The Newfoundland population: a unique resource for genetic investigation of complex diseases

Rahman, Proton; Jones, Albert L.; Curtis, Joseph; Bartlett, Sylvia E.; Peddle, Lynette; Fernandez, Bridget A.; Freimer, Nelson B.

doi:10.1093/hmg/ddg257

Cited by 92 publications

(77 citation statements)

References 33 publications

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“…Newfoundland has a wellrecognized young founder population of southwest English and Irish descent, with an overall extended linkage disequilibrium and genetic homogeneity similar in magnitude to that of the Old Order Amish (23). Alberta has a more heterogeneous Caucasian population that arose through migration of ancestors from multiple parts of northern Europe.…”

Section: Discussionmentioning

confidence: 99%

Association of interleukin‐23 receptor variants with ankylosing spondylitis

Rahman¹,

Inman²,

Gladman³

et al. 2008

Arthritis & Rheumatism

161

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Objective. Recent studies have shown that a nonsynonymous single-nucleotide polymorphism (SNP) (Arg381Gln; rs11209026) in the interleukin-23 receptor (IL-23R) gene on chromosome 1p31 is associated with Crohn's disease and psoriasis. Given the clinical and immunologic overlap between ankylosing spondylitis (AS) and these diseases, and the potential function of this candidate SNP, this study was undertaken to examine the association of IL-23R variants with AS in multiple Canadian populations.Methods. We examined 3 cohorts of AS patients from established rheumatic disease centers in Canada. The majority of AS patients were Caucasians of northern European descent, and all patients satisfied the modified New York classification criteria for AS or for juvenile spondylarthritis. We examined 424 AS probands and 401 controls from Alberta, 251 AS probands and 122 controls from Toronto, and 121 AS probands and 219 controls from Newfoundland. Ten IL-23R SNPs were genotyped, 9 of which were incorporated in the haplotype analysis. Allele and haplotype associations were calculated using the WHAP software package. P values for haplotype associations were calculated using a permutation test.Results. The primary SNP of interest in a previous study of inflammatory bowel disease (IBD) (Arg381Gln; rs11209026) was found to be protective against AS in the Newfoundland population (P ‫؍‬ 0.04) and in the Toronto population (P ‫؍‬ 0.04) in singlemarker univariate analysis. The strongest association, however, was with SNP rs11465804 (P ‫؍‬ 0.007 for the Newfoundland population and P ‫؍‬ 0.0007 for the Toronto population). A 3-marker sliding window omnibus test revealed a significant association with markers rs10489629, rs2201841, and rs11465804 in both the Newfoundland population (P ‫؍‬ 0.04) and the Alberta population (P ‫؍‬ 0.034). Our results were independent of the IBD and psoriasis status of the AS patients.Conclusion. This concurrent analysis of 3 distinct AS populations and their regional controls demonstrates a disease association with the IL-23R locus and implicates the same polymorphisms associated with IBD and psoriasis.Spondylarthritis (SpA) is a group of inflammatory conditions of which the main clinical feature is inflammation of the spine. Ankylosing spondylitis (AS) is regarded as the prototypic SpA and is a complex multifactorial disease resulting from gene-environment interaction. Genetic factors have a substantive role in AS susceptibility and expression (1). AS is highly heritable, as evidenced by the results of population-based epidemiologic studies. The sibling recurrence risk ( s ) in AS is Ͼ80, and heritability of Ն90% for AS has been estimated from twin studies (for review, see ref. 1). HLA-B27 is the major gene associated with AS and is present in Ͼ95% of Caucasians of northern European ancestry. Despite the prominence of HLA-B27 in genetic susceptibility to AS, its contribution to overall genetic predisposition is only ϳ16-40% (1). Furthermore, since the genetic contribution of the entire major histocompatibilit...

