3.74) 0.54 (0.22-1.33) 1.53 (0.71-3.30) 1.67 (0.92-3.03) 1.03 (0.47-2.27) 0.63 (0.28-1.41) 1.08 (0.49-2.40) 1.12 (0.33-3.84) 
rs1137100 (K109R) AA 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 
LEPR AG 1.65 (0.82-3.34) 1.03 (0.64-1.66) 0.57 (0.33-0.98) 1.22 (0.71-2.08) 0.96 (0.61-1.49) 0.85 (0.50-1.42) 1.18 (0.73-1.89) 0.81 (0.45-1.47) 1.05 (0.48-2.30) 
Nonsynonymous coding GG 0.91 (0.19-4.42) 2.20 (1.08-4.47) 0.53 (0.19-1.50) 0.58 (0.17-2.03) 0.86 (0.34-2.21) 0.75 (0.28-2.02) 0.56 (0.20-1.56) 0.78 (0.26-2.38) 2.60 (0.90-7.50) 
rs1137101 (Q223R) AA 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 
LEPR AG 1.56 (0.71-3.4) 1.78 (1.03-3.05) 0.74 (0.41-1.33) 1.39 (0.77-2.53) 1.25 (0.76-2.04) 1.12 (0.62-2.03) 1.05 (0.62-1.76) 1.41 (0.74-2.68) 1.05 (0.48-2.30) 
Nonsynonymous coding GG 1.10 (0.39-3.08) 2.11 (1.09-4.10) 0.48 (0.22-1.05) 1.28 (0.60-2.74) 1.67 (0.90-3.10) 0.90 (0.43-1.87) 0.89 (0.45-1.75) 1.29 (0.56-2.96) 1.05 (0.39-2.88) 
rs8179183 (K656N) GG 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 
LEPR GC 1.73 (0.85-3.51) 0.66 (0.39-1.12) 1.64 (0.91-2.95) 1.10 (0.62-1.94) 0.86 (0.53-1.41) 0.99 (0.55-1.76) 1.16 (0.71-1.89) 1.22 (0.67-2.22) 1.05 (0.48-2.30) 
Nonsynonymous coding CC 1.95 (0.36-10.7) 0.63 (0.18-2.24) 2.43 (0.48-12.3) 1.75 (0.52-5.88) 1.44 (0.54-3.85) 1.38 (0.29-6.59) 0.99 (0.25-3.90) 0.45 (0.06-3.52) 5.33 (0.52-55.1) 
rs1042571 GG 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 
POMC GA 1.42 (0.70-2.89) 0.76 (0.47-1.25) 1.26 (0.72-2.20) 0.83 (0.46-1.47) 0.83 (0.52-1.33) 1.13 (0.66-1.94) 0.97 (0.59-1.60) 0.94 (0.50-1.76) 1.05 (0.48-2.30) 
3′-UTR AA 1.49 (0.30-7.43) 1.50 (0.44-5.07) 7.48 (1.31-42.6) 0.95 (0.26-3.46) 1.56 (0.54-4.48) 3.50 (0.49-24.9) 1.15 (0.35-3.73) 3.14 (0.93-10.6) 3.72 (0.30-46.8) 
rs1800206 (L162V) CC 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 
PPARα CG 3.98 (1.85-8.57) 0.76 (0.35-1.64) 0.71 (0.30-1.71) 1.12 (0.53-2.39) 1.13 (0.59-2.15) 0.56 (0.22-1.43) 1.12 (0.59-2.15) 1.30 (0.57-2.94) 1.05 (0.48-2.30) 
Nonsynonymous coding GG  3.20 (0.26-39.8) 1.54 (0.09-26.7)  7.63 (1.02-57.3) 1.24 (0.09-17.8)  2.92 (0.22-39.0)  
rs3856806 (H447H) CC 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 
PPARγ CT 0.98 (0.43-2.25) 0.94 (0.54-1.65) 2.58 (1.41-4.72) 0.95 (0.50-1.80) 1.25 (0.76-2.05) 1.65 (0.90-3.0) 0.89 (0.50-1.60) 1.12 (0.59-2.16) 1.05 (0.48-2.30) 
Synonymous coding TT 9.45 (1.35-66.2) 0.40 (0.04-3.63) 4.81 (0.83-27.7) 5.59 (0.90-34.8) 1.22 (0.28-5.30)  3.21 (0.33-31.3) 1.15 (0.13-9.93)  
rs1128977 (A140A) GG 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 
RXRγ GA 1.29 (0.61-2.74) 0.86 (0.53-1.41) 0.59 (0.34-1.04) 1.66 (0.92-2.99) 1.41 (0.89-2.24) 0.90 (0.53-1.54) 1.16 (0.70-1.90) 0.81 (0.44-1.49) 1.05 (0.48-2.30) 
Synonymous coding AA 1.63 (0.62-4.32) 1.11 (0.59-2.09) 0.75 (0.35-1.58) 1.84 (0.85-4.0) 1.01 (0.52-1.96) 0.66 (0.30-1.47) 0.92 (0.46-1.87) 1.18 (0.55-2.53) 0.59 (0.15-2.30) 
rs4684677 (L90Q) AA 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 
GHRL AT 0.70 (0.25-1.99) 0.67 (0.30-1.52) 1.09 (0.43-2.78) 0.46 (0.17-1.25) 0.83 (0.40-1.70) 0.79 (0.33-1.89) 0.65 (0.30-1.42) 0.41 (0.12-1.38) 1.05 (0.48-2.30) 
Nonsynonymous coding TT     12.68 (0.7-229) 0.80 (0.08-8.38)    
rs696217 (M72L) CC 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 
GHRL CA 3.26 (1.50-7.09) 1.74 (0.96-3.14) 1.01 (0.49-2.10) 1.71 (0.83-3.55) 0.86 (0.45-1.63) 1.23 (0.62-2.44) 1.03 (0.52-2.03) 0.49 (0.17-1.42) 1.05 (0.48-2.30) 
Nonsynonymous coding AA    3.82 (0.35-42.2)   3.50 (0.31-39.2) 1.32 (0.15-11.8)  
rs7566605 GG 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 
INSIG2 GC 0.81 (0.39-1.67) 0.73 (0.44-1.19) 1.08 (0.61-1.89) 0.88 (0.50-1.53) 1.10 (0.69-1.73) 1.0 (0.59-1.70) 0.93 (0.58-1.51) 1.58 (0.88-2.86) 1.05 (0.48-2.30) 
10 kb upstream CC 1.28 (0.46-3.60) 0.82 (0.39-1.72) 1.34 (0.53-3.38) 0.57 (0.20-1.61) 1.03 (0.51-2.09) 0.72 (0.27-1.94) 0.86 (0.38-1.94) 0.93 (0.33-2.61) 2.97 (1.0-8.97) 
Locus descriptionGenotypeEAC
EGJAC
ESCC
BMI ≤25 kg/m2
BMI 25-29.9 kg/m2
BMI ≥30 kg/m2
BMI ≤25
BMI 25-29.9
BMI ≥30
BMI ≤25
BMI 25-29.9
BMI ≥30
OR* (95% CI)OR* (95% CI)OR* (95% CI)OR* (95% CI)OR* (95% CI)OR* (95% CI)OR* (95% CI)OR* (95% CI)OR* (95% CI)
rs1501299 GG 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 
ADIPOQ GT 0.52 (0.25-1.11) 0.89 (0.56-1.43) 0.69 (0.40-1.20) 0.74 (0.42-1.30) 1.25 (0.8-1.96) 0.82 (0.48-1.41) 0.92 (0.57-1.50) 0.98 (0.55-1.74) 1.05 (0.48-2.30) 