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Section: Discussionmentioning

confidence: 99%

Association of interleukin‐23 receptor variants with ankylosing spondylitis

Rahman¹,

Inman²,

Gladman³

et al. 2008

Arthritis & Rheumatism

161

View full text Add to dashboard Cite

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“…The Newfoundland population, with relative genetic and environmental homogeneity, may offer opportunities for finding such modest signals. 34 Estimates for the power of this study were obtained using Epi6 statistical software (v. 6.04b, 1997). Assuming equal numbers (200) in each group of unrelated individuals defined as either obese or nonobese across all baseline frequencies in one group we estimate 80% power of detecting associations for allele frequency differences of at least 10% in the other group, with statistical significance P ¼ 0.05.…”

Section: Discussionmentioning

confidence: 99%

Bardet–Biedl syndrome 1 genotype and obesity in the Newfoundland population

Fan

Rahman

Peddle³

et al. 2004

Int J Obes

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BACKGROUND AND OBJECTIVES:Obesity is one of the primary clinical features of Bardet-Biedl Syndrome (BBS), a genetically heterogeneous disorder that is usually inherited as an autosomal recessive trait. It has been suggested that heterozygous carriers of BBS are predisposed to obesity. We set out to identify the common mutation in BBS1 families from southwest Newfoundland and to examine the relationship between this mutation and obesity in the general population. METHODS AND SUBJECTS:We genotyped BBS1 families from Newfoundland to determine the nature of the mutation causing BBS in this population. We then screened 200 obese individuals (average body mass index (BMI) ¼ 37.9 kg/m 2 ; average waist to hip ratio ¼ 0.935; average waist ¼ 113.8 cm) and 200 ethnically matched, unrelated, controls (average BMI ¼ 25.0 kg/m 2 ; average waist to hip ratio ¼ 0.896; average waist ¼ 86.9 cm) from the same geographic region for the presence of this mutation. RESULTS: All affected members of the six Newfoundland BBS1 families were homozygous for the most common BBS1 mutation (M390R). This mutation was found in the heterozygous state in three of the 200 obese individuals and also in three of the 200 matched controls. CONCLUSIONS: The high frequency of BBS1 in Newfoundland appears to be the result of a founder event. Our data do not support the hypothesis that the M390R BBS1 mutation plays a significant role in the frequency of obesity in the general public in Newfoundland.

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“…This was likely because probands from Newfoundland stem from a more genetically homogeneous founder population than the admixed Toronto probands (17). In Newfoundland PsA probands, paternally transmitted disease was associated with a higher carriage of PsA risk allele HLA-B*08, and lower carriage of psoriasis risk allele MICA-129Met.…”

Section: Discussionmentioning

confidence: 99%

Further Evidence Supporting a Parent‐of‐Origin Effect in Psoriatic Disease

Pollock

Thavaneswaran

Pellett

et al. 2015

Arthritis Care & Research

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ObjectiveTo further explore the “parent‐of‐origin” effect in a large cohort of well‐phenotyped patients with cutaneous psoriasis without arthritis (PsC) and psoriatic arthritis (PsA).MethodsSelf‐reported family history was obtained from PsA patients from Toronto and Newfoundland satisfying the Classification of Psoriatic Arthritis criteria, and PsC patients from Toronto, who were examined by a rheumatologist to exclude PsA. Proportions of probands with paternally and maternally transmitted psoriatic disease were compared by McNemar's and chi‐square tests. Baseline clinical and genetic characteristics of probands with paternally and maternally transmitted disease were compared using logistic regression.ResultsA total of 849 probands reported a first‐degree relative affected with psoriatic disease (PsC or PsA), of which 532 (63%) reported an affected parent. A significantly larger proportion of probands reported an affected father compared to an affected mother with psoriatic disease (289 [57%] versus 220 [43%], respectively; P = 0.003). This paternal transmission bias was evident in PsA (P = 0.006) and PsC probands, although it did not reach statistical significance in PsC probands (P = 0.20). Furthermore, the proportion of paternal PsC–proband PsA pairs (161 of 214 paternal transmissions [75%]) was significantly larger than maternal PsC–proband PsA pairs (103 of 161 maternal transmissions [64%]) (P = 0.02). Newfoundland probands with paternally transmitted disease had higher HLA–B*08 carriage (P = 0.04) and lower MICA–129Met carriage (P = 0.03). Males had higher HLA–B*38 carriage (P = 0.05) and a higher prevalence of nail lesions (P = 0.01).ConclusionWe have provided further epidemiologic evidence of a paternal transmission bias in psoriatic disease.

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The Newfoundland population: a unique resource for genetic investigation of complex diseases

Cited by 92 publications

References 33 publications

Association of interleukin‐23 receptor variants with ankylosing spondylitis

Association of interleukin‐23 receptor variants with ankylosing spondylitis

Bardet–Biedl syndrome 1 genotype and obesity in the Newfoundland population

Further Evidence Supporting a Parent‐of‐Origin Effect in Psoriatic Disease

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