Intron TT  0.80 (0.31-2.03) 0.22 (0.05-1.05) 1.29 (0.54-3.12) 1.46 (0.7-3.05) 1.63 (0.67-3.98) 0.52 (0.19-1.49) 0.93 (0.30-2.85) 1.01 (0.20-4.95) 
rs2167270 GG 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 
LEP GA 2.13 (0.98-4.63) 1.92 (1.15-3.20) 0.84 (0.49-1.45) 1.39 (0.79-2.47) 0.97 (0.60-1.54) 0.92 (0.54-1.57) 1.24 (0.76-2.03) 0.85 (0.47-1.54) 1.05 (0.48-2.30) 
5′-UTR AA 1.76 (0.59-5.25) 1.87 (0.94-3.74) 0.54 (0.22-1.33) 1.53 (0.71-3.30) 1.67 (0.92-3.03) 1.03 (0.47-2.27) 0.63 (0.28-1.41) 1.08 (0.49-2.40) 1.12 (0.33-3.84) 
rs1137100 (K109R) AA 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 
LEPR AG 1.65 (0.82-3.34) 1.03 (0.64-1.66) 0.57 (0.33-0.98) 1.22 (0.71-2.08) 0.96 (0.61-1.49) 0.85 (0.50-1.42) 1.18 (0.73-1.89) 0.81 (0.45-1.47) 1.05 (0.48-2.30) 
Nonsynonymous coding GG 0.91 (0.19-4.42) 2.20 (1.08-4.47) 0.53 (0.19-1.50) 0.58 (0.17-2.03) 0.86 (0.34-2.21) 0.75 (0.28-2.02) 0.56 (0.20-1.56) 0.78 (0.26-2.38) 2.60 (0.90-7.50) 
rs1137101 (Q223R) AA 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 
LEPR AG 1.56 (0.71-3.4) 1.78 (1.03-3.05) 0.74 (0.41-1.33) 1.39 (0.77-2.53) 1.25 (0.76-2.04) 1.12 (0.62-2.03) 1.05 (0.62-1.76) 1.41 (0.74-2.68) 1.05 (0.48-2.30) 
Nonsynonymous coding GG 1.10 (0.39-3.08) 2.11 (1.09-4.10) 0.48 (0.22-1.05) 1.28 (0.60-2.74) 1.67 (0.90-3.10) 0.90 (0.43-1.87) 0.89 (0.45-1.75) 1.29 (0.56-2.96) 1.05 (0.39-2.88) 
rs8179183 (K656N) GG 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 
LEPR GC 1.73 (0.85-3.51) 0.66 (0.39-1.12) 1.64 (0.91-2.95) 1.10 (0.62-1.94) 0.86 (0.53-1.41) 0.99 (0.55-1.76) 1.16 (0.71-1.89) 1.22 (0.67-2.22) 1.05 (0.48-2.30) 
Nonsynonymous coding CC 1.95 (0.36-10.7) 0.63 (0.18-2.24) 2.43 (0.48-12.3) 1.75 (0.52-5.88) 1.44 (0.54-3.85) 1.38 (0.29-6.59) 0.99 (0.25-3.90) 0.45 (0.06-3.52) 5.33 (0.52-55.1) 
rs1042571 GG 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 
POMC GA 1.42 (0.70-2.89) 0.76 (0.47-1.25) 1.26 (0.72-2.20) 0.83 (0.46-1.47) 0.83 (0.52-1.33) 1.13 (0.66-1.94) 0.97 (0.59-1.60) 0.94 (0.50-1.76) 1.05 (0.48-2.30) 
3′-UTR AA 1.49 (0.30-7.43) 1.50 (0.44-5.07) 7.48 (1.31-42.6) 0.95 (0.26-3.46) 1.56 (0.54-4.48) 3.50 (0.49-24.9) 1.15 (0.35-3.73) 3.14 (0.93-10.6) 3.72 (0.30-46.8) 
rs1800206 (L162V) CC 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 
PPARα CG 3.98 (1.85-8.57) 0.76 (0.35-1.64) 0.71 (0.30-1.71) 1.12 (0.53-2.39) 1.13 (0.59-2.15) 0.56 (0.22-1.43) 1.12 (0.59-2.15) 1.30 (0.57-2.94) 1.05 (0.48-2.30) 
Nonsynonymous coding GG  3.20 (0.26-39.8) 1.54 (0.09-26.7)  7.63 (1.02-57.3) 1.24 (0.09-17.8)  2.92 (0.22-39.0)  
rs3856806 (H447H) CC 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 
PPARγ CT 0.98 (0.43-2.25) 0.94 (0.54-1.65) 2.58 (1.41-4.72) 0.95 (0.50-1.80) 1.25 (0.76-2.05) 1.65 (0.90-3.0) 0.89 (0.50-1.60) 1.12 (0.59-2.16) 1.05 (0.48-2.30) 
Synonymous coding TT 9.45 (1.35-66.2) 0.40 (0.04-3.63) 4.81 (0.83-27.7) 5.59 (0.90-34.8) 1.22 (0.28-5.30)  3.21 (0.33-31.3) 1.15 (0.13-9.93)  
rs1128977 (A140A) GG 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 
RXRγ GA 1.29 (0.61-2.74) 0.86 (0.53-1.41) 0.59 (0.34-1.04) 1.66 (0.92-2.99) 1.41 (0.89-2.24) 0.90 (0.53-1.54) 1.16 (0.70-1.90) 0.81 (0.44-1.49) 1.05 (0.48-2.30) 
Synonymous coding AA 1.63 (0.62-4.32) 1.11 (0.59-2.09) 0.75 (0.35-1.58) 1.84 (0.85-4.0) 1.01 (0.52-1.96) 0.66 (0.30-1.47) 0.92 (0.46-1.87) 1.18 (0.55-2.53) 0.59 (0.15-2.30) 
rs4684677 (L90Q) AA 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 
GHRL AT 0.70 (0.25-1.99) 0.67 (0.30-1.52) 1.09 (0.43-2.78) 0.46 (0.17-1.25) 0.83 (0.40-1.70) 0.79 (0.33-1.89) 0.65 (0.30-1.42) 0.41 (0.12-1.38) 1.05 (0.48-2.30) 
Nonsynonymous coding TT     12.68 (0.7-229) 0.80 (0.08-8.38)    
rs696217 (M72L) CC 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 
GHRL CA 3.26 (1.50-7.09) 1.74 (0.96-3.14) 1.01 (0.49-2.10) 1.71 (0.83-3.55) 0.86 (0.45-1.63) 1.23 (0.62-2.44) 1.03 (0.52-2.03) 0.49 (0.17-1.42) 1.05 (0.48-2.30) 
Nonsynonymous coding AA    3.82 (0.35-42.2)   3.50 (0.31-39.2) 1.32 (0.15-11.8)  
rs7566605 GG 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 
INSIG2 GC 0.81 (0.39-1.67) 0.73 (0.44-1.19) 1.08 (0.61-1.89) 0.88 (0.50-1.53) 1.10 (0.69-1.73) 1.0 (0.59-1.70) 0.93 (0.58-1.51) 1.58 (0.88-2.86) 1.05 (0.48-2.30) 
10 kb upstream CC 1.28 (0.46-3.60) 0.82 (0.39-1.72) 1.34 (0.53-3.38) 0.57 (0.20-1.61) 1.03 (0.51-2.09) 0.72 (0.27-1.94) 0.86 (0.38-1.94) 0.93 (0.33-2.61) 2.97 (1.0-8.97) 
*

ORs and 95% CIs adjusted for age (in years), sex, smoking, and frequency of gastroesophageal reflux symptoms.

View Large

The Australian Cancer Study constitutes one of the largest available collections of tissue and risk factor data from esophageal cancer patients and has an estimated 80% power to detect ORs between 1.4 and 2.0 for allele frequencies between 0.05 and 0.45. Thus, our case-control sample had adequate power to find moderate risk alleles in the selected genes if they existed. Of the 12 SNPs tested, we identified modest positive associations for two mutations [PPARγ (H447H) and GHRL (M72L)] and a sizable inverse association for one SNP [ADIPOQ (rs1501299)]; however, none of the associations was statistically significant at the Bonferroni corrected threshold. To the best of our knowledge, this is the first study to comprehensively evaluate obesity-related SNPs in relation to risk of esophageal cancer. A recent review (23) examined all studies before February 2007 regarding polymorphisms and risk of EAC and ESCC. From 100 studies reviewed, no obesity-related genes were examined.

We further investigated the potential role of selected SNPs within strata of BMI. We observed some evidence of decreasing risks of EAC associated with LEP (5′-UTR), RXRγ (A140A), and GHRL (M72L) with increasing adiposity; however, these trends were not statistically significant. The other SNPs tested displayed inconsistent trends across BMI strata, indicating no relationship with esophageal cancer risk regardless of BMI.

In summary, we tested 12 SNPs across three groups of cases compared with controls. We found no convincing associations between any of the SNPs tested and risk of EGJAC or SCC. However, the finding of weak associations between LEP, ADIPOQ, and GHRL and risk of EAC suggests that further investigation of the SNPs tested here, and other SNPs within the same genes, may be warranted.

Investigators: David C. Whiteman, M.B.B.S., Ph.D.; Penelope M. Webb, M.A., D.Phil.; Adele C. Green, M.B.B.S., Ph.D.; Nicholas K. Hayward, Ph.D.; Peter G. Parsons, Ph.D.; and David M. Purdie, Ph.D.

Clinical collaborators: B. Mark Smithers, F.R.A.C.S.; David Gotley, F.R.A.C.S., Ph.D.; and Andrew Clouston, F.R.A.C.P., Ph.D.

Project Manager: Suzanne Moore, R.N., M.P.H.

Research Nurses: Suzanne O'Brien, R.N., M.P.H.; Ellen Minehan, R.N.; Deborah Roffe, R.N.; Sue O'Keefe, R.N.; Suzanne Lipshut, R.N.; Gabby Connor, R.N.; Hayley Berry, R.N.; Frances Walker, R.N.; Teresa Barnes, R.N.; Janine Thomas, R.N.; Linda Terry, R.N., M.P.H.; Michael Connard, B.Sc.; Leanne Bowes, B.Sc.; Mary Rose Malt, R.N.; and Jo White, R.N.

Laboratory staff: Peter Schultz, Lauren Aoude, Loralie Parsonson, and Stephen Walsh.

Grant support: Queensland Cancer Fund project grant and National Health and Medical Research Council of Australia Program grant 199600. N.K. Hayward, P.M. Webb, and D.C. Whiteman are supported by Research Fellowships from the National Health and Medical Research Council of Australia.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

We thank Shahram Sadeghi, M.D., and Harish Babu, M.D., for assisting with pathology abstractions; Nirmala Pandeya, M.Med.Sci., for data cleaning and programming; and all the study participants.

1
Blot WJ, DS, Kneller RW, Fraumeni JF, Jr. Rising incidence of adenocarcinoma of the esophagus and gastric cardia.
JAMA
 
1991
;
13
:
1287
–9.
2
Lord RV, LM, Ward RL, Giles GG, Thomas RJ, Thursfield V. Rising incidence of oesophageal adenocarcinoma in men in Australia.
J Gastroenterol Hepatol
 
1998
;
13
:
356
–62.
3
Wayman J, Forman D, Griffin SM. Monitoring the changing pattern of esophago-gastric cancer: data from a UK regional cancer registry.
Cancer Causes Control
 
2001
;
12
:
943
–9.
4
Lindblad M, Rodriguez LA, Lagergren J. Body mass, tobacco and alcohol and risk of esophageal, gastric cardia, and gastric non-cardia adenocarcinoma among men and women in a nested case-control study.
Cancer Causes Control
 
2005
;
16
:
285
–94.
5
Lagergren J, Bergstrom R, Nyren O. Association between body mass and adenocarcinoma of the esophagus and gastric cardia.
Ann Intern Med
 
1999
;
130
:
883
–90.
6
Vaughan TL, Davis S, Kristal A, Thomas DB. Obesity, alcohol, and tobacco as risk factors for cancers of the esophagus and gastric cardia: adenocarcinoma versus squamous cell carcinoma.
Cancer Epidemiol Biomarkers Prev
 
1995
;
4
:
85
–92.
7
Veugelers PJ, Porter GA, Guernsey DL, Casson AG. Obesity and lifestyle risk factors for gastroesophageal reflux disease, Barrett esophagus and esophageal adenocarcinoma.
Dis Esophagus
 
2006
;
19
:
321
–8.
8
Whiteman DC, Sadeghi S, Pandeya N, et al. Combined effects of obesity, acid reflux and smoking on the risk of adenocarcinomas of the oesophagus.
Gut
 
2008
;
57
:
173
–80.
9
Holmes RS, Vaughan TL. Epidemiology and pathogenesis of esophageal cancer.
Semin Radiat Oncol
 
2007
;
17
:
2
–9.
10
Calle EE, Thun MJ. Obesity and cancer.
Oncogene
 
2004
;
23
:
6365
–78.
11
Hager J, Clement K, Francke S, et al. A polymorphism in the 5′ untranslated region of the human ob gene is associated with low leptin levels.
Int J Obes Relat Metab Disord
 
1998
;
22
:
200
–5.
12
Yiannakouris N, Yannakoulia M, Melistas L, Chan JL, Klimis-Zacas D, Mantzoros CS. The Q223R polymorphism of the leptin receptor gene is significantly associated with obesity and predicts a small percentage of body weight and body composition variability.
J Clin Endocrinol Metab
 
2001
;
86
:
4434
–9.
13
Vasseur F, Helbecque N, Dina C, et al. Single-nucleotide polymorphism haplotypes in the both proximal promoter and exon 3 of the APM1 gene modulate adipocyte-secreted adiponectin hormone levels and contribute to the genetic risk for type 2 diabetes in French Caucasians.
Hum Mol Genet
 
2002
;
11
:
2607
–14.
14
Baker M, Gaukrodger N, Mayosi BM, et al. Association between common polymorphisms of the proopiomelanocortin gene and body fat distribution: a family study.
Diabetes
 
2005
;
54
:
2492
–6.
15
Vohl M-CLP, Gaudet D, Brewer CG, et al. Molecular scanning of the human PPAR-α gene: association of the L162V mutation with hyperapobetalipoproteinemia.
J Lipid Res
 
2000
;
41
:
945
–52.
16
Agostini M, Schoenmakers E, Mitchell C, et al. Non-DNA binding, dominant-negative, human PPARγ mutations cause lipodystrophic insulin resistance.
Cell Metab
 
2006
;
4
:
303
–11.
17
Rankinen T, Zuberi A, Chagnon YC, et al. The human obesity gene map: the 2005 update.
Obesity
 
2006
;
14
:
529
–644.
18
Korbonits M, Gueorguiev M, O'Grady E, et al. A variation in the ghrelin gene increases weight and decreases insulin secretion in tall, obese children.
J Clin Endocrinol Metab
 
2002
;
87
:
4005
–8.
19
Hall DH, Rahman T, Avery PJ, Keavney B. INSIG-2 promoter polymorphism and obesity related phenotypes: association study in 1428 members of 248 families.
BMC Med Genet
 
2006
;
7
:
83
.
20
Doecke JD, Zhao ZZ, Pandeya N, et al. Polymorphisms in MGMT and DNA repair genes and the risk of esophageal adenocarcinoma. Int J Cancer 2008;122.
21
Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps.
Bioinformatics
 
2005
;
21
:
263
–5.
22
WHO. Obesity: preventing and managing the global epidemic. Report of a WHO consultation. Geneva: WHO Technical Report Series; 2000.
23
Hiyama T, Yoshihara M, Tanaka S, Chayama K. Genetic polymorphisms and esophageal cancer risk.
Int J Cancer
 
2007
;
121
:
1643
–58.
American Association for Cancer Research
2